Goldfrank's Toxicologic Emergencies, 10e

43: Essential Oils

Lauren Kornreich Shawn

INTRODUCTION

Essential oils are a class of volatile oils that are extracted through steam distillation or are cold pressed from the leaves, flowers, bark, wood, fruit, or peel of a single parent plant. The term essential refers to the essence of a plant, rather than an indispensable component of the oil or a vital biologic function. These organic compounds are a mixture of complex hydrocarbons that give the oil its aroma, therapeutic properties, and occasionally cause toxicity. More than 500 essential oils exist and can be categorized into five chemical groups: terpenes, quinines, substituted benzenes, aromatic/aliphatic esters, and phenols and aromatic/aliphatic alcohols.

HISTORY AND EPIDEMIOLOGY

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The potential for toxicity arises from several aspects of oil production, use, and regulation. These oils are not under the US Food and Drug Administration (FDA) regulation; therefore, they may not contain the specific ingredient intended for use or may contain excessive amounts of the active ingredient, other chemicals, or various adulterants. Furthermore, there is no standardized nomenclature for many of these herbs or for the exact chemical composition of specific oil. Even with the strictest production guidelines, oils can vary by the environment the plant was grown in and by part of the plant primarily used in production. Sometimes these differences are utilized to confer a particular property to the oil in terms of aroma or believed therapeutic benefit.

Therapeutic use of essential oils can be traced back thousands of years in history to the ancient Greeks and ancient Egyptians, and it is also described in biblical writings. The first documents detailing an actual distillation process date back to the ninth century, when such oils were imported into Europe from the Middle East.¹⁵⁸ By the 16th century, concepts of separating fatty oils and essential oils from aromatic water became more defined, and oils were used frequently for fragrance, flavoring, and medicinal purposes. By the 19th century, these processes became industrialized, and specific chemicals could be identified and mass produced. Essential oils fell out of favor in the early 20th century, as new medications and a desire for modernization developed. However, in the past 30 years, resurgence in interest and use of essential oils developed as many people deemed natural products to be safer and more environmentally friendly. This chapter highlights some of the most commonly used oils for medicinal purposes that also have the greatest potential for toxicity.

Absinthe

History.

Artemisia absinthium is more commonly known as wormwood because of its use as an anthelmintic in ancient times. It is a member of the Compositae family, which also includes ragweed, chrysanthemums, marigolds, and daisies.¹³⁹ Absinthe is a liqueur composed of ethanol, oil of wormwood, and various other herbs, and it is known for its green color and bitter taste. It became a favorite among the artists and poets of Paris during the city’s Belle Époque in the 19th century. Bohemian society enjoyed the drink by pouring water on top of a sugar cube that was suspended over a glass of absinthe. The addition of sugar water not only made the drink more palatable but also enhanced the herbal aroma and green coloration, which was referred to as the “louche effect.”¹⁰¹ This ritual was commonly performed in the early evening and thus the “green hour” was akin to a Parisian “happy hour.”¹⁰

The earliest recorded use of wormwood is found in the Ebers papyrus, which covers writing from 3550 to 1550 b.c.in Egypt.¹⁰ During the first century a.d., Pliny described wormwood’s anthelmintic properties in Historia Naturalis. Dioscorides’ De Materia Medica, which was considered an authoritative medical text through the Middle Ages, described wormwood’s ability not only to treat intestinal worms but to repel fleas and other pests with topical application.¹⁰ For millennia, wine was commonly fortified with wormwood, and the formulation is still known today, albeit in much more dilute concentrations, as vermouth (derived from the German word for wormwood, Wermut).¹¹⁷

Absinthe was first distilled in Switzerland but came to prominence during the early 19th century, with Pernod’s distillery in France.¹⁰¹ During the French-Algerian wars of the 19th century, absinthe was used medicinally by the French troops to ward off infection and prevent dysentery.¹⁰⁰ Subsequently, the returning troops introduced the drink to French society. As early as 1850, descriptions of toxicity were documented. By the 1910s, many countries had made it illegal. In the 20th century, thujone was discovered to be the toxic component of absinthe. Absinthe is still available as Pernod, a formulation that is free of thujone. However, thujone-containing absinthe, as well as recipes for making it at home, can be obtained over the Internet.

Pharmacology.

The bitter taste and anthelmintic properties come from the lactones absinthin and anabsinthin.¹³⁹ However, the toxicity of wormwood is due to its thujone content. Thujone is a monoterpene ketone, which exists in α- and β-diastereoisomeric forms. Oil of wormwood may contain up to 70% thujone (α- and β-thujone).¹³⁹ The amount of the β isomer often exceeds that of α-thujone but is less toxic.⁸¹ After oral absorption, both isomers undergo species specific hydroxylation reactions by the cytochrome (CYP) P450 system and are subsequently glucuronidated and renally eliminated.⁸⁰α-Thujone is metabolized primarily to 7-hydroxy α-thujone by CYP3A4 in humans, but there are at least six other metabolites, some of which are more prominent in other animal models.⁸⁰ The 7-hydroxy metabolite achieves a higher concentration in the brain, but it is less potent in binding the GABA_A receptor and is less toxic compared to its parent compound.⁸¹

Pathophysiology.

α-Thujone is generally accepted to be the more toxic of the two isomers and is a noncompetitive GABA_A receptor antagonist, similar to picrotoxin.⁸¹ This antagonism causes neuroexcitation, which may result as hallucinations or seizures in a dose-dependent fashion. Ethanol enhances GABA activity and may have a protective effect by reducing seizures in mice.⁸¹ In the 1970s, it was speculated that thujone mediated the psychotropic effects of absinthe via cannabinoid receptors. However, further research demonstrated that despite low affinity for the CB1 and CB2 receptors, thujone failed to evoke any chemical signaling from that binding.¹¹² Currently, research suggests that the psychotropic effects may be mediated by α-thujone’s ability to desensitize the 5-HT₃ receptor.⁴⁵

Thujones induce the synthesis of 5-aminolevulinic acid synthetase, leading to increased porphyrin production.¹⁸ Individuals with defects in heme synthesis may develop porphyrialike symptoms upon ingestion of thujones. Some have speculated that Vincent Van Gogh suffered from porphyria secondary to ingestion of absinthe and other volatile oils.

Clinical Features.

