Hindawi Evidence-Based Complementary and Alternative Medicine Volume 2019, Article ID 6216745, 14 pages https://doi.org/10.1155/2019/6216745

Review Article The Effects of Various Essential Oils on Epilepsy and Acute Seizure: A Systematic Review

Tyler A. Bahr ,1,2 Damian Rodriguez,1 Cody Beaumont,1 and Kathryn Allred 1

1 doTERRAInternational,LLC,389S.1300W,PleasantGrove,UT84062,USA¯ 2University of Texas Health Science Center San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA

Correspondence should be addressed to Kathryn Allred; [email protected]

Received 19 March 2019; Revised 3 May 2019; Accepted 15 May 2019; Published 22 May 2019

Academic Editor: Daniela Rigano

Copyright © 2019 Tyler A. Bahr et al. Tis is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Many essential oils (EOs) have anticonvulsant activity and might beneft people with epilepsy. Lemongrass, lavender, clove, dill, and other EOs containing constituents such as asarone, carvone, citral, eugenol, or linalool are good candidates for evaluation as antiepileptic drugs. On the other hand, some EOs have convulsant efects and may trigger seizures in both epileptic and healthy individuals. Internal use of EOs like sage, hyssop, rosemary, camphor, pennyroyal, eucalyptus, cedar, thuja, and fennel can cause epileptic seizures because they contain thujone, 1,8-cineole, camphor, or pinocamphone, which have been identifed as convulsive agents. While more research is needed to confrm their mechanisms of action, it appears that the convulsant or anticonvulsant properties of essential oils are largely due to (1) their ability to modulate the GABAergic system of neurotransmission and (2) their capacity to alter ionic currents through ion channels. Tis review presents a systematic analysis of the current research on EOs and epilepsy, including human case studies, animal models, and in vitro studies.

1. Introduction Essential oils (EOs) are one particular class of natural medicines obtained by distillation of plant material to obtain Approximately 20-30% percent of patients with epilepsy a volatile, hydrophobic extract. EOs have been used as sufer from seizures that cannot be controlled using any anticonvulsants in traditional medicine in many cultures antiepileptic drugs (AEDs) that are currently available [1]. worldwide, especially in the Middle East, India, China, and Although surgery is another method of controlling epilepsy, Brazil. It is no surprise that much of the research on EOs and it is used selectively in patients whose seizures originate from their antiepileptic efects has been produced by institutions a single, localizable site. Other treatments for epilepsy are still in these regions. Even today, some herbal remedies are in developmental stages [1]. Although this generation’s AEDs ofen more accessible than synthetic drugs for individuals in tend to have fewer side efects, there is still risk for psycholog- developing communities located in these parts of the world ical complications, such as anxiety, depression, and cognitive [3]. impairment [1]. Despite these limitations, AEDs are likely to EOs have been documented for anxiolytic, sedative, remain the primary treatment for epileptic patients because neuroprotective, and anticonvulsive properties by academic of their ease of use and wide availability. According to Ekstein research groups worldwide [4–7]. Despite a large amount in 2010, “New drug therapies with efcacy against drug- of primary research describing the antiepileptic potential of resistant seizures, favorable adverse events profles, especially many EOs, no prior review article has summarized these in regard to neurological and psychiatric efects, and, if fndings exclusively in the context of epilepsy and seizures to possible, low costs to patients and high worldwide availability our knowledge. are clearly needed” [2]. A large amount of evidence suggests Compounds found in EOs have been shown to interact that natural medicines may be one potential source of new with and exert pharmacological action on central nervous antiepileptic drugs [2]. system targets involved in epilepsy. Structures involved in 2 Evidence-Based Complementary and Alternative Medicine neurotransmitter release and metabolism such as NMDA, receptor agonist used to mimic complex human partial GABAA,GABAB, glycine, and acetylcholine receptors, as well seizures. Te pilocarpine model shares many similarities to as the acetylcholinesterase and GABA transaminase enzymes human temporal lobe epilepsy in terms of neurochemistry are modulated by certain EO compounds [8–14]. Other and its efects on cerebral networks [81]. Drugs efective EO compounds infuence neuronal excitability and action against complex partial seizures in humans are usually potential dynamics by modulating voltage-gated sodium and efective against spontaneous seizures in model animals calcium channels [15, 16]. chronically exposed to pilocarpine. EOs and their constituent compounds have unique chem- Te two main models used to study acute seizure were ical properties that make them good candidates for drug pentylenetetrazole (PTZ) and maximal electroshock (MES) design. Since the plant enzymes that produce terpenes are models. PTZ is thought to be a GABAA receptor antagonist. stereoselective, many EOs contain only one enantiomer of Administrationof PTZ triggersepileptiform activity that imi- a compound. Tis can be advantageous in cases where one tates absence seizures and generalized tonic-clonic seizures enantiomer has pronounced efects while the other is inactive [81, 82]. Maximal electroshock is a method where electrodes or afects a diferent target. Another key property of EOs in are placed on the ears and an electric current sufcient to the context of epilepsy is their ability to cross the blood-brain induce seizure is passed through the animal’s central nervous barrier (BBB). Drug candidates likely to cross the BBB are system. MES is an animal model of tonic-clonic seizures and usually of small size (<400 Da) and high lipid solubility [17]. can also be used to study the changes in gene expression, cell Virtually all compounds found in EOs meet these criteria. signaling, and synaptic plasticity since there is no chemical agent acting on neurological structures afer the seizure [81]. 2. Materials and Methods Some authors in the present review used other drugs to induce acute seizures. Above-threshold doses of pilocarpine 2.1. Systematic Review. Te present review employed a sys- and kainic acid, which are also used to model chronic tematic search of the National Institute of Health PubMed epilepsy, can be efective models of acute seizure. Picrotoxin database for all articles containing the keyword “essential and strychnine are two other less common proconvulsants. oils,” together with either of the three keywords “epilepsy,” Picrotoxin (PCTX) antagonistically binds to the GABAA “epileptic,” or “seizure.” Only primary research articles pub- receptor complex and in theory works similarly to PTZ. lished in the English language between 1900 and 2017 with Strychnine (STRN), a glycine and acetylcholine antagonist, relevant information on EOs and epilepsy were included can also be used to produce tonic-clonic, absence, and in the review. Publications documenting the activity of myoclonic seizures [81]. methanolic or aqueous extracts but not EOs were excluded, In the majority of the studies, EOs or their isolated as were articles describing the activity of EOs in the context compounds were administered via intraperitoneal injection of diseases other than epilepsy. and the dosage was standardized across all test animals Of the 122 research articles identifed in the initial search, by milliliters or milligrams per kilogram body weight. Te ffy-eight were excluded. Of these ffy-eight, thirty-three did animal studies included in this review were not screened for not contain information about essential oils in the context of their inclusion or exclusion of controls. epilepsy or seizures and were excluded for being irrelevant to the subject at hand. Eight were excluded because they were 2.3. Human Case Reports. No clinical trials have been con- published in a language other than English, and sixteen others ductedonEOsasantiepilepticdrugs.Eightcasestudiesof were excluded because they were review articles, commen- adverse events in humans were the only source of human taries, or other publications which are not considered original clinical research data in this review. Generally, these were research. A total of sixty-four articles meeting the inclusion peer-reviewed publications produced by physicians or by criteria were systematically reviewed and classifed into two researchers using data from hospital records. categories depending on whether the research documented positive or negative outcomes. Of the articles included in this 3. Results review, ffy-four of the publications (84%) reported positive outcomes and ten of the publications (16%) reported negative 3.1. Essential Oils with Anticonvulsive Efects. Many EOs outcomes. and their isolated constituents have been documented for their anticonvulsive properties. Oils high in monoterpenes 2.2. Animal Models. Two main types of animal models and monoterpenoids such as a-pinene, limonene, myrcene, emerged in this review: models of acute seizure and models asarone, carvone, citral, eugenol, and linalool predominate. of chronic epilepsy. Animal models of chronic epilepsy aim TisdataisconsolidatedinTable1. to simulate spontaneous seizure, neurological insult that results from seizure, and lasting changes in the epileptic 3.1.1. Oils High in a-Pinene, Limonene, and Other Monoter- brain. Animal models of acute seizure aim to simulate the penes. EOs containing alpha-pinene and other monoter- hyperexcitation of neural circuitry that causes convulsions penes show anticonvulsant efects in animal models. Angelica and neurological lesion. archangelica, which contains alpha-pinene, 3-carene, and Te majority of the studies that investigated the efects limonene, decreases the duration of tonic convulsions and of EOs on chronic epilepsy used the pilocarpine or electric decreases the postseizure recovery time in PTZ mice [22]. It kindling models. Pilocarpine is a muscarinic acetylcholine also increases latency for clonic convulsions and decreases Evidence-Based Complementary and Alternative Medicine 3

