Tropical and Subtropical Agroecosystems, 21 (2018): 69 – 89 Castillo et al., 2018

Invited Review

ESSENTIAL OILS AS MODIFIERS OF HUMAN BEHAVIOR1

[ACEITES ESENCIALES COMO MODIFICADORES DEL COMPORTAMIENTO HUMANO]

María Andrea Castillo1,2, Yenddy Carrero3, Kendy Eduardo Urdaneta1,2,4, Mathieu Renouf3,5, Charly Lubin3,5, Montiel Nola2 and Neomar Semprún- Hernández1,2,3,*

1 Research Division, Autism Immunology Unit of Maracaibo, 4001, Maracaibo, Venezuela. Email: [email protected] 2Cátedra Libre de Autismo, Vicerrectorado Académico, Universidad del Zulia, 4001, Maracaibo, Venezuela 3Laboratorio de Biología Molecular y Celular. Facultad de Ciencias de la Salud. Universidad Técnica de Ambato. Ambato-Ecuador 4Departamento de Biología, Facultad Experimental de Ciencias, Universidad del Zulia, Maracaibo, Venezuela 5Faculté de Médecine et de Pharmacie. Université de Poitiers. Poitiers-France *Corresponding author

SUMMARY

The aim of this review was to know the effect, properties and mechanism of action of essential oils in order to enhance their use as a treatment and adjuvant in some neurodegenerative pathologies and others associated to stress and human behavior, based on clinical trials and descriptive research. Some studies suggest that essential oils have been widely used in various applications, mainly in the pharmaceutical, cosmetic, food and agricultural industries since middle age. At the same time, based on human and animal studies has been established the effects of some essential oils about their behavior in the treatment of depression, anxiety, schizophrenic, sleep disorders in the regulation of mood modulating several such as , noradrenaline, , glutamate, and gamma-aminobutyric acid also in some degenerative diseases such as Parkinson's or Alzheimer, as well as in the associated behaviors in depressive disorders, Autism spectrum disorder, ADHD, drugs addictions, people with stress and sleep disorders.

Keywords: essential oils, behavior, depression, anxiety, autism, ADHD, Parkinson's, Alzheimer

RESUMEN

Esta revisión tiene como objetivo conocer el efecto, propiedades y mecanismo de acción de los aceites esenciales para potenciar su uso como tratamiento y coadyuvante en algunas patologías neurodegenerativas y otras asociadas al estrés y al comportamiento humano, basado en ensayos clínicos y trabajos descriptivos. Algunos estudios sugieren que desde la edad media, los aceites esenciales han sido ampliamente utilizados en diversas aplicaciones, principalmente en las industrias farmacéutica, cosmética, alimentaria y agrícola. Al mismo tiempo, a partir de estudios en humanos y animales se han establecido los efectos de algunos aceites esenciales sobre el comportamiento en el tratamiento de la depresión, ansiedad, esquizofrenia, trastornos del sueño y en en la regulación del estado de ánimo modulando varios neurotransmisores: serotonina, noradrenalina, dopamina, glutamato y ácido gamma- aminobutírico; también en algunas enfermedades degenerativas como el Parkinson o el Alzheimer, así como en los comportamientos asociados en los trastornos depresivos, trastornos del espectro autista, trastorno de déficit de atención con hiperactividad (TDAH) , adicciones a las drogas, personas con estrés y trastornos del sueño.

Palabras clave: aceites esenciales, comportamiento, depresión, ansiedad, autismo, TDAH, Parkinson, Alzheimer

1 Submitted May 22, 2017 – Accepted August 20, 2017. This work is licensed under a Creative Commons Attribution 4.0 International License