Clinical features of acute toxicity are similar to those of ethanol intoxication, including euphoria and confusion, which may progress to restlessness, visual hallucinations, and delirium. Seizures have also occurred. Studies in 19th-century France revealed that the oil of wormwood component in absinthe, rather than the ethanol or other aromatic herbs, was responsible for auditory and visual hallucinations and seizures in humans and dogs.^4,12 Absinthism was recognized as a distinct disease from alcoholism as early as 1850s. It was characterized by delirium, hallucinations, tremors, and seizures. Although thujone is the purported xenobiotic in the development of these symptoms, the patients also drank excessive amounts of ethanol, so differentiating this syndrome from chronic sequelae of alcoholism is difficult.⁴

Rhabdomyolysis and acute kidney injury (AKI) have occurred following ingestion of oil of wormwood intended for preparation as absinthe.¹⁵⁹ The etiology of the rhabdomyolysis has not been elucidated.

Camphor

History.

Originally derived from the bark of the camphor tree (Cinnamomum camphora), camphor has been widely used for centuries. It was described in writings from Marco Polo’s visits to China, and in the 16th century it was referred to as the “balsam of disease.”¹¹ Camphor has been used as an abortifacient, a contraceptive, a cold remedy, an aphrodisiac, an anti aphrodisiac, a lactation suppressor, and an antiseptic.^9,69 In the late 19th and early 20th centuries, it was also regarded as a cardiac stimulant and used extensively to treat congestive heart failure and cardiovascular compromise during influenza outbreaks.^{49,64,67,107,110} By the 1920s, studies demonstrated that camphor was not an effective cardiovascular stimulant, and its use began to fall out of favor.¹¹⁰ In the 20th century, camphor was predominantly used as a topical rubefacient to provide local analgesia and antipruritic effects. It also became a key ingredient in paregoric (camphorated tincture of opium), a common household remedy for diarrhea and cough used until 1970. Throughout the 20th century, camphor was also available as a nonprescription remedy in the forms of camphorated oil, which was 20% camphor in cottonseed oil, and spirits of camphor, which was 10% camphor in alcohol. Consequential toxicity occurred in cases where camphorated oil was mistaken for castor oil and ingested in large amounts.^12,32,152 In 1982, the FDA limited any product from containing more than 11% camphor as well as placed an outright ban on camphorated oil after numerous reports of significant morbidity and mortality. Today camphor can be found in topical products such as Vick’s Vapo-Rub and Tiger Balm. It was also used extensively as a moth repellant. Despite restrictions on its sale by the FDA, concentrated camphor products are still found in the United States. They are illegally sold in various immigrant communities for use as pesticides and medicinal remedies.⁹²

Pharmacology.

Camphor is a bicyclic monoterpene ketone that is rapidly absorbed from the gastrointestinal (GI) tract. Serum concentrations can be detected within 15 minutes of ingestion.^121,125 It is also readily absorbed from the skin and mucous membranes.⁹² It also has been documented to cross the placenta and blood–brain barrier.¹²⁵ A detectable concentration was found in amniotic fluid 20 hours after maternal ingestion.¹²⁵ Camphor is very lipophilic with a large volume of distribution. It is metabolized in the liver by CYP2A6 to 5-exo-hydroxycamphor, but other studies using animal models have cited 5-endo-hydroxycamphor and 3-hydroxycamphor as significant metabolites.^71,128,152 These metabolites then undergo glucuronidation and are excreted in the urine.¹²⁸

Pathophysiology.

The mechanism for seizure activity is still unknown. Camphor desensitizes the transient receptor potential vanilloid subtype 1 (TRPV1) channel, a nonspecific cation channel that mediates thermosensation and nociception in the peripheral nervous system (Fig. 43–1).¹⁶⁴ Similar to other topical analgesics with effects on these channels, it is postulated that desensitization mediates the analgesic and cooling effect of topical camphor products. There are TRPV1 receptors found in the central nervous system (CNS), but it is unknown whether they are implicated in the CNS effect of camphor toxicity. Autopsies of case reports and animal studies have shown neuronal necrosis and degeneration on pathology, but the mechanism of action remains elusive.¹⁴¹

FIGURE 43–1.

The transient receptor potential vanilloid subtype 1 (TRPV1) receptor is a nonspecific cation channel that is located on the skin and bladder, in the peripheral nociceptors and the dorsal horn of the spinal cord, and in the airway. Stimulation by heat, acidemia, and inflammation increases its activity, whereas camphor, capsaicin, and resiniferatoxin are direct agonists. Once open, TRPV1 stimulates intracellular signaling via PIP₂ to relay sensation of burning pain, noxious heat, airway tightness, and micturition.

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Hepatotoxicity is also reported and can range from a mild elevation in aminotransferase concentrations to fulminant hepatic failure. Children seem to be more susceptible to hepatotoxicity since they have relatively immature liver enzymes and glucuronidation systems. The hepatotoxicity may present similarly to Reye syndrome but does not have the same characteristic findings on biopsy.⁸⁷

Clinical Features.

Camphor toxicity is reported after nasal, topical, inhalational, and oral administration.^{32,88,121,137,147,155} Toxicity has developed within 5 to 90 minutes after ingestion.¹² Case reports of delayed onset of symptoms are complicated by unknown time of ingestion or concomitant illness.¹⁰⁹ In a retrospective review of 182 cases, no patient developed symptoms more than 6 hours after ingestion.⁶⁹ The ingestion of 2 g has caused significant toxicity in adults and as little as 0.7 to 1 g of 20% camphorated oil (1 teaspoon) has been fatal in children.^32,141 Other reports describe children having seizures but surviving after ingesting 0.5 to 6 g of camphor.¹³⁴

Generally, the first symptoms are related to GI irritation and include nausea and vomiting, although patients who were exposed via topical or inhalational administration rarely suffer from GI symptoms. Patients have complained of feeling warm, faint, and vertiginous as well as headaches.⁸⁸ Severe symptoms include confusion, agitation, delirium, and hallucinations.^20,29,49,147 Seizures are common and usually develop within minutes to a few hours of exposure.¹³⁴ Status epilepticus is reported.^39,92

Clove Oil

History.