Table 1: Essential oils with anticonvulsant activity.

EO or Constituent Study Type Dosage Efects Reference animal (mice) PTZ, alpha-Asarone 200 mg/kg Little efect on acute PTZ, MES model animals [18] MES animal (rat) Chronic daily treatment at this dose for 28 days pilocarpine abolished all convulsions and prevented mortality in alpha-Asarone 200 mg / kg [18] spontaneous 100% of animals. 100% of control animals experienced recurrent seizures convulsions and mortality was 40% in the controls. Protected against MES seizures. Interacted alpha-Asarone animal (mice) MES 25 mg/kg [19] competitively with chlorpromazine. Slightly increased susceptibility and mortality. No efect beta-Asarone animal (mice) MES 25 mg/kg [19] on chlorpromazine activity. Increased brain GABA levels and decreased glutamate content by inhalation of the oil. PTZ-seizure animals which inhaled the oil for 30 days had brain higher Acorus gramineus animal (mice) PTZ 30 days inhalation GABA levels and lower glutamate levels, close to the [20] rhizome control animals which did not go through PTZ-induced seizures periodically. Te mechanism was determined to be inhibition of the GABA transaminase enzyme. ED50 for MES. No efect on PTZ induced seizures, but Acorus tatarinowii Schott animal (mice) PTZ, 1.25 g / kg; prolonged latency and decreased convulsive rate. Also [21] rhizome MES decreased mortality. Angelica archangelica animal (mice) MES, 400 mg/kg 83% protection, 16% mortality from PTZ seizures [22] Linn. PTZ Angelica archangelica animal (mice) MES, 100% protection from MES seizures, no mortality; 500 mg/kg [22] Linn. PTZ duration reduced 20-fold, latency increased four-fold ED50 for PTZ seizures. Increased latency to pilocarpine animal (mice), PTZ, andPCTX-inducedconvulsions.Preventedonsetof Artemisia annua L. pilocarpine, PCTX, 470 mg/kg [23] PTZ and STRN-induced seizures. Motor inhibition was STRN asideefect. animal (mice) PTZ, Artemisia dracunculus L. 0.84 mL / kg ED50 for MES animals [24] MES model animal (mice) PTZ, Artemisia dracunculus L. 0.26 mL/kg ED50 for PTZ animals [24] MES animal (mice) PTZ, 0% of convulsive movements compared to PTZ-only Bunium persicum 1mL/kg [25] MES control animal (mice) PTZ, 0% of convulsive movements compared to MES only Bunium persicum 1.25 mL / kg [25] MES control Reduced mortality by 50% compared to kainic acid-only group. Signifcantly reduced seizure activity animal (mice) kainic score around two-fold. Also lessened seizure severity by trans-Caryophyllene 60 mg/kg [26] acid inhibiting malondialdehyde synthesis and preserving activity of GPx, SOD, and CAT. Reduced levels of the infammatory cytokines TNF-a and IL-1B. 55% reduction in average duration of convulsions, Calamintha ofcinalis animal (mice) PTZ 50 mg/ kg latency period 21.7 times longer than controls and [27] comparable to animals treated with 1 mg/kg diazepam. 75% reduction in seizure duration, latency period 22.2 Calamintha ofcinalis animal (mice) PTZ 100 mg/kg [27] times longer than controls Carum Carvi L. animal (mice) PTZ 42.3 mg/kg ED50 for PTZ clonic seizures [28] Carum Carvi L. animal (mice) PTZ 97.6 mg/kg ED50 for PTZ tonic seizure [28] animal (mice) PTZ, R-Carvone 200 mg/kg no efect [29] PCTX animal (mice) PTZ, S-Carvone 200 mg/kg Signifcantly increased latency of convulsions [29] PCTX Cinnamosma Prevention of all convulsions and mortality. Some slight madagascariensis animal (rats) PTZ 0.8 mL/kg [30] sedative efects were observed. Danguy 4 Evidence-Based Complementary and Alternative Medicine