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INTRODUCTION groups. The first one arehypericin, pseudohypericin and isohypericin (a naphthodianthrone), respectively New active substances research are rapidly present in fresh material (Vanhaelen and Vanhaelen- increasing, this leads us to study medicinal and Fastre, 1983). Hypericin is considered to be the most to improve in the production of the herbal plants important active ingredient. However, hypericin has constituents with beneficial biological activity, World only been shown to have activity (e.g.monoamine Health Organization reported that, medicinal plants oxidase inhibitor) in vitro and has failed to exert are the best source of drugs (WHO, 2010). detectable effects in animal models (Butterweck and Nevertheless, these molecules must be highly Schmidt, 2007). The second one active constituents investigated about its pharmacokinetics, mechanism are (a prenylatedphloroglucinol), of action, tolerability, clinical drug–drug Interactions, adhyperforin (Ayuga and Rebuelta 1986; American effects, adverse effects, contraindications, salient Herbal Pharmacopeia, 1997) and oxygenated features and safety. Pain is one of the main problems analogues of hyperforin (Verotta et al., 2000). of various diseases (Chevalier, 1996), the pain can be Experimentally, hyperforin, inhibit of physical or neurological and psychiatric, being several neurotransmitters such as serotonin, produce by depression, anxiety, stress, schizophrenia, noradrenaline, dopamine, glutamate, and gamma- Alzheimer, insomnia and convulsions (Kourosh et al., aminobutyric acid in vitro and in vivo many of which 2014) and how these essential oils might be used in are involved in the regulation of mood, motivation, the treatment of abnormal behavior understanding and reward (Capasso et al., 2003). how to modulate it’s pathophysiology. The aim of this review was to describe the effect of some Preclinical studies on the central nervous system essential oils on human behavior activity of L. (Hp) extracts suggest that it also displays anxiolytic, sedative, ST. JOHN'S WORT ESSENTIAL OIL nootropic, antischizophrenic, anticonvulsant, (Hypericum perforatum L.) antidiabetic, and analgesic activities and that it may be beneficial in the treatment of alcohol, , and Taxonomy: Family: Hypericaceae - Genus: caffeine addiction in experimental animals (Can et al., Hypericum - Specie: H. perforatum. 2011; Can and Ozkay, 2012) moreover has anti- inflammatory, wound healing and anti-nociceptive Active compounds behavior modifiers: hyperforin, effects (Motallebnejad et al., 2008; Suntar et al., hypericin, and pseudohypericin. 2010). Also is describe to prevent Alzheimer’s disease, hypericin may interfere with the processes of Effects on human behavior and animal models: polymerization of beta-amyloid peptide responsible regulation of mood, motivation, and reward, drugs for the onset of Alzheimer’s disease (Griffith et al., addictions, anxiolytic, sedative, nootropic activities, 2010). Recent clinical studies found Hp extracts to be anti-depressive, anti-schizophrenic and anti- efficacious and well tolerated in the treatment of mild nociceptive effects to moderate depressive episodes and for the short- term treatment of symptoms in mild depressive Hypericum perforatum L., also known as hypericum disorders (Luo, 2004; Kasper et al.,2010; Chen et al., or St. John’s Wort, is a herbaceous perennial 2011). The pharmacokinetics of hyperforin, native to Europe and Asia, recently introduce in North hypericin, and pseudohypericin, the components of America (Barnes et al., 2001), nowadays it has a Hp extracts that are presumed to be responsible for its worldwide distribution (Patocka, 2003). There are pharmacological effects, has been studied and despite many pharmacologicals active compounds that could structural similarity, hypericin, pseudohypericin, and be extracted from the roots, leaves and flowers such hyperforin exhibit pharmacokinetic differences. After as flavonoids derivated as flavonols, flavones and oral administration of singledoses of a range from glycosides biflavonoids including biapigeninand 300-1800mg of Hp extract (0.3% of hypericin), amentoflavone (Berghöfer and Hölzl, 1987). Tannins hypericin was detectable in the blood after1.3h, and like Proanthocyanidins, the condensed type, have peak plasma concentrations were reachedafter ~4.6 h been reported (Bisset, 1994). Other phenols and and steady-state levels by 4 days (Staffeldt et al., volatile oils for example methyl-2-octane, n-nonane 1994; Brochmoller et al., 1997; Upton, 1997). The and traces of methyl-2-decane. Acids (isovalerianic, plasmahalf-life of hypericin is reported to be ~25h nicotinic, myristic, palmitic, stearic), carotenoids, (Nangia et al., 2000). Although the bioavailability of choline, nicotinamide, pectin, b-sitosterol, straight hypericin is~14%, the therapeutic concentration of chain saturated hydrocarbons and alcohols (Brondz et hypericin in brain remains unknown, and although it al., 1983). has been suggested that brain levels reach only 5% of plasma levels, hypericin’shalf-life in the brain may be However the major active pharmacological weeks (Upton, 1997). compounds of the extract are considered into two