Clove oil is extracted from the plant Syzygium aromaticum, also known as Eugenia aromatica. This evergreen plant is native to the Maluku islands of Indonesia (traditionally known as the Spice Islands). Its dried, unopened buds are known as cloves, a descriptive name derived from the Latin word clavus, meaning nail. During the Chinese Han dynasty, subjects were required to chew cloves in order to mask bad breath when appearing before the emperor. In medieval and Renaissance Europe, cloves were considered to be a valuable commodity. They were used for flavoring and fragrance, as well as for medicinal purposes, and that tradition remains intact today. The first recorded medicinal use of cloves in Western society can be found in The Practice of Physic, which was written in French in the 1640s and translated into English in 1687.³⁷ Clove oil is commonly mixed with zinc oxide as a sealant in dentistry, a practice that has been described as far back as 1873.⁸³ Clove oil is still used to alleviate toothaches, and one study found it just as effective as topical benzocaine for analgesia.³

Pharmacology.

Typically, clove oil contains 60% to 90% eugenol, which is the primary active component. Eugenol undergoes sulfonation and glucuronidation in the liver, with a minor pathway involving the CYP450 system to form a reactive intermediate that requires glutathione for proper elimination.¹⁴⁹

Pathophysiology.

The anesthetic properties of eugenol are mediated by blockade of various ion currents in nerves. This was initially demonstrated by the ability to block conduction of action potentials in frog sciatic nerves.⁹⁷ Given the structural similarity to capsaicin, studies sought to determine if the effects were mediated by a common mechanism. Studies of rat dorsal root ganglion cells suggest that eugenol acts in both a capsaicin receptor mediated pathway and by an independent pathway.¹¹⁵ Capsaicin requires the TRPV1 receptor to inhibit voltage-gated calcium channels in order to desensitize peripheral nociceptors, but eugenol does not (Fig. 43–1).^103,114 Eugenol also inhibits voltage-gated sodium channels independently of TRPV1, and this likely mediates its anesthetic effects.¹¹⁸ Eugenol similarly can block voltage-gated potassium channels in neurons, which suggests a possible mechanism for the irritating effects of eugenol as potassium efflux is required to terminate action potentials and neurotransmitter release.¹⁰⁵

Studies with rat hepatocytes demonstrated that eugenol can cause glutathione depletion and subsequent hepatotoxicity in a dose- and time-dependent manner. The loss of glutathione occurred prior to the onset of cell death in these studies.¹⁵⁰ Furthermore, N-acetylcysteine (NAC) was able to prevent glutathione depletion and cell death.

Eugenol inhibits prostaglandin synthetase, which may support its claims as an antiinflammatory agent in dentistry.⁸³

Clinical Features.

There are several reports of allergic reactions and local irritation when eugenol zinc oxide was used for dental procedures.^14,98,132 There are fewer case reports of systemic toxicity from other forms of exposure. However, in case reports of infants and children ingesting clove oil, depressed mental status, anion gap metabolic acidosis,and hepatotoxicity complicated by coagulopathy and hypoglycemia is reported.^{22,56,75,86,102}

A single case report described a 24 year-old woman who developed permanent infraorbital anesthesia and anhidrosis after spilling a small amount of clove oil on her face in an attempt to relieve a toothache.⁸⁴

Acute respiratory distress syndrome is reported with intravenous administration of clove oil. Similar findings of perivascular, interstitial, and alveolar edema are found in animal studies. The proposed mechanism is oxidant mediated, but this has not been verified.^93,162

Eucalyptus Oil

History.

Oil of eucalyptus is derived primarily from Eucalyptus globulus, a tree native to Australia. Eighteenth-century British explorers noted that the aboriginal people traditionally used eucalyptus as a fever remedy, so they brought it to England for further examination. The introduction of eucalyptus oil to the West led to an increased demand, because it was increasingly used to treat the symptoms of the common cold and influenza. The oil was believed to be so effective that there were public campaigns to grow the trees in areas of Europe stricken with malaria and other infectious diseases. Great effort was made to determine how best to cultivate these plants in the colder, damper European environment.^6,126 In the 19th and early 20th centuries, eucalyptus oil was a common household remedy for coughs and fevers, and it was also used as an antiseptic.³⁶ It was even reported as effective in treating hemorrhage, burns, and diabetes.^7,140,151

Pharmacology.

Eucalyptus oil contains almost 70% eucalyptol, a monoterpene cyclic ether also known as 1,8-cineole. It is rapidly absorbed from the GI tract and metabolized by the 3A family of CYP enzymes, particularly 3A4 and 3A5.⁵⁰ In rats, the main urinary metabolites are 2-hydroxycineole, 3-hydroxycineole, and 1,8-dihydroxycineol-9-oic acids.^50,108 In humans, only the 2-hydroxy and 3-hydroxy metabolites are found.⁵⁰

Pathophysiology.

The effect of eucalyptus on upper respiratory symptoms may be due to a myorelaxant effect as potassium-induced contractions of airway smooth muscle are inhibited.¹⁰⁶ However, it also potentiates acetylcholine-induced contractions of the trachea in vitro, possibly by inhibiting acetylcholinesterase.¹⁰⁶ Some authors have hypothesized that this mediates the upper respiratory irritation that commonly plagues workers who process eucalyptus trees for papers and other materials. Eucalyptol inhibits monocytes from producing several cytokines, particularly tumor necrosis factor (TNF)-α and interleukin (IL)-1β, from being produced.⁹⁰ It also suppresses arachidonic acid metabolism. Some hypothesize that this makes eucalyptol effective at controlling mucous hypersecretion and a potential adjunct in controlling asthma and chronic obstructive pulmonary disease, for which it is commonly used as an alternative medicine.^89,90,161

The mechanism of toxicity has yet to be elucidated. Some research suggests that eucalyptol may affect the autonomic nervous system.⁵⁷ Animal studies have proven to be difficult to interpret as mice seem relative insensitive to the oil and other animals require extremely high amounts to achieve toxic effect.⁴³ Significant morbidity and mortality are rare.

Clinical Features.

Typical symptoms include drowsiness, slurred speech, ataxia, nausea, and vomiting.^58,143 Rarely, seizures and coma can occur.⁷⁰ Symptom onset is usually within minutes to hours and rarely exceeds 4 hours. In children, significant toxicity has been reported after ingesting as little as a teaspoon. Fatalities have been reported in adults who have ingested as little as 4 mL, but a patient survived a 120- to 200-mL ingestion after receiving mannitol infusions and dialysis.^58,70 Inhalational and dermal exposures seem to have minimal toxicity as long as the patient is promptly removed or decontaminated from the exposure.¹⁴³

Lavender

History.