Table 1: Continued. EO or Constituent Study Type Dosage Efects Reference Increased seizure latency by around 50% and reduced the percent of animals with convulsions by 75% in PTZ animal (mice) PTZ, Citronellol 400 mg / kg model. For MES animals, the reduction in convulsions [31] MES, PCTX was identical at the same dosage of 400 mg/kg, with 75% protection from tonic convulsions. Compound action potentials reduced by 90% in nerve Citronellol In vitro nerve fbers 6.4 mM solution bundle bathed in citronellol. Tere was no efect on [31] repolarization, but only the initial depolarization. Increased the clonic seizure threshold by 50%. Te EO provided 92% seizure protection and 100% survival, Citrus aurantium animal (mice) PTZ, 40 mg / kg compared to 0% protection and 30% surivival in [32] blossom MES controls. fumazenil reversed protection, indicating the involvement of GABA-ergic system. animal (mice) MES, Citrus aurantium peel 1g/kg Increased latency period for MES and PTZ [33] PTZ Decreased spontaneous activity induced by PTZ in a Cuminum cyminum Linn in vitro neurons, PTZ 1% v/v [34] concentration dependent manner Curzerene animal (mice) PTZ 0.4 mg/kg 100% prevention of PTZ convulsions and mortality [35] Curzerene animal (mice) PTZ 0.25 mg/kg ED50 [35] Delayed clonic seizures induced by PTZ and blocked tonic extensions induced by MES. Prevented 40% of animal (mice) MES, Cymbopogon citratus 1g/kg tonic convulsions in PTZ animals and 80% of tonic [36] PTZ convuslions in MES animals. No signifcant efect on clonic convulsions. oral dose of 200 Cymbopogon citratus animal (mice) PTZ No efect [37] mg/kg Increased seizure latency 8-fold and also increased Cymbopogon citratus & Animal (mice) PTZ, latency to death in both PTZ and strychinine models. 200 mg/kg [38] Cymbopogon winteranius STRN Efects blocked by fumazenil and potentiated by diazepam. Seizure latency increased nearly seven fold. Percent of animal (mouse) PTZ, animals experiencing convulsions was reduced by 50% Cymbopogon winterianus PCTX, phenytoin, 200 mg/kg [39] and survival increased from 20% (control) to 70% (EO STRN treatment group). p-Cymene animal (mice) MES 970 mg/kg ED50 for MES seizures [40] p-Cymene animal (mice) PTZ 393 mg/kg ED50 for PTZ seizures [40] Delayed onset of generalized tonic-clonic seizures. in vitro and animal Induced hyperpolarization of neurons via GABA Dehydrofukinone 100 mg/kg [41] (mice) PTZ activation. Decreased calcium mobilization from synapse. Activity could be reversed by fumazenil. 100% protection from PTZ and STRN-induced animal (mice) PTZ, convulsions. Co-treatemnt with fumazenil, a GABA Denettia tripetala 200 mg/kg [42] STRN receptor antagonist, abolished the anticonvulsant efects on the EO and the constituent. Signifcantly delayed onset of clonic seizures, prevented animal (mice) PTZ, Elettaria cardamomum 1mL/kg allPTZseizuresand62.5%ofMESseizuresatthisdose. [43] MES Showed some degree of movement toxicity. animal (mice) PTZ, Only 12.5% inhibition of PTZ convulsions. No efect on (-)-Epoxycarvone 300 mg/kg [44] pilocarpine, STRN STRN animals. Protected against pilocarpine seizures. Increased latency to PTZ-induced seizure onset with 100% survival. Prevented tonic seizures induced by animal (mice) PTZ, (+)-Epoxycarvone 300 mg/kg MES. Exhibited 25% inhibition of PTZ convulsions. No [44] pilocarpine, STRN efect on strychine animals. Protected against pilocarpine seizures. Abolished all convulsions in MES mice and 100% animal (mice) MES, survival. Nearly doubled PTZ seizure threshold, but Eugenia caryophyllata 0.1 mL/kg [45] PTZ only reduced convulsions by 20% in mice above the threshold. Evidence-Based Complementary and Alternative Medicine 5

Table 1: Continued. EO or Constituent Study Type Dosage Efects Reference No diference in seizure latency, but decreased duration animal (mice) Eugenol - and intensity of pilocarpine-induced seizures about [16] pilocarpine threefold each. Depressed transient and late components of sodium patch-clamp current. It also decreased L-type calcium currents and Eugenol - [16] electrophysiology delayed rectifer potassium currents at higher concentrations. 55% reduction in average duration of convulsions. Latency period was 21.7 times longer than controls and comparable to animals treated with 1 mg/kg diazepam. animal (rats) 100 mg/kg for 7 Eugenol Neuronal loss was prevented by eugenol treatment in [46] pilocarpine days epileptic animals in all hippocampal sub-regions including DG, CA3, and CA1. Seizure stage and mortaility were improved. For MES animals, the EO reduced convulsion time nearly tenfold and reduced recovery time six-fold. In animal (mice) MES, Gardenia lucida resin 300 mg/kg PTZ animals, the EO increased latency fourfold and [47] PTZ reduced number of convulsions twofold. Loss of motor function was a side efect. PTZ seizure latency increased two-fold. Side efects included palpebral ptosis, decreased response to touch, Hydroxydihydrocarvone animal (PTZ) 400 mg/kg [48] increased sedation. Decreased motor activity. Protected against PTZ-induced convulsions. Prevented all convulsions in PTZ mice and 0% animal (mice) PTZ, Laurus nobilis leaf 0.75 mL/kg mortality. Also produced sedation and motor [49] MES impairment at anticonvulsant doses In MES animals, prevented 80% of convulsions. Only animal (mice) PTZ, Laurus nobilis leaf 1mL/kg 10% mortality. Also produced sedation and motor [49] MES impairment at anticonvulsant doses. in vitro human Lavender and rosemary essential oils both inhibit Lavandula angustifolia embryonic kidney 0.034 mg/mL CaV3.2 T-type calcium channels. Linalool was [50] cells determined to be the active component. Inhalation of 1 mL of lavender oil 15 minutes before treatment with 50 mg/kg PTZ prevented all convulsions in 100% of the animals and prevented mortality. All animal (mice) PTZ, Lavandula angustifolia Inhalation of 1 mL animals in the control group experienced seizures and [51] strychinine there was a 100% mortality rate at this dose. In this experiment, lavender had no efect on STRN induced seizures. supressed spontaneous activity and PTZ induced Linalool in vitro snail neurons 0.1 mM [52] epileptiform activity Induced epileptiform activity. Tis epileptiform was Linalool in vitro snail neurons 0.4 mM [52] reversed by calcium channel blockers. In vitro assays showed that linalool displaced an NMDA antagonist,MK801,whichdirectlyinteractswith NMDA receptors. Tis suggests a direct interaction Linalool in vitro - [53] between linalool and NMDA receptors. Tere was no efect on muscimol binding, so no conclusive evidence was obtained about a GABAergic mechanism. animal (mice) MES, Increased latency period and decreased mortality in all Linalool - [54] PTZ, STRN models animal (mice) MES, Moderately reduced duration of tonic seizures induced Linalool oxide 150 mg/kg [55] PTZ by MES and increased latency to PTZ seizures. Lippia alba, citral animal (mice) PTZ 100 mg/kg Increased seizure latency and percentage of survival [56] chemotype Lippia alba, limonene animal (mice) PTZ 200 mg/kg Increased seizure latency and percentage of survival [56] chemotype Lippia alba, myrcene animal (mice) PTZ 200 mg/kg Increased seizure latency and percentage of survival [56] chemotype 6 Evidence-Based Complementary and Alternative Medicine