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Hyperforin is reported to have antibacterial activity be an uptake inhibitorof 5-HT, dopamine, against gram-positive bacteria (Schempp et al., , GABA and L-glutamatein 1999b; Taponen et al., 2006). Nevertheless, synaptosomal preparations (Chatterjee et al., 1998; antibacterial effects of hyperforin are only observed at Wonnemann et al., 2000), it has been reported that the high concentrations (Fiebich et al., 1999). Hyperforin mode of action of hyperforin in serotonin uptake did not exhibit any growth inhibitory effect against inhibition seems to be associated with the elevation of gram-negative bacteria, such as Enterococcus free intracellular sodium ion concentrations (Singer et faecalis, Escherichia coli and Pseudomonas al., 1999) and that this maybe secondary to activation aeruginosa, or against Candida albicans (Schempp et of the Na+/H+ exchange as a result of a decrease in al., 1999b). However, Hp essential oils, intracellular pH (Singer et al., 2000). , flavonoids, and tannins show antibacterial and antifungal activity (Saddiqe et al., LAVENDER ESSENTIAL OIL (L. angustifolia 2010). These characteristics might alter intestinal Mill. - L. hybrida, L. dentata L. and L. latifolia microbiota acting as antibiotics, antimycotics and Medik) antiparasitics that deregulate intestinal balance (Sandler et al., 2000; Kantarcioglu et al., 2015), In an Taxonomy: Family: Lamiaceae - Genus: open study of 3250 patients, the most commonly Lavandula - Species: L. angustifolia - L. hybrida - L. reported side effects were gastrointestinal symptoms dentata - L. latifolia. (0.6%) (Woelk et al., 1994), which could be related to the gut-brain-axis unbalance, altering neuronal Active compounds behavior modifiers: and regulation and disrupting central functioning (Mayer linalyl acetate et al., 2015). Effects on human behavior and animal models: At first, attention was focused on hypericin as the anxiolytic, anti-depressive, anti-stress, improves sleep constituent of St John's wort believed to be quality. responsible for the herb's effects. However, experimental (Chatterjee et al., 1998a, b) Lavandula is a genus of well-known plants native to and clinical evidence (Laakmann et al., 1998) has the lands surrounding the Mediterranean Sea and now emerged to indicate that hyperforin is one of the southern Europe through northern and eastern Africa major constituents required for antidepressant activity and Middle Eastern countries to south Asia and have (Schrader, 2000). Nevertheless, Hp extracts show been used for centuries as an essential oil for efficacy in the treatment of mild to moderate therapeutic purposes (Barrett, 1996). Lavender depression leading to its successful use as an essential oil (LEO) is a complex mixture mostly antidepressant. The obtained results of a study with extracted from Lavandula species like L. angustifolia. rats pregnant suggest lasting changes in the L. hybrida, L. dentata and L. latifolia. LEO has been performances displayed in the CNS, depression and trialed to treat convulsion, pain, and central nervous anxiety tests, indicating that the use of Hypericum system disorders such as anxiety, depression, stress, during gestation could interfere with the behavioral sleep disorders and vascular-brain diseases in many development of the offspring reducing anxiety and countries (Cavanagh and Wilkinson, 2002). Its major depression when they become adults. Suggesting that clinical benefits are concentrated in the central these alterations are associated with the nervous system (Choi and Lee, 2012). Furthermore, it reprogramming of the brain regions related to changes has antimicrobial activity against bacteria and fungi. in emotional reactivity (Campos et al., 2017). Antispasmodic (Schulz et al., 1997) and anti- Inhibition of monoamineoxidase (MAO) type A and inflammatory effects have additionally been reported B in rat brain mitochondria in vitro was described for (Silva et al., 2015). Lavandula species contains more hypericin (Suzuki et al, 1984; Rahimi et al., 2009; than 160 substances which major components are two Linde, 2009). However, other studies have reported monoterpenes; linalool and Linalyl acetate (Cavanagh only weak or noMAO inhibition (Thiede and Walper, and Wilkinson, 2002). Each of these constituents can 1994; Yu, 2000) because its concentration was too vary significantly between species, in oils derived low to explain the clinical effects (Butterweck, 2003). from different cultivars and be influenced by the Hypericum extract demonstrated significant receptor distillation process (Mc Gimpsey and Porter, 1999). affinity for adenosine, GABAa, GABAb, Several studies have been made to explain and benzodiazepine (Cott, 1997). Hypericine inhibits the understand the mechanism of these compounds in the synaptosomal uptake of serotonin (5- nervous system (Hossein et al., 2013). hydroxytryptamine; 5-HT), dopamine and norepinephrine with approximately equal affinity and LEO may exert pharmacological properties via also led to a down-regulation of beta receptors and modulating the glutamate NMDA receptor in the upregulation of 5-HT2 receptors in rat frontal cortex cerebral cortex (Elizabetsky et al., 1995; Lopez et al., (Muller et al., 1997). Hyperforin has been shown to

