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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 New York Institute of 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 Ki of 35.9+/-3.3µg/mL and menthol a Ki 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 clove94) have been found to increase glutathione in vitro and in vivo.87,92-94 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.
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