Lavender is one of the most commonly used essential oils for fragrance and aromatherapy.²⁸ It was used by the ancient Romans and Greeks for its believed antimicrobial, carminative, sedative, and antidepressive properties. The oil is produced by steam distillation of the flower heads and foliage of the Lavandula species. However, the chemical composition and fragrance of the oil is determined by the proportion of flowers distilled within a particular batch.

There are four commonly used lavenders: Lavandula latifolia, a Mediterranean variety; Lavandula angustifolia, commonly known as English lavender (or L. officinalis); Lavandula stoechas, commonly known as French lavender; and Lavandula x intermedia, which is a sterile cross between L. latifolia and L. angustifolia.²⁸ The lavenders generally have the same major chemical constituents in their oils and ethnobotanical history, but some species have specific therapeutic benefits ascribed to them. For example, L. stoechas was traditionally used as a headache remedy, L. latifolia as an abortifacient, and L. angustifolia as a diuretic.²⁸ However, many of these effects, regardless of species used, have never been substantiated in the medical and scientific literature. Lavender oil is most commonly used in aromatherapy to enhance mood, decrease anxiety, or control pain. Most studies demonstrating improved pain control, decreased anxiety, or improved mood were small studies or poorly controlled.

Pharmacology.

The main components of lavender oil contains linalool, linalyl acetate, 1,8-cineole, β-ocimene, terpinen-4-ol, and camphor.²⁸ The proportion of each within a given batch of oil may depend on the plant used and type of distillation. Plants with smaller camphor components, such as L. angustifolia, are used more for fragrance and cosmetic purposes because their aroma is considered to be more pleasant. Plants with higher camphor content have been traditionally used for insect repellant and antimicrobial uses.

Linalool and linalyl acetate are the components believed to be responsible for the neuropsychiatric effects of lavender oil, specifically sedative and narcotic effects. These compounds are rapidly absorbed through the skin and can reach peak serum concentrations as soon as 19 minutes postexposure.^28,85 Linalool inhibits both nicotinic receptor–mediated acetylcholine release and glutamate release.^122,135

L. angustifolia has activity against methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecalis as well as other bacteria.¹⁶³ Its potential as an antimicrobial and preservative in cosmetics is demonstrated.⁹⁹

Pathophysiology.

Lavender oil is very allergenic. Linalool is not electrophilic or chemically reactive, suggesting it would not be a contact allergen.⁷² Linalyl acetate has an electrophilic center and is a weak allergen in studies.¹³⁸ However, both of these compounds immediately oxidize when exposed to air, generating hydroperoxides, which are strong allergens. This oxidation occurs regardless of whether pure linalool, linalyl acetate, or lavender oil is used.^72,138

A case series reported the development of gynecomastia in three prepubertal boys using lavender oil.⁷⁸ All three children had extensive endocrine evaluations, with no abnormalities detected, and in each case the gynecomastia resolved when lavender oil was discontinued. In vitro data showed that lavender oil elicits a dose-dependent increase in estrogen responsivity and antiandrogenic activity in breast cancer cell cultures, similar to the effects of estradiol.⁷⁸

Clinical Features.

The predominant clinical feature of exposure is contact dermatitis. Unexplained or “idiopathic” gynecomastia in prepubertal boys with negative endocrine evaluations should prompt questions regarding the use of these essential oils.

Nutmeg

History.

Nutmeg and mace originate from the evergreen tree Myristica fragans, which is native to the Maluku islands of Indonesia (Spice Islands) and was imported to Europe as early as the mid-12th century.^59,136 However, today, nutmeg is more commonly imported to the United States from Malaysia, Grenada, Trinidad and other parts of the Caribbean.¹³⁶ The name nutmeg refers to the seed of the tree, which looks like a glossy brown nut. Mace is derived from the scarlet-colored aril that encloses the seed.

Although nutmeg is a common household spice and flavoring agent, it has been used for centuries for various ailments, including digestive disorders, cholera, rheumatic disease, psychiatric disorders, and pain.⁵⁹ Mace has been used as an aphrodisiac, but nutmeg has been commonly used in Europe and North America, albeit ineffectually, as an emmenagogue and abortifacient.¹²³ Indeed, most of the cases of nutmeg poisoning in the early 20th century were due to women attempting to terminate pregnancies or induce menses.⁶⁸ However, most cases of toxicity today are due to people using nutmeg as a natural high.^1,27,120,131 The first reported case of nutmeg poisoning is attributed to Lobel, who described delirium in a pregnant woman who ingested 10 or 12 nutmeg seeds in 1576.²⁷ In 1832, the famous scientist Purkinje demonstrated the toxicity of nutmeg by ingesting seeds, causing delirium and then stupor.⁶⁸

Pharmacology.

The nutmeg seed yields 7% to 16% volatile oil, 4% to 8% of which is myristicin.⁷³ Myristicin is believed to be the psychoactive component of the oil, but some studies have brought that into question. It was initially hypothesized that myristicin was metabolized to the amphetamine derivative 3,4-methylenedioxy-5-methoxyamphetamine (MMDA) by the addition of ammonia to the allyl side chain. Elemicin, another main ingredient of the volatile oil, would be metabolized to 3,4,5-trimethoxyamphetamine (TMA).¹³³ This was further supported by detection of MMDA by thin layer chromatography of rat liver incubated with myristicin.²⁰ However, in vivo studies could neither replicate these results nor find evidence of the amphetamine derivatives. Gas chromatography of urine from rats and humans exposed to nutmeg, pure myristicin, or elemicin did not detect MMDA, TMA, or evidence of the original compounds.¹⁷ However, other metabolites were found, suggesting extensive liver metabolism. It was later determined that CYP3A4 and CYP1A2 were primarily involved in the formation of myristicin’s main metabolite, 5-allyl-1-methoxy-2,3-dihydroxybenzene.¹⁶⁶

Pathophysiology.