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2017) as well as neurotoxicity induced by hydrogen Effects on human behavior and animal models: peroxide and tert-butyl hydroperoxide (tBHP) (Kozics euphoria, a feeling of relaxation, and intensification et al., 2017). Linalool is able to bind the serotonin of ordinary sensory experiences, anxiolytic, sedative, transporter (SERT), contributing to its anti-schizophrenic pharmacological properties. Besides that, it alters plasma adrenocorticotropic hormone (ACTH), is a genus of plants with flowers that can be catecholamine and gonadotropin levels in cultivate all around the world if its conditions are ovariectomised rats, these hormones have a role to adequate. This plant has a long history in traditional play in the stress response and may explain any medicine of China, Europe, Greeks and India tension relieving properties of lavender (Yamada et (Kuddus et al., 2013). Used since ancient times to al., 2005). Other authors such as Delaveau (1989) and alleviate chronic pain derived from diseases. It was a Aoshima (2001) indicate an interaction with the very popular drug for consumption but eventually GABA-A receptor, which is widely known to be derailed by political factors in the United States (US) involved in the etiology of anxiety. These compounds consisting of propagandas. Therefore, a misguided mentioned have shown multiple bioactivities on stigma of Cannabis was created in 1930s, associating neuro-psychiatric disorders (Baron, 2015). psychosis, mental deterioration, addiction, and violent crimes to marijuana use (Whiting et al., 2015). Authors have compared LEO with benzodiazepines Nowadays, there are countries in South America, due to its similar mechanism and results as an Europe and some states of United States of America anxiolytic, having positive thoughts because of its (among others) that legalized its consumption and lack of side effects (Bradley et al., 2007).Choi et al., with this, many studies has been made to analyze its studied in 2013 the effects of aromatherapy, showing benefits. There are 3 primary cannabis species: a decrease in anxiety and an improvement in sleep Cannabis sativa, Cannabis indica, and Cannabis quality with no significant differences in systolic and ruderalis. These, have more than 400 compounds, diastolic blood pressure. Although, other studies show although, there is two that are mainly that inhaled aromatherapy is not the only way to studied; Δ9- (THC) and exploit all its properties. In a randomized, double- (CBD) (D’souza and Ranganathan, blind controlled trial in 2010, investigators used an 2015). Cannabinoids are a set of psychoactive oral LEO capsule to prove it´s anxiolytic efficacy. compounds present in a resin secreted from the leaves Their results revealed efficacy and safety for the relief and blossomed buds of Cannabis; preparations of the of anxiety disorder and anxiety related disturbed sleep plant can be in the form of hachish, marijuana and (Kaspera et al., 2010). Because of its relaxing, commercial products (González et al., 2002). antioxidant and stress reliever properties, it has been used in therapies for Autism Spectrum Disorder and Cannabis potency is influenced by genetics, growing ADHD (Autism Parenting Magazine, 2016). conditions (especially light), harvest time, the part of the plant used, drying, storing and processing (Potter, This essential oil can be used in massages to treat 2014). Cannabis can be administrated by inhalation muscular pain, neck pain (Yip and Tse, 2006), Low (smoking), ocular, dermic, intravenous, oral and back pain (Yip and Tse, 2004), and menstrual pain rectal for therapeutic reasons (Pinar-Sueiroa et al., (Marzouk et al., 2013). In an experimental study, 28 2011). Smoking is the most common way to be used patients with neck pain had manual acupressure with for recreational purposes (Ribeiro and Philip, 2016). lavender oil. After a month of treatment the manual When marihuana is inhaled, subjects experience acupressure group had 23% reduced pain intensity euphoria, a feeling of relaxation, and intensification compared to the control group (Yip and Tse, 2006). of ordinary sensory experiences (Rodriguez, 2012). Essential oils have been so common and popular that Chronic consumption can result in tolerance, it has even being used in baths with positive findings dependence, withdrawal syndrome, cognitive (Morris, 2002). deterioration, and increased risk of psychiatric illnesses (Budney et al., 2004). CANNABIS ESSENTIAL OIL (Cannabis sativa L., Cannabis indica Lan. and Cannabis ruderalis When Cannabis preparations are consumed in the Janish.) form of cigarettes it is absorbed by the lungs. The entrance of THC in blood and the subsequent Taxonomy: Family: Cannabaceae - Genus: distribution in tissues are very fast. Ingestion of oral Cannabis - Species: C. sativa – C. indica – C. cannabinoids results in initially lower THC plasma ruderalis. levels than taken by inhalation (González et al., 2002). Its bioavailability is reduced orally because of Active compounds behavior modifiers: Δ9- its sensitivity to acidity of gastric juice, liver and tetrahydrocannabinol (THC), cannabidiol (CBD) and intestinal metabolism, and its access to enterohepatic others minors. circulation (Agurell et al., 1986). Therefore, it is