Table 1: Continued. EO or Constituent Study Type Dosage Efects Reference Completely prevented all seizures at all and produced a Mentha piperita animal (mice) PTZ 1.6 mL/kg [57] rate of 100% survival. Mentha spicata animal (mice) PTZ 1.6 mL/kg 12-fold increase in seizure latency [57] Increased latency to PTZ seizure and death 2-fold. 100% animal (mice) MES, protection from convulsions induced by MES. Delayed Myristica fragrans STRN, bicuculline, 0.2 mL/kg onset of convuslions by STRN. At high doses, was a [58] PTZ weak proconvulsant. No motor impariment was observed. animal (mice) MES, Average of about 30 percent protection from MES Ocimum gratissimum L. 1g/kg [59] PTZ convulsions. Little efect on PTZ convulsions Nearly doubled the PTZ seizure threshold. Protected animal (mice) MES, Pimpinella anisum fruit 1mL/kg against 80% of convulsions and prevented death in 90% [60] PTZ of animals for both PTZ and MES conditions. Latency increased fve-fold with a treatment of 3 mL / kg. Inhibited production of dark neurons in diferent Pimpinella anisum fruit animal (mice) PTZ 3 mL / kg [61] regions of brain in epileptic rats. Prolonged latency and reducedamplitudeanddurationofPTZseizures. alpha-Pinene animal (mice) PTZ 440 mg/kg ED50 for PTZ seizures [40] Reduced severity of PTZ seizures but not strychine or animal (mice) PTZ, Psidium Guyanensis leaf 400 mg/kg picroptoxin. Cafeine reversed the efect, suggesting [62] PCTX, STRN that the mechanism involves the adenosine system. Number of stimulations necessary for frst appearance animal (amygdala Rosa damascena 750 mg/kg of seizure was larger in animals treated with the EO. [63] electrical kindling) Seizure duration was shorter in the treatment groups. in vitro human Rosemary essential oil was found to inhibit CaV3.2 Rosmarinus ofcinalis embryonic kidney 0.054 mg/mL T-type calcium channels. Rosmarinic acid was found to [50] (HEK) cells be the active component. Smyrnium cordifolium animal (mice) PTZ 223 mg/kg ED50 [35] 3 hr inhalation twice per day doubled onset latency of PTZ-induced seizures and abolished lethality. Efects were minimal for pcrotoxin and strychinine treated Inhalation for 3 hrs animals. Inhalation of the oil inhibited the activity of SuHeXiang Wan animal (mice) PTZ at a time, twice per [64] GABA transaminase, increasing GABA content and day decreasing glutamate content in the brain to levels similar to controls. EO inhibited the binding of a GABA ligand at the benzodiazepine site. Increased latency period to PTZ-induced seizure 10 fold and latency to 2-MP induced seizure 5-fold, with activity comparable to 4 mg/kg DZP in both cases. Terpinen-4-ol animal (mice) PTZ 200 mg/kg Prevented 87% of seizures induced by PTZ. Alleviated [65] 3-MP (a gaba antagonist) mediated convulsions. However, fumazenil didn't reverse the efect. Decreased I Na through voltage-dependent sodium channels. animal (mouse) MES, Signifcantly increased latency of convulsions and Terpinen-4-ol 200 mg/kg [66] PTZ, PCTX inhibited PCTX induced seizures animal (mouse) MES, Terpinen-4-ol 300 mg/kg Decreased tonic convulsions at 300 mg/kg. [66] PTZ, PCTX animal (mice) MES, Increased latency period and decreased mortality in all Terpineol - [54] PTZ, STRN models animal (mice) Tetrapleura tetraptera 0.4mL Protected78%ofanimalsatadoseof0.4mL. [67] leptazol Tymoquinone animal (mice) PTZ 93 mg/kg ED50 for PTZ seizures [40] Increased seizure latency more than ten-fold. 1S-(-)-Verbenone animal (mice) PTZ 200 mg/kg [68] Upregulated COX-2, BDNF and c-fos. Signifcantly increased latency period for tonic animal (mice) PTZ, Zataria Multifora 0.35 mL/kg convulsions and completely prevented tonic [69] MES convulsions. animal (mice) MES, Zhumeria majdae 0.26 mL/kg ED50 for PTZ and MES induced convulsions [70] PTZ Evidence-Based Complementary and Alternative Medicine 7 mortality in PTZ seizures. Te peel of Citrus aurantium, has antiepileptic efects on PTZ seizures in both its enan- also high in limonene, increases latency to both PTZ- and tiomeric forms, however the (S)-isomer is more active MES-induced seizures, increases sleep time in pentobarbital- [44]. Another carvone derivative, hydroxydihydrocarvone, treated animals, and decreases anxiety [33]. Nigella sativa, increases seizure latency at high doses, but comes with which contains alpha-pinene, p-cymene, and thymoquinone negative side efects including palpebral ptosis, decreased (a GABAB agonist) [14] inhibits MES convulsions, but its response to touch, and decreased motor activity [48]. activity can be reversed by GABAA antagonists PCTX and bicuculline indicating a GABAA-dependent mechanism of 3.1.4. Oils Hydrodistilled from Cymbopogon spp. EOs action [40]. Both the myrcene and limonene chemotypes obtained from plants of the genus Cymbopogon contain mult- of Lippia alba increase the latency period and survival of iple compounds with anticonvulsive activity including citral, mice with PTZ-induced seizures [56]. Te alpha-pinene rich citronellol, and citronellal. Cymbopogon citratus EO, prima- resin of Gardenia lucida prolongs pentobarbital hypnosis rily composed of citral, increases latency and decreases tonic and protects against intensity and frequency of seizures and convulsions in various models of acute seizure including the animal mortality in PTZ and MES models, with loss of motor PTZ,MES,andSTRNmodels[36,38].TeefectsoftheEO function as a side efect [47]. were blocked by fumazenil and potentiated by diazepam, suggesting that citral modulates GABA neurotransmission 3.1.2. Oils High in Asarone. Asarone is a compound found [38]. Another study on C. citratus oil tested the efects of in the rhizomes of plants of the genus Acorus and Asarum. a similar dosage given orally rather than intraperitoneally, Chronic daily treatment with the alpha isomer has been but found that the oral route of administration abolished its shown to improve the latency and severity of pilocarpine- anticonvulsive efect [37]. Lippia alba (citral chemotype), induced seizures [18]. Coadministration of the alpha isomer another EO high in citral, was shown to have anticonvulsive with chlorpromazine decreased the efects of chlorpromazine efects on PTZ mice [56]. in animals, suggesting competition for the same site [21]. Cymbopogon winteranius is primarily composed of cit- Chlorpromazine is an antagonist of various receptors includ- ronellal. C. winteranius oil was not observed to afect STRN- ing dopamine, serotonin, histamine, adrenergic, and cholin- inducedseizuresandhadonlymoderateefectsonPCTX ergic receptors. In MES animals, EO of Acorus tatarinowii seizures, but did signifcantly improve latency and number prolonged seizure latency and decreased the convulsive rate of convulsions in phenytoin, MES, and PTZ animals [31, 39]. and mortality, although it had no efect on PTZ-induced Like C. citratus, C. winteranius oilalsoseemstoexertanticon- seizures [19]. Acorus gramineus EO was found to inhibit vulsant efects dependent on GABAergic transmission [38]. the GABA transaminase enzyme. Animals that inhaled the Citronellol, another compound found in C. winteranius and oil for 30 days while receiving regular PTZ treatments had other Cymbopogon species, is nearly identical to citronellal signifcantly higher brain GABA levels and signifcantly lower except that it has an alcohol group rather than an alde- glutamate levels than animals that did not inhale the oil. In hyde group. Isolated citronellol had signifcant anticonvulsive fact, neurotransmitter levels in the animals that inhaled the efects in animals [31]. A follow-up experiment investigated oil during the PTZ seizure regimen were almost identical to compound action potentials in nerve bundles. Te amplitude the levels found in control animals that did not go through of action potentials decreased more than 90% in a 6.4 mM PTZ-induced seizures periodically [20]. solution of citronellol. Electrophysiology recordings revealed that citronellol had no efect on repolarization, but that 3.1.3. Oils High in Carvone. Carvoneisamonoterpeneketone it strongly depressed the initial depolarization during the found in mint plants and some Mediterranean spices. Te action potential [31]. S (+) enantiomer is the primary chemical constituent of Anethum graveolens (dill) and Carum carvi (caraway) oils, 3.1.5. Oils High in Eugenol. Like citronellol, eugenol also has a while the R (+) enantiomer is the primary constituent of depressive action on action potentials. It activity as a sodium Mentha spicata (spearmint) oil and can also be found in channel blocker has been confrmed using whole-cell elec- some chemotypes of Calamintha ofcinalis (calamint) oil. trophysiology. Isolated eugenol depressed transient and late Interestingly, the stereochemistry of carvone plays a major components of the sodium current. It also decreased L-type role in its anticonvulsant properties. In one study, 200 calcium currents and delayed rectifer potassium currents at mg/kg of S-carvone signifcantly increased the latency of higher concentrations [16]. In animal models, treatment with convulsions in animals treated with PTZ and PCTX while the eugenol decreased the duration and intensity of pilocarpine- same of dose of R-carvone had no efect [29]. induced seizures about threefold each and increased the Carum carvi oil, high in (S)-(+)-Carvone, efectively latency by about 50%. Daily eugenol treatment in pilocarpine inhibits tonic-clonic seizures induced by PTZ without any chronic epilepsy animals prevented neuronal loss in the neuromuscular side efects [28]. Spearmint oil has not been hippocampus, decreased seizure stage, and decreased seizure documented for any anticonvulsant efects. However, one mortality [46]. study found the oil of Calamintha ofcinalis to moderately Eugenol is the primary constituent in Eugenia caryophyl- reduce the duration of convulsions and increase the latency lata (clove) oil and some Mediterranean spice oils. One study period to PTZ seizures [27]. Tis efect might indicate on clove oil found that a dose of 0.1 mL/kg prevented all a minor presence of S-carvone or perhaps the presence convulsions with a 100% survival rate in mice treated with of active carvone derivatives. Epoxycarvone, for example, MESprotocol.Tissamedosagenearlydoubledthethreshold 8 Evidence-Based Complementary and Alternative Medicine for PTZ-induced seizures, but produced some motor impair- superoxide dismutase, and glutathione peroxidase activity ment [45]. Laurus nobilis EO, also high in eugenol, prevented [26]. (+)-Dehydrofukinone, a sesquiterpene ketone, increases PTZ convulsions and 80% of MES convulsions at doses of the latency to PTZ-induced seizures in mice. Whole-cell 0.75 mL/kg and 1 mL/kg, respectively [49]. Eugenol is also electrophysiology experiments showed that dehydrofukinone the primary constituent in Ocimum gratissimum, which had induced hyperpolarization, decreasing calcium mobilization modest anticonvulsant efects in MES and PTZ mice [59]. Te from the synapse. Activity could be blocked by fumazenil, presence of the proconvulsive constituent 1,8-cineole in this indicating that the compound’s mechanism is GABAergic oil probably explains why this O. gratissimum showed weaker neuronal inhibition [41]. Smyrnium cordifolium EO, which is efects against seizures than other eugenol-containing EOs. high in the sesquiterpenes curzerene, cadinene, and elemene, protected PTZ mice against all convulsions and mortality at 3.1.6. Oils High in Linalool. Linalool is a monoterpene alco- a dose of 0.4 mg/kg [35]. hol proven to potentiate GABAA function in mammalian Monoterpene alcohols may have potential as AEDs. electrophysiology experiments [83]. Linalool derivatives and Terpineol prolonged narcotic efects of hexobarbital, ethyl metabolites including linalool oxide, linalyl acetate, 8- alcohol, and chloral hydrate and protected against MES- and oxolinalyl acetate, 8-carboxylinalyl acetate, and 8-oxolinalool PTZ- but not STRN-induced convulsions [54]. Terpinen- also afect GABAA function or have anticonvulsive efects 4-ol was found to alleviate convulsions mediated by 3- [55, 83]. In snail neurons, linalool has an inhibitory efect on MP (a GABAA antagonist); however, its activity was not sodium channels and augments potassium currents. At lower reversed by fumazenil, indicating that it does not bind to concentrations, linalool suppresses spontaneous activity and the benzodiazepine site [65]. It also protected against PTZ PTZ-induced epileptiform activity. At higher concentrations, and PCTX-induced convulsions in mice [66]. In whole-cell it somehow induces epileptiform activity which can be electrophysiology experiments, terpinen-4-ol decreased the reversed by calcium channel blockers [52]. sodium current, so its anticonvulsant activity might involve In addition, it is possible that linalool may have neuro- an additional mechanism in which neuronal excitability is protective efects by modulating NMDA receptors. NMDA- decreased [65]. In one study, peppermint oil, with its main mediated calcium toxicity is one major mechanism of injury constituent menthol, was tested against a panel of other EOs from epileptic seizures. In vitro assays showed that linalool andwasfoundtohavethehighestanticonvulsiveactivity. displaced an NMDA antagonist, MK801, which directly inter- Ocimum basilicum, Mentha spicata, Lavandula angustifolia, actswithNMDAreceptors[53].Tissuggestsadirectinterac- Rosmarinus ofcinalis, Mentha pulegium, Origanum dictam- tion between linalool and NMDA receptors; however, it is not nus,andOriganum vulgare were the other EOs tested [57]. currently known if this interaction results in NMDA receptor Other monoterpenoids are documented for similar activ- inhibition. Lavender EO and its main constituent linalool ity. Te monoterpene ketone verbenone increased seizure were also found to inhibit T-type calcium channels in human latency more than tenfold and upregulated COX-2, BDNF embryonic kidney cells [50]. If this mechanism applies to and c-fos in PTZ animals [68]. Zataria multifora EO, high neurons, lavender might attenuate cellular excitability by in monoterpene phenols carvacrol and thymol, increased the decreasing intracellular calcium and might further protect onset time of clonic seizures and prevented PTZ tonic con- against calcium toxicity during seizure events. vulsions in PTZ and MES mice [69]. SuHeXiang Wan oil, rich Lavender and other EOs high in linalool demonstrate in borneol and eugenol, markedly delayed the appearance of strong anticonvulsive efects in animal models of seizure. PTZ-induced convulsions but showed only weak inhibition Zhumeria majdae, Cinnamosma madagascariensis,andCitrus on PCTX- and STRN-induced convulsions. Daily inhalation aurantium blossom oil all increased latency and survival and of the oil inhibited the activity of GABA transaminase, decreased convulsions in PTZ-treated animals [30, 32, 70]. increasing GABA content and decreasing glutamate content In one experiment with lavender oil, inhalation of 1 mL of in the brain to levels similar to controls. Te EO inhibited the the EO vapor 15 minutes before PTZ treatment prevented binding of a GABA ligand at the benzodiazepine site [64]. all convulsions in 100% of the animals and resulted in a Only a few EOs with nonterpene constituents have been 100% survival rate. All animals in the control group (PTZ but found to inhibit seizures. Tese include Myristica fragrans no lavender oil) experienced seizures and there was a 100% (myristicin, elemicin, and safrole), Dennettia tripetala (1- mortalityrateatthisdose[51]. nitro-2-phenylethane), and Rosa damascena (rose oxide and phenyl ethyl alcohol) [42, 58, 63]. 3.1.7. Other Oils/Constituents with Anticonvulsive Activity. Many other EOs and their isolated constituents have demon- 3.2. Essential Oils with Proconvulsive Efects. Some EOs strated anticonvulsive activity in animal models. Cumin EOs contain constituents with convulsant activity. Reports of of the species Cuminum cyminum and Bunium persicum have adverse events in humans are the primary source of research been shown to inhibit epileptiform activity in animal models on these EOs. EOs of the species Salvia ofcinalis (sage), and in in vitro neurons, respectively [25, 34]. Both share the Tuja plicata (thuja), Cedrus spp. (cedar), Hyssopus ofci- same two major constituents, cuminaldehyde and p-cymene. nalis (hyssop), Eucalyptus spp.(eucalyptus),Cinnamomum Certain sesquiterpene compounds have positive efects camphora (camphor), Mentha pulegium (pennyroyal), and on animal models of epilepsy. Trans-caryophyllene has pro- Anethum graveolens (fennel), as well as the constituents 1,8- tective efects on kainic acid-induced seizure by inhibiting cineole, camphor, thujone, and pinocamphone have pro- malondialdehyde synthesis and maintaining healthy catalase, ducedseizureswhenusedbothinternallyandtopically.Data Evidence-Based Complementary and Alternative Medicine 9

Table 2: Essential oils with proconvulsive activity.

EO or Constituent Study Type Dosage Efects Reference 1,8-Cineole (isolated animal 0.5 mL/kg Induced tonic-clonic seizures [71] constituent) Blend (rosemary EO Breakthrough (relapse) seizure in an unknown, and camphor human adult man epileptic patient afer 8 years free of [72] applied topically constituent) seizures Tree episodes of tonic convulsions lasting one minute each. Hundreds of similar seizures the next day. As a result, Blend (eucalyptus, unknown, human (12 months) the patient developed long-term status [73] pine, and thyme EOs) applied topically epilepticus and showed developmental delay for at least 4 years following the event. Camphor (isolated animal 0.5 mL/kg Induced tonic-clonic seizures [71] constituent) about 1 teaspoon Generalized tonic-clonic seizure and Camphor oil human (3 years) [74] taken internally respiratory depression within 20 minutes Generalized tonic-clonic seizure afer 10 Camphor oil human (15 months) about 20 mL [74] minutes unknown but Fennel oil human adult woman Tonic-clonic seizure lasting 45 minutes [75] large amount 0.13 g/kg; 1.25 Hyssop oil animal Caused convulsions; lethal dose [76] g/kg 25 ng/mL blood pulegone content and 41 ng/mL Epileptic encephalopathy in and liver Pennyroyal oil human infant [77] blood failure menthofuran content 0.5g/kg; 3.2 g/kg Sage oil animal Caused convulsions; lethal dose [76] intraperitoneally 10 drops taken Tonic-clonic seizure followed by Sage oil human (53 yrs) [73] internally 15-minute coma mouthful-sized Tonic-clonic seizure, unconscious for 1/2 Sage oil human (54 yrs) amount taken [73] hour following the seizure internally unknown, taken 33-day old boy experienced tonic-clonic Sage oil human (33 days) [78] internally convulsions lasting 20 minutes 5mLtaken Generalized tonic-clonic seizure lasting Sage oil human (5 1/2 yrs) [78] internally 10 minutes Sage,cedar,thuja, human (multiple unknown, taken Tonic-clonic convulsions in humans [76] hyssop cases) internally unknown, Tuja (arborvitae) oil human (7-months) 8 tonic-clonic seizures at diferent times [79] applied topically Tujone (isolated 25 mg/kg; 50 All animals experienced seizures; all animal [80] constituent) mg/kg animals died on the EOs and constituents with convulsive properties are convulsions lasting 20 minutes afer consuming an unknown found in Table 2. amount of sage oil [78]. In another report, a 5-1/2-year- old girl ingested about 5 mL of sage oil and subsequently 3.2.1. Oils High in Tujone. Tujone is the primary chem- experienced a generalized tonic-clonic seizure lasting 10 ical constituent in sage oil, although sage oil also contains minutes [78]. In another case report, a healthy 54-year-old signifcant levels of 1,8-cineole and camphor. Te ingestion woman with no history of epilepsy had taken sage orally of small quantities of sage EO has caused tonic-clonic for years as a purported treatment for her hyperlipidemia. seizures in humans, especially in children [73, 76]. According One day, she took a higher dose than normal and noticed to one report, a 33-day-old boy experienced tonic-clonic involuntary convulsions in her tongue. Half an hour later she 10 Evidence-Based Complementary and Alternative Medicine experienced a generalized tonic-clonic seizure and then fell prevented onset of PTZ and STRN-induced seizures [23]. unconscious for a full hour (Burkhard et al., 1999). A 53-year- Ocimum gratissimum EO, high in eugenol but also high in 1,8- old man was given about ten drops of sage oil by a coworker cineole, showed good anticonvulsant activity as did the EO and afer 20 minutes he began to experience a tonic-clonic of Zhumeria majdae, which is high in linalool but also high seizure followed by a coma that lasted ffeen minutes [73]. in camphor [59, 70]. Elettaria cardamomum (cardamom) EO, Animal studies investigated the minimum dosages necessary which contains high levels of 1,8-cineole, signifcantly delayed to produce convulsions and mortality. 0.5 g/kg was sufcient the onset of clonic seizures, prevented all PTZ seizures, to trigger seizures and 3.2 g/kg was lethal [78]. and prevented 62.5% of MES seizures at a dose of 1mL/kg Like sage oil, thuja and cedar EOs are high in thujone and [43]. Psidium guyanensis (guava) leaf EO, high in 1,8-cineole are also known to cause convulsions, sometimes even when and also alpha-pinene, reduced the severity of PTZ but not used topically [73, 76]. In one report, a 7-month-old child STRN or PCTX seizures [62]. Tetrapleura tetraptera EO, experienced eight tonic-clonic seizures at diferent times due predominantly composed of 1,8-cineole, protected 78% of to repeated topical exposure to an unknown amount of thuja animals from leptazol-induced seizures at a dose of 0.4 mL EO. EEG and MRI scans appeared normal and seizures ceased [67]. One potential explanation for these conficting results is afer discontinuation of the thuja EO [79]. Toxicology studies that 1,8-cineole may be a weak partial GABAA antagonist. It on alpha- and beta-thujone revealed that a dosage of 25 mg/kg is possible that 1,8-cineole competes for the same site as other is sufcient to trigger seizures and a dosage of 50 mg/kg is convulsant drugs; however, its efects are much weaker, giving lethal in 100% of mice [80]. the appearance of anticonvulsant activity.

3.2.2. Oils High in 1,8-Cineole and Camphor. EOs of camphor, 3.2.3. Other Oils with Proconvulsive Efects. Some other rosemary, and eucalyptus which are high in 1,8-cineole and EOs that do not contain thujone, 1-8-cineole, or camphor camphor (note that camphor is the name of the EO and can cause seizures. Hyssop EO, predominantly composed the isolated compound) have produced adverse epileptic of the compound pinocamphone, can cause tonic-clonic reactionsinhumans.Forexample,inonereporta3-year-old convulsions in humans [73, 76]. In animals, 0.13g/kg was girl of 15 kg had been using chest rub with 19% camphor oil for sufcient to trigger seizures and 1.25 g/kg was lethal [73]. nasal congestion. Her father mistakenly gave her a teaspoon Pennyroyal EO may cause epileptic and toxic efects due to of the oil and within 20 minutes she had a generalized tonic- its pulegone and menthofuran content, especially in infants clonic seizure [74]. In another report, a 15-month-old boy of [67, 78]. In one report, an infant consumed pennyroyal oil 10 kg opened a bottle of camphor oil and consumed 20 mL. He and was hospitalized for epileptic encephalopathy and liver developed a generalized tonic-clonic seizure afer 10 minutes failure. Blood levels of pulegone and menthofuran were 25 [74]. In animal models, 1,8-cineole and camphor were both and 41 ng/mL, respectively [67]. able to induce seizures at a dosage of 0.5 mL/kg [71]. Anethum graveolens (fennel) EO is also documented for Topical application of these EOs can also cause seizures, having proconvulsive efects [73, 75]. A woman consumed a especially in people with epilepsy. Another patient with a his- large number of cakes containing an unknown quantity of tory of epilepsy experienced a breakthrough (relapse) seizure fennel EO and experienced tonic-clonic convulsions lasting afer a massage with a blend of sea fennel, maritime pine, 45minutes.Tisistheonlyadversereportassociatedwith sea-buckthorn, and rosemary EOs. Te camphor content in fennel oil, and the chemotype of the fennel oil was unknown rosemary EO was thought to be the cause of the seizure. [75]. Fennel EO is usually rich in anethole; however, animal Te patient had not had a seizure in 8 years and did not studies on oils high in anethole demonstrate that anethole experience any seizures again for at least a year following likely possesses neuroprotective and anticonvulsant efects. the incident [72]. In another case report, a 12-month-old For example, Pimpinella anisum EO elevated the PTZ seizure girl with no prior history of epilepsy was bathed in a wash threshold and suppressed MES and PTZ convulsions in mice containing an unknown quantity of eucalyptus, pine, and [60, 61]. It also inhibited the production of dark neurons in thyme oil. A few minutes afer her last bath, she experienced epileptic rats, a side efect of chronic epilepsy [61]. Artemisia an episode of tonic convulsions lasting about one minute dracunculus oil, another oil high in anethole, showed dose- and experienced two more similar episodes later that day. dependent anticonvulsive efects in both PTZ and MES mice Over the next few days, her seizures became increasingly [24]. Taken together, these results suggest that the adverse frequent and could not be controlled by anticonvulsant drugs. reaction associated with the fennel EO may not associated As a result of the seizures, the child was developmentally with anethole, but another chemical constituent found in delayedandbecamepronetofutureseizures.Teseizures fennel EO. persisted following the discontinuation of EO use; therefore the researchers suggested the child had underlying epilepto- 4. Discussion genic encephalopathy. Eventual epileptic events were likely for the child, but her exposure to EOs may have initiated and 4.1. Summary of the Research. In this review, we fnd that exacerbated the activity [73]. many EOs demonstrate anticonvulsant activity and might Paradoxically, oils high 1,8-cineole have produced some beneft people with epilepsy. Plants of the genus Cymbopogon positive results in animal models of seizure. Artemisia annua or Acorus are likely to produce EOs with anticonvulsive prop- EO, high in camphor, 1,8-cineole, and p-cymene, increased erties. Te chemical compounds asarone, carvone, eugenol, latency to pilocarpine and PCTX-induced convulsions and linalool, monoterpene alcohols, and some sesquiterpenes are Evidence-Based Complementary and Alternative Medicine 11 also likely to have positive efects on epilepsy by acting on and epilepsy do not ft in the scope of this review. As of various nervous system targets. the publication of this review, no primary research exists Some of the research studies in this review described investigating hemp oil in the context of epilepsy. EOs that were composed of multiple constituent compounds, but many described EOs that were predominantly composed 4.4. Limitations. Tis review has limitations. Te publica- of one compound. When many oils containing the same tions included in this review were gathered exclusively from major constituent had similar efects, it was inferred that that PubMed; other scientifc databases were not searched for specifc constituent was the active component responsible for relevant publications. Poison databases were not searched for the oils’ anticonvulsive efects. However, further research is reports of potential EO-induced seizures. Furthermore, the needed to confrm that these compounds are in fact the active animal studies included in this review were not screened for components of the EOs. their inclusion or exclusion of controls.

4.2. Mechanisms of Action. While more research is needed 5. Conclusion to confrm their mechanisms of action, it appears that one mechanism for the anticonvulsant properties of EOs is their Because of their lipophilic nature, EO compounds can eas- ability to modulate GABAergic neurotransmission. Alpha- ily cross the blood-brain barrier. Tis property, combined asarone and SuHeXiang Wan oil, for instance, both inhibit with the aforementioned pharmacology of their constituents, the GABA transaminase enzyme, increasing brain GABA makes EOs excellent candidates for investigation into their levels and decreasing brain glutamate levels in animal models potential as AEDs. Tat said, certain EOsshould be used with of chronic epilepsy. Te constituents linalool, alpha-pinene, caution due to case reports and animal studies demonstrating thymoquinone, and terpinen-4-ol either potentiated GABA that they may induce seizures, specifcally EOs of sage, thuja, activity or were found to bind the GABAA receptor at the cedar, hyssop, eucalyptus, camphor, pennyroyal, and fennel, benzodiazepine site. as well as the constituents 1,8-cineole, camphor, thujone, and A second mechanism explaining the anticonvulsive pinocamphone. Future research will be necessary to deter- action of EOs is their capacity to block ionic currents. mine the pharmacological action of these compounds, but Eugenol, the principal component of clove oil, inhibits action GABAA antagonism appears to be one potential mechanism. potential generation by blocking sodium channels. Citronel- Together, these results suggest that many EOs may be lol depresses the depolarization phase of action potentials promising for treating people with epilepsy. While some in nerve fbers, probably by the same mechanism. Terpinen- EOshaveconvulsiveproperties,theseobservationscannotbe 4-ol also decreased sodium currents in electrophysiology generalized to all EOs. Many EOs have had positive efects experiments. on animal models of chronic and acute epilepsy. Because Blending is a popular practice among people who use diferent EOs afect diferent targets, blends and formulations EOs. Traditionally, mixtures and formulations of two or more of EOs should be considered. Future experiments including EOs were believed to sometimes exhibit synergy. At this time human clinical trials should also be considered as a next step however, no blends have been studied for their anticonvulsive in verifying whether EOs might be used as AEDs in people potential except for SuHeXiang Wan oil, which did show with epilepsy. signifcant efects on brain GABA levels in a model of chronic epilepsy. From these and other results discussed Conflicts of Interest in this review, it is possible that a blend of anticonvulsive oils might serve as a multitarget pharmacological approach Tyler A. Bahr, Damian Rodriguez, Cody Beaumont, and to controlling epilepsy and could be more efective than Kathryn Allred are employees of doTERRA,¯ a company that any single oil alone. For example, a combination of acorus manufactures essential oils. EO high in asarone, lemongrass EO high in citronellol and citral, lavender EO high in linalool, and clove EO high in Authors’ Contributions eugenol would simultaneously suppress action potentials, potentiate GABAA receptor activity, and increase synaptic Tyler A. Bahr interpreted the data and wrote the paper. GABA levels by inhibiting the GABA transaminase enzyme. Damian Rodriguez, Cody Beaumont, and Kathryn Allred Future research should be conducted on antiepileptic blends. participated in the writing and revision of the paper.

4.3. CBD and Epilepsy. Another chemical that has recently Acknowledgments become popular in the world of natural products and is undergoing investigation for possible benefts in regard to Tis study was funded by doTERRA¯ Intl. (Pleasant Grove, seizures and epilepsy is cannabidiol (CBD). CBD itself has UT, USA). Estee Crenshaw, Casey Harding, and Devin been shown anecdotally and clinically to provide beneft and Martinez participated in the revision of the paper. signifcant relief to epileptic patients [84, 85]. CBD comes from the Cannabis plant and is provided in many dosage References forms, one of which is hemp essential oil. While present in hemp oil, CBD itself is not an essential oil; as such, [1] D. Schmidt, “Drug treatment of epilepsy: Options and limita- studies which investigated CBD alone with regard to seizures tions,” Epilepsy & Behavior,vol.15,no.1,pp.56–65,2009. 12 Evidence-Based Complementary and Alternative Medicine

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