Studies in mice suggested that nutmeg and fresh myristicin are monoamine oxidase inhibitors but that excessive doses could reverse that effect,¹⁵⁴ and nutmeg was shown to be not as potent as known monoamine oxidase inhibitors on the market at the time. In the 1960s, nutmeg was studied as a possible antidepressant in five patients with mixed results, but a formal trial of nutmeg as a psychiatric medication was never conducted.¹⁵⁴

Animal data show that nutmeg can induce tachycardia and increase the speed of conduction through the atrioventricular node in the acute setting, but chronic exposure caused bradycardia.¹³⁰ The exact mechanism for this is unknown.

Cats appear to be exquisitely sensitive to nutmeg and develop not only acute mental status changes with nutmeg exposure but liver damage leading to hepatic encephalopathy.¹⁵³ This has not been reported in humans.

Clinical Features.

Tachycardia, nausea, and dry mouth are common in acute exposures. Some patients develop GI distress and vomiting. CNS symptoms can range from giddiness to a sense of detachment or impending doom to hallucinations and delusions.^{1,8,38,68,120} Nutmeg ingestion rarely causes significant morbidity or mortality. Only two deaths have been reported. In 1887, an 8 year-old boy became comatose after ingesting two nutmegs and died the next day; however, he also received a wide variety of analeptics that may have been more harmful than the initial exposure.²⁷ The other case involved a detectable serum myristicin concentration on autopsy of a 55 year-old woman who had a toxic serum concentration of flunitrazepam and whose stomach contents smelled strongly of nutmeg.¹⁴⁴ It is unclear if the nutmeg contributed to her death.

Pennyroyal

History.

Oil of pennyroyal is derived from the plant Mentha pulegium from the Labiatae family. It has a mintlike odor and is still used as a flavoring and fragrance agent in foods and cosmetics. Its initial use was as a flea repellant. Pulegium is derived from the word pulex, which is Latin for flea.⁶⁶ Pennyroyal has been used for centuries as an emmemagogue and abortifacient, and most reported toxicity has resulted from women ingesting large quantities to induce these effects. Dioscorides listed pennyroyal as an abortifacient in his Da Materia Medica, and the Greek playwright Aristophanes made frequent reference to it in his plays.¹²⁴ Women still use pennyroyal for these purposes today.

Pharmacology.

The primary active ingredient in pennyroyal is pulegone, a monoterpene. In particular, r(+)-pulegone is the active isomer.⁶⁵ Pulegone is metabolized by the CYP450 system into several metabolites, including menthofuran, which is thought to be the metabolite primarily responsible for hepatotoxicity, although other reactive intermediates are also implicated.^66,148

Pathophysiology.

In animal studies, pennyroyal causes centrilobular hepatic necrosis.⁶⁵ In a rat model, pulegone depletes glutathione in hepatocytes and in the plasma. Furthermore, hepatotoxicity is significantly increased in glutathione-depleted animals. However, another unknown reactive metabolite has been implicated because blocking the CYP450 system prevents glutathione depletion. Menthofuran had a minimal effect on glutathione concentrations in the plasma and liver, and its ability to cause hepatotoxicity was not affected by glutathione depletion, suggesting a role on another reactive metabolite.¹⁴⁸r(+)-pulegone also causes necrosis in lung epithelium, but the mechanism remains unknown.⁶⁵

Recently, r(+)-pulegone has been shown to decrease inward current from L type calcium channels as well as block the inward rectifying potassium channels on the rat myocardium.⁴²

Clinical Features.

Common initial signs and symptoms are nausea, abdominal pain, and vomiting, often occurring within a few hours of exposure.⁵ CNS toxicity, including seizures and coma, can develop in severe cases.^19,51 Ingestion of as little as 5 mL has been implicated in severe CNS toxicity. However, in most cases, ingestion of 10 mL is primarily associated with GI symptoms and mild CNS symptoms such as dizziness and lethargy. Fatal cases involving liver failure, kidney failure, and disseminated intravascular coagulation have occurred with ingestion of 15 mL, but these often involve large amounts or multiple doses over a short period of time.^2,146,156 In reported cases, patients either ingested a tea brewed from the leaves of M. pulegium, a tablet containing the herb, oil of pennyroyal, or essence of pennyroyal, which is an alcoholic preparation.^19,31,51,63 Most cases of severe toxicity involved women ingesting large amounts of the herb in order to induce an abortion; however, two cases involved confusing the leaves of M. pulegium for nontoxic mint leaves to make tea.¹³

Peppermint Oil (Menthol)

History.

Menthol or peppermint oil is one of the most commonly used flavoring agents in the world. It is derived from the distillation of leaves of the Mentha piperita herb, which is native to Europe and parts of Asia but easily grows in North America as well.¹¹¹ Before World War II, menthol was primarily exported from China and Japan, but as those trade routes became disrupted during and after the war, Brazil became the predominate exporter.⁵² Peppermint flavor is common in oral care products, candies, cosmetics, pharmaceuticals, and beverages. Pure crystalline menthol was extracted from plants and introduced as a medicine in the 19th century. In the late 19th century, its use in upper respiratory illness was described, but the author cautioned that more information was needed to “become familiar with its actions and know its limitations.”⁵³ However, menthol is still used today for many remedies with little supporting data. It is sold as an herbal remedy for pruritus, GI disorders such as irritable bowel syndrome, cough and cold symptoms, as well as a topical analgesic.¹⁶⁵ Pure distilled peppermint oil is more expensive and primarily produced by the United States for toothpaste and other dental care products. Corn mint oil, also known for its minty scent and flavor, is derived from Mentha arvensis and can contain 70% to 80% menthol. However, menthol derived from this plant has a more herbaceous flavor and is less commonly used commercially.⁵²

Pharmacology.

There are four pairs of optical isomers that exist for menthol given its three asymmetric carbons on the central ring of the structure. However, only the -/- menthol form is found in nature and is the most potent.⁵² Peppermint oil typically contains 30% to 55% menthol.⁷⁶

Menthol is very lipid soluble and easily absorbed through the skin. Menthol is rapidly metabolized by the CYP450 system to primarily to p-menthane-3,8 diol and then glucuronidated and eliminated in the urine.⁵² Menthol is a moderate inhibitor of CYP3A4, but its effects on the metabolism of other drugs such as the dihydropyridine calcium channel blockers are not clear.⁴⁸ In human pharmacokinetic studies, only glucuronidated menthol is detected in urine in ranges of 45% to 46% of the menthol ingested.⁶¹ The plasma half-life of menthol glucuronide was determined to be 56.2 minutes and 42.6 minutes, respectively, when mint teas and candies were used.⁶¹

Pathophysiology.

In the late 19th century, Goldscheider hypothesized that the cooling effects of menthol involved stimulation of a thermoreceptor. Two independent studies demonstrated the transient receptor potential cation channel subfamily M member 8 (TRPM8) is activated by both menthol and thermal stimuli in the cool to cold range of 46° to 82°F (8°–28°C) (Fig. 43–2).¹¹⁹ TRPM8 is a member of the transient receptor potential family of excitatory ion channels (the same receptor family as TRPV1).¹⁵ Menthol and cold stimuli increase intracellular calcium, which leads to depolarization and generation of an action potential. Currently, there are six known transient receptors that perceive temperatures ranging from noxious heat to noxious cold, depending on the type or combination of receptors activated (Fig. 43–2).^119,157 These receptors are primarily expressed by small-diameter sensory neurons of the dorsal root ganglion and trigeminal nerves.¹⁵ Some data suggest that menthol’s analgesic properties are mediated by its effects on sodium channels.⁶⁰

FIGURE 43–2.

Schematic of the six known mammalian thermo-TRP channels based on their temperature threshold for activation. Certain natural substances can activate these receptors, which may lead to burning or noxious heat sensation.

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Menthol has been investigated as an adjunct to irritable bowel syndrome therapy. In vitro data with isolated animal ileum and jejunum tissue show that menthol reduces contractions by reducing calcium influx, even when such tissue was exposed to acetylcholine, histamine, and serotonin.⁷⁹ In some countries, menthol is sold in an acid resistant preparation as a carminative for irritable bowel symptoms. Menthol and peppermint oil both inhibit 5-HT₃ receptors in vitro as well as reduce serotonin-induced contractions of rat ileum, which could mediate some of the antiemetic effects.⁷⁶

Menthol is commonly used to relieve the symptoms of upper respiratory infections, in particular rhinitis. However, studies have shown that despite the sensation of improved airflow and decreased congestion, menthol actually causes increased nasal congestion.^53,54 Inhalation of menthol, camphor, or eucalyptus did not decrease nasal resistance to airflow, despite the fact that all of the subjects reported an increased sensation of airflow.²⁴ Similar results were found for nasal menthol lozenges.⁵⁵

Clinical Features.

Application of menthol to skin or mucosa causes the sensation of coolness or warmth. Case reports regarding menthol toxicity are rare. One report pertains to Olbas oil, which contains 35% menthol. However, it also contains 35% eucalyptus oil, as well as other oils in smaller amounts. In this report, the child developed ataxia, nystagmus, and altered mental status.¹¹⁶

Pine Oil

History.

Pine oil is commonly used as a household cleaner, varnish, and polish. In the past, it had medicinal uses as an expectorant and topical liniment. Turpentine is an oleoresin solvent—a mixture of pine oils and resins distilled from the tree genus Pinus. Pine oil is also distilled from the same trees but does not include any resins. Turpentine is used as a degreaser and paint thinner. Pine oil is commonly found in Pine-Sol and similar household cleaners. These cleaners typically include 20% pine oil, 6% to 10% isopropyl alcohol, and other hydrocarbons.

Pharmacology.

The lethal dose is in the range of 60 to 120 g in adults.⁹⁶ The major terpene is 1-α-terpineol. The major metabolite is bornyl acetate, which is produced by the enzymatic processes of hydration, hydroxylation, rearrangement, acetylation, and reduction in the liver.⁹⁶ The metabolites are excreted through the kidneys and by exhalation. Pine oil is readily absorbed, and clinical effects usually occur within 2 to 3 hours postingestion.⁹¹

Pathophysiology.

Pine oil and turpentine are volatile hydrocarbon compounds with low viscosity. Aspiration and inhalational injury is common when low-viscosity hydrocarbons are ingested or inhaled (Chap. 108). Animals injected with pine oil develop acute respiratory distress syndrome (ARDS), but the mechanism is unknown.¹⁴²

Clinical Features.

The most common reported symptoms are impaired mentation, psychomotor agitation, delirium, headache, nausea, ataxia, and GI distress. GI irritation and gastritis are reported, but actual perforation or high-grade lesions have not been found.³³ Acute kidney injury is also reported.⁹⁶ An isolated case report of hemorrhagic cystitis occurring after a patient ingested turpentine for several days to treat a cold is described.⁹⁴ Fatalities are rare, but are more likely to occur when the patient is elderly.¹⁶⁰ The most severe outcomes involve an aspiration pneumonitis that can develop into ARDS or a secondary pneumonia.^21,91

Tea Tree Oil

History.

Tea tree oil is derived from the distillation of leaves of Melaleuca alternifolia, a plant that is native to Australia. The Melaleuca genus belongs to the Myrtaceae family and contains more than 230 species. The international standard for tea tree oil does not specify which Melaleuca species must be used but rather dictates a certain chemical content.²⁵ Traditionally, M. alternifolia has been the primary source for the oil. Nevertheless, synonyms and ambiguous naming of various oils and plants make it difficult to identify the primary plant product. Tea tree oil is also known as melaleuca oil or ti tree oil in many cases. Furthermore, ti tree is the Maori and Samoan common name for plants of the Cordyline genus, a completely different plant.²⁵ There are oils from other Melaleuca species on the market that possess different chemical properties from that of tea tree oil, further complicating matters. Tea trees can also be known as paperbark trees, but paperbark oil may refer to oil from another type Melaleuca tree or even a nonrelated tree such as Leptospermum species.

The first reported use of M. alternifolia was in Australian Aborigines. Crushed leaves were inhaled to treat coughs and cold symptoms, and poultices of the leaves were applied to wounds. Oral histories describe swimming or bathing in healing lakes composed of decaying fallen tea tree leaves as a treatment for a variety of ailments.²⁵ The oil itself was not distilled until the 20th century, at which time it was touted as an antibacterial agent. Commercial production began after medicinal properties of the oil were first reported in the 1920s. Production slowed after World War II, presumably because of the increased use of antibiotics and decreased desire to use natural products. Renewed interest in the oil began in the 1970s, and production increased as well as became more standardized.

Pharmacology.

Data on safety and toxicity are scant. Pharmacokinetic and pharmacodynamic data are even more lacking. Animal studies and case reports of human poisoning demonstrate toxicity with oral exposure. The LD₅₀ for rats is 1.9 to 2.6 mL/kg, and rats dosed with less than 1.5 mL/kg appeared lethargic and ataxic.²⁵

Tea tree oil is comprised of terpene hydrocarbons and contains more than 100 components.²⁵ There can be variability in the composition of oils sold on the market, but there is an international standard stipulating that tea tree oil should contain at least 30% terpinen-4-ol, which is believed to be the primary antimicrobial agent and less than 15% 1,8-cineole, which is believed to be primarily responsible for the irritating properties.²⁵ There are other hydrocarbons found in tea tree oil that help make up its specific chemotype for the standard, but are less involved in the presumed medicinal properties.

Pathophysiology.

Tea tree oil is predominately used as a topical antiseptic, and its antimicrobial effects have been the most studied use of the oil. Studies show that it is bactericidal, and its mechanism of action has been partly elucidated. Tea tree oil, as a lipophilic hydrocarbon, has been found to disrupt the membranes of liposome model systems, supporting the hypothesis that it kills bacteria by disrupting their cell membranes.³⁵ Tea tree oil does not cause bacteria to lyse per se but makes them more susceptible to lysis when exposed to hypertonic medium, or at least it causes an inability to recover from leakage of intracellular contents over time. This is demonstrated by leakage of potassium ions and 260-nm light-absorbing material (a marker of leakage of cytoplasm contents) in S aureus and Escherichia coli.^26,34 Tea tree oil also inhibits respiration in S aureus.^26,35 The hydrocarbons 1,8-cineole and terpinen-4-ol were found to be primarily responsible for this phenomena.²⁶ Although 1,8-cineole was initially thought not to play a role in the antimicrobial activity of the oil, it seems to penetrate and disrupt the cellular membranes of bacteria. Terpinen-4-ol and α-terpineol have been shown to have the greatest antimicrobial activity.

Tea tree oil also has antiinflammatory effects. Specifically, it has been shown to inhibit lipopolysaccharide-induced production of the inflammatory mediators TNF-α, IL-1α, IL-10, and prostaglandin E₂ by monocytes in vitro.⁷⁴

Clinical Manifestations.

Skin irritation and allergic reactions are common effects with topical exposure. The allergic reactions are hypothesized to occur after the oil has undergone significant oxidation.¹²⁹ The hydrocarbon 1,8-cineole has been implicated as the main irritating component, but there are little data to support this theory. In some of the cases of prepubertal gynecomastia reported in boys exposed to lavender oil, the patients were also exposed to tea tree oil.⁷⁸ However, it has not been demonstrated that tea tree oil affects the endocrine system. When ingested, tea tree oil commonly causes drowsiness, ataxia, and slurred speech. Case reports of children unintentionally ingesting a 100% concentration of tea tree oil show symptoms developing within 30 minutes of exposure. One child had resolution of symptoms within 5 hours and another had to be intubated but had improvement in neurologic symptoms within 10 hours.^48,122 In all reported cases of pediatric and adult oral poisoning, patients have responded well to supportive care alone; no deaths have been reported.^48,122,135

Oil of Wintergreen

History.

Oil of wintergreen was originally derived from Gaultheria procumbens, or the Eastern Teaberry, which is a fragrant ground cover plant found in North America. The leaves were steamed and distilled to produce the oil that was used topically to relieve the symptoms of rheumatism. Oil of wintergreen is also obtained from the twigs of Sweet Birch, or Betula lenta. The active ingredient in oil of wintergreen is methyl salicylate, which has a pleasant, minty smell and taste, posing a significant hazard to children. Pure oil of wintergreen contains at least 98% methyl salicylate, but most commercial preparations of methyl salicylate contain far less.⁴⁷ FDA regulations require that any drug containing more than 5% methyl salicylate have a warning against using it other than as a topical agent and keeping it out of the reach of children.⁴⁰ Oil of wintergreen has been used as a fragrance and flavoring agent in foods and household products.⁸² It is also found in topical preparations worldwide, such as Tiger Balm and Ben-Gay, which are used to treat inflammation and myalgias. In many Asian countries, topical oils with benign, poetic names such as red flower oil and white flower oil contain high concentrations of methyl salicylate and are quite toxic when ingested.^29,30 Further confusing consumers and practitioners, there are many other names for this essential oil, including checkerberry oil, sweet birch oil, mountain tea, teaberry, groundberry oil, gaultheria oil, and spicewood oil.⁴⁷

The first reported case of toxicity occurred in 1832, when six soldiers used the oil to flavor their tea.⁴⁶ The seminal case series was reported in the 1930s in which 43 exposures were tabulated, 20 of which involved children under the age of 4 years and had a 75% fatality rate.¹⁴⁵ The smallest lethal dose in this series was 4 mL of oil of wintergreen and 6 mL was reported to be a lethal dose in a 21 year-old man.

Pharmacology.

Methyl salicylate is absorbed both from the GI tract and transdermally. Normally, only 12% to 20% of topical salicylate is absorbed from the skin after 10 hours of application.¹²⁷ Heat, inflamed or broken skin, and prolonged use of occlusive dressings can increase absorption.^23,77,113 Children have died following topical application.²³ Children are presumed to be at greater risk for toxicity due to their higher surface area–to–weight ratio and more permeable skin. Once absorbed, methyl salicylate enters the circulation and is transported to the liver, where it undergoes hydrolysis to form salicylic acid.⁴¹ Methyl salicylate is a carboxylic acid ester. Most of the studies of salicylate metabolism involve aspirin, which is a phenolic ester. It is assumed that all forms of salicylate have similar properties after they are converted to salicylic acid. The salicylic acid undergoes conjugation with glycine and glucuronic acid, forming salicyluric acid, salicyl acyl, and phenolic glucuronide. Salicylates then undergo renal elimination in the forms of salicyluric acid (75%), free salicylic acid (10%), salicylic phenol (10%) acyl (5%) glucuronides, and gentisic acid (<1%).^16,41,104

Pathophysiology.

Five milliliters (one teaspoon) of oil of wintergreen is equivalent in salicylate content to 7 g of aspirin, which has been a fatal amount in some reported cases. An extensive discussion of salicylate pathophysiology is given in Chap. 39.

Clinical Features.

An overdose of methyl salicylate presents similarly to that of other salicylates such as aspirin. Salicylate poisoning is characterized by diaphoresis, nausea, vomiting, tinnitus, hyperpnea, and tachypnea. Mental status changes are sign of severe toxicity. Symptom onset can be within a few hours given rapid absorption of the oil. Severe toxicity is associated with seizures, cerebral edema, ARDS, coma, and death. Further details on evaluation and management can be found in Chap. 39.

DIAGNOSTIC TESTING

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Laboratory testing is of little utility in most essential oil toxicity, and the patient’s clinical status will determine what tests are indicated. Some essential oil exposures do require specific studies, and they are listed below. Generally, blood or urine concentrations of the active ingredients are not available in a meaningful time frame and cannot and should not guide management. Patients who present with altered mental status or seizures warrant a complete evaluation that may include a rapid assessment of glucose, basic metabolic studies, a head computed tomography scan, and lumbar puncture for serious potential structural, infectious, or metabolic etiologies. In patients who present with respiratory distress, chest radiographs, and continuous pulse oximetry are warranted.

Absinthe: Laboratory studies should include a complete blood count (CBC), chemistry panel, creatine phosphokinase concentration, and glucose monitoring in patients who present with seizures. Urinalysis should be performed to evaluate for myoglobinuria.
Pennyroyal: CBC and liver function studies, including the aminotransferases, bilirubin, prothrombin time, and partial thromboplastin time, and a β-human chorionic gonadotropin in women are indicated, because many women ingest pennyroyal to terminate unwanted pregnancies.
Oil of wintergreen: Serum salicylate concentrations, blood gas, serum potassium concentration, and urine pH should be sent every 1 to 2 hours to determine extent of toxicity and need for treatment (Chap. 39).

TREATMENT

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The mainstay of treatment of symptomatic essential oil toxicity is supportive care, including monitoring of vital signs, intravenous fluids, and supplemental oxygen as needed. A dose of activated charcoal may be helpful in alert patients with an intact airway, but if there is a concern for seizures, activated charcoal may need to be withheld or deferred until the airway is protected. Dermal exposures should be properly decontaminated to prevent further absorption. Benzodiazepines are the mainstay of treatment in patients who present with agitation and seizures.

A few of the essential oils require specific treatment:

Absinthe: If rhabdomyolysis is present, hydration and urinary alkalization may be appropriate, depending on the clinical severity.
Camphor: Most patients need supportive care with a focus on airway and circulatory management as well as aggressive treatment of seizures. Barbiturates are frequently cited as a first-line treatment of seizures based on one animal study that demonstrated decreased neuronal damage with administration of pentobarbital.¹⁴¹ However, it is likely that appropriate use of benzodiazepines would be just as effective. Given the risk of seizures and altered mental status, inducing emesis is not recommended. There is no proof of any benefit with orogastric lavage, and the rapid absorption of camphor from the GI tract decreases its likelihood of utility. The molecular weight and lipophilic nature of camphor indicates that it would likely be absorbed by activated charcoal. One animal study that underdosed the amount of activated charcoal as well gave subtoxic doses of camphor indicated that activated charcoal was not effective.⁴⁴ There have been no further studies examining this issue; however, given the risk of aspiration from emesis and seizure, activated charcoal should only be considered in patients with massive life-threatening ingestions and protected airways. There have been case reports of improvement in mental status and seizures with lipid dialysis (using soybean oil) as well as hemoperfusion with either activated charcoal or amberlite resin.^62,95 However, camphor has a very large volume of distribution (2–4 L/kg), and these cases documented only a small percentage of body load effectively being removed, thus limiting its utility.
Clove oil: In patients who exhibit signs of hepatotoxicity, NAC should be administered. Although no definitive studies on NAC use in this patient population are available, the suggestion that NAC is protective in the rat model, combined with the safety profile of NAC, warrant its use in the setting of eugenol-induced hepatotoxicity.⁸⁰
Pennyroyal: One case of ingestion of a potentially fatal amount of pennyroyal was successfully treated with lavage, activated charcoal, and NAC.⁵ Given in vitro studies showing glutathione depletion, it would be reasonable to administer NAC in cases of pennyroyal-induced hepatotoxicity. Because there is no established dosing regimen, using the same regimen used for APAP toxicity would be reasonable.¹⁴⁸
Oil of wintergreen: Alkalization with sodium bicarbonate and hemodialysis may be indicated in cases of severe toxicity. Exchange transfusion has been used successfully in children with life-threatening toxicity following methyl salicylate overdose (Chap. 39).⁴⁷

SUMMARY

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Essential oils are increasingly used as an alternative form of medical therapy.
These oils contain mixtures of complex hydrocarbons that have the potential to be toxic.
Cutaneous use of these products in moderation is associated with minimal toxicity. However, ingestion, prolonged inhalation, or excessive topical use may cause significant morbidity and mortality.
Patients and health care providers should have open dialogues about the therapeutic use of these products and any concerning exposures should be referred to the regional poison centers for guidance in management.

Acknowledgment

Sara Eliza Halcomb, MD, contributed to this chapter in previous editions.

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Absinthe

History.

Pharmacology.

Pathophysiology.

Clinical Features.

History.

Pharmacology.

Pathophysiology.

FIGURE 43–1.

Clinical Features.

Clove Oil

History.

Pharmacology.

Pathophysiology.

Clinical Features.

Eucalyptus Oil

History.

Pharmacology.

Pathophysiology.

Clinical Features.

Lavender

History.

Pharmacology.

Pathophysiology.

Clinical Features.

Nutmeg

History.

Pharmacology.

Pathophysiology.

Clinical Features.

Pennyroyal

History.

Pharmacology.

Pathophysiology.

Clinical Features.

Peppermint Oil (Menthol)

History.

Pharmacology.

Pathophysiology.

FIGURE 43–2.

Clinical Features.

Pine Oil

History.

Pharmacology.

Pathophysiology.

Clinical Features.

Tea Tree Oil

History.

Pharmacology.

Pathophysiology.

Clinical Manifestations.

Oil of Wintergreen

History.

Pharmacology.

Pathophysiology.

Clinical Features.

Acknowledgment

References

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