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Tropical and Subtropical Agroecosystems, 21 (2018): 69 – 89 Castillo et al., 2018 necessary to ingest a greater amount to get the same panic and paranoia, especially in new users (Gowing physiological effect as for the respiratory one. et al., 1998) some authors have studied the benefits that provides CBD with THC. They came to the The discovery of an endogenous system conclusion of that when administered together, CBD renewed medical interest in marijuana, and data from may also have the ability to reverse the unwanted and recent years indicate that the anxiogenic effects of THC by antagonizing THC regulates the function of various types of synapses pharmacodynamically (Bhattacharyya et al., 2010; (Aggarwal, 2013) including inflammation, appetite Fusar-Poli et al., 2010). Treatment of neurologycal regulation, neural development, immune function, disorders, are studied on the field of endocanabinoid cardiovascular function, synaptic plasticity and system, due to an abundance of CB1 receptors in the learning, pain, memory, psychiatric disease, striatum, a component of the Cortico-Striato- psychomotor behavior, regulation of stress, emotion, Thalamo-Cortical circuit which is believed to be among others (Howlett, 2004; Rodriguez et al., 2005; dysfunctional in Obsessive Compulsive Disorder Greco et al., 2010; Serrano and Parsons, 2011; (OCD) (Schindler et al., 2008) . Many synapses in Aggarwal, 2013). The endocannabinoid system this region are also glutamatergic and glutamate consists of the cannabinoid 1 (CB1) and 2 (CB2) hyperactivity is believed to be one mechanism that receptors, the endogenous cannabinoid receptor underlies OCD symptomology (Wu et al., 2012). ligands (endogenous cannabinoids) N- Cannabinoids inhibit glutamate release in the central arachidonoylethanolamine (, or AEA) and nervous system (Gomes et al., 2011), therefore 2-arachidonoylglycerol (2-AG), as well as their reduces motor activity having positive effects in the degrading enzymes fatty acid amide hydrolase treatment of OCD, Trichotillomania and Tourette’s (FAAH) and monoacylglycerol lipase, respectively syndrome (TS) (Grant et al., 2011). (Serrano and Parsons, 2011; Battista et al., 2012). CB1 is a G protein wich has a presynaptical function To summarize other medicinal benefits, it has been in the central nervous system. CB2 receptors are showed positive results treating conditions like thought to be linked to immune function and are Autism spectrum disorder (Kurz and Blass K, 2010), concentrated in peripheral tissues (Pacher et al., Gastrointestinal disorders (irritable bowel syndrome, 2006). Δ9-Tetrahydrocannabinol (THC), known as inflammatory bowel disease, pain (Kimball et al., the main psychoactive component of Cannabis, exerts 2010; Naftali et al., 2013), Parkinson’s disease its effects through the endocannabinoid system, by (Muller-Vahl et al., 1999), depression and anxiety acting on CB1, CB2 receptors (Turna et al., 2017) and (Petersen, 1976), as well as an antidepressant (El-Alfy seems to possess antiseizure activity (Schulz et al., et al., 2010) and analgesic (Elikottil et al., 2009). 1997). Clendinning in London was one of the first Western physicians to treat migraine with Cannabis in the In the other hand, Cannabidiol (CBD) is a 1840s, since then, usage of marihuana for migraines phytocannabinoid which lacks the significant and headaches have been described with positive psychoactive, or “high-inducing,” effects of THC but findings (Clendinning, 1843; Greene, 1872; Osler and has demonstrated anti-inflammatory, analgesic, McCrae, 1915; McGeeney, 2013). anticonvulsant, and anxiolytic properties (Blessing et al., 2015). Although the mechanism behind these The dosis in those studies were suministrated by effects remains unclear, the function of CBD may be inhalation and suppositories. Cannabis has great related to its action as an antagonist/inverse agonist of therapeutic properties that can be harnessed to the CB1 receptors (Thomas et al., 2007) or as a positive maximum if they are well administered and allosteric modulator of 5HT1A receptors (Rock et al., controlled. However, because of inconsistencies in 2012). An attribute of CBD is that possess amount of dosage across studies, there is no clear neuroprotective and anti-inflammatory effects conclusion on whether there exists a safe amount of (Hampson et al., 2000). A preclinical study revealed Cannabis use. Further studies are needed in order to that tetrahydrocannabinol (THC) and cannabidiol standardize these variables for each disease and (CBD) clearly have anticonvulsant properties in disorder. animal models of acute seizures and epilepsy (Wallace et al., 2002; Jones et al., 2010). BERGAMOT ESSENTIAL OIL (Citrus bergamia Risso & Poit.) High CBD content Cannabis report only minor side effects, such as somnolence or fatigue, and only a few Taxonomy: Family: Rutaceae - Subfamily: patients withdrew treatment due to side effects (Porter Citroideae - Tribe: Citreae - Genus: Citrus - Specie: and Jacobson, 2013; Press et al., 2015). On the other C. bergamia. hand, THC has significant addictive potential. Even though it has been demonstrated the negative side Active compounds behavior modifiers: linalool, effects of high dosis of THC (anxiety, dysphoria, linalyl acetate and Limonene.

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decrease the CS level, that can be linked with a stress Effects on human behavior and animal models: reduction, and that the effects depend of the time anxiolytic/relaxation effects, anti-stress between the inhalation and the effect on the brain. That could be increased by water et volatile oil mix, Citrus bergamia is a fragrant fruit with green color to ameliorate the physiological and psychological similar to the lime, originates from the Mediterranean effect of the BEO. Another study show that liposomal region, particularly from southern Italy and Greece. BEO can be used to limit the use of toxic solubilizing Genetics had shown that it’s probably a hybrid agents especially to improve the anticancer activity of between Citrus limetta and Citrus aurantium. the oil on human neuroblastoma cells but we could Bergamot can be used to make perfumes, food, expect a similar effect with liposomal BEO on cosmetics, and aromatherapy. In fact, Bergamot oil behavior troubles (Celia et al, 2013). (BEO) is commonly used against psychological stress and anxiety in aromatherapy, but there is also some According to others studies (Rombolà et al, 2017) it interesting ways like it affects the state of mood, seems to be an interesting way to treat some disorders anticancer activity, and inhibition of oxydative stress. of the behavior, especially while anxiolytic dose of All those particularities are due to the component of benzodiazepine (DZP) seems to affect the vigilance of the plant. The most abundant compounds are the the rats, unlike BEO which allows to the rats some monoterpene hydrocarbons d-limonene (25.62%– alert behaviors. In fact, spontaneous behavior is 53.19% of the whole essential oil), the monoterpene reflected in the electroencephalographic (EEG) ester, linalyl acetate (15.61%–40.37%), and the activity and it is known that hippocampal rhythmic monoterpene alcohol, linalool (1.75%–20.26%) slow activity and cortical low voltage fast activity (Melliou et al, 2009). dominate the EEG during “voluntary movements” but not during sedation. Incidentally, previous results According to recent research in a combination of indicated that systemic doses of BEO increase alpha fields, such as analysis, pharmacology, EEG frequency correlate to relaxation, and beta and psychology, a variety of volatile oils have brainwave activity, associated with being alert and specific neuropharmacological effects. The individual awake. A different EEG pattern is observed with DZP volatile oil compounds are detected by the olfactory that decreases delta and alpha and increases beta- nerve on the back of the nasal cavity, which carries 3/gamma activity. Therefore, both behavioral and more than 1,000 kinds of receptors and is directly EEG data seem to support the hypothesis that other connected via the intracranial olfactory bulb to the systems, in addition to the limbic system in the hypothalamus and thus to the GABAergic, could be likely involved in the autonomic nervous system. Accordingly, effects on anxiolytic/relaxant effect of bergamot oil (Rombolà et the endocrine and immune systems have been al, 2017). Aromatherapy with bergamot oil seems to demonstrated. Furthermore, volatile oil components be promising in treating behavior disorders all the inhaled during aromatherapy can pass from the more when chronic benzodiazepines use induces alveoli into the capillary blood vessels. Even if drowsiness, lethargy, dizziness, vertigo, sedation, rubbed into the skin, they can enter through the tolerance and dependence (Tampi et al, 2014). subcutaneous tissue into the capillaries and pass the blood-brain barrier with the bloodstream, thus Another interesting way of use of Bergamot oil is to affecting the entire central nervous system. restore opioids analgesic efficacy, with the bergamot (Watanabe and Kimura, 2015). Bergamot oil seems to polyphenolics fraction (BPF) that allow an have effects on hypothalamus pituitary adrenocortical antioxidant function. In fact, mice treated by several axis, by reducing anxiety and stress. (Rombolà et al, morphine intakes develop an analgesic tolerance. It 2017). was observed that repeated administration of morphine for several consecutive days produced When a stressor reaches the cerebral cortex, tolerance to the opioid and an increase in superoxide adrenocorticotropic hormone (ACTH) is released formation in the L4-L5 portion of the mice spinal from the hypothalamus stimulating the secretion of cord. BPF co-administration was able to inhibit cortisol from the adrenal cortex. Based on this morphine tolerance reducing O2- chronic morphine- knowledge, a recent study have used salivary cortisol induced increase. The increase of superoxide anion of 41 healthy females (CS) levels as an indicator for leads to the oxidation of glutamine-synthetase which stress reduction in previous research projects, normally allow to the synapse to reduce the demonstrating that during emotional improvement stimulation by reducing glutamate level. The after relaxation cortisol levels are also reduced antioxidant effect of BPF seems to restore the normal (Watanabe and Kimura, 2015). They also measured function and make more effective the long term use of the heart rate frequency to see the activity of the morphine. It could be an interesting way for the use of parasympathetic nervous system. Results have shown BEO in behavior disorders because of reducing the that it really increase the parasympathetic system and glutamate level, neurotransmitter which is responsible

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Tropical and Subtropical Agroecosystems, 21 (2018): 69 – 89 Castillo et al., 2018 of excitation in the nervous system (Lauro et al., absorbed and distributed to body organs, including 2016). the brain, before excretion (Fiorella Casamenti and Stefani, 2016). OLIVE ESSENTIAL OIL (Olea europea L.) The most widespread neurodegenerative conditions in Taxonomy: Family: Oleaceae - Genus: Olea - the population are associated with ageing and Specie: O. eurepea. comprise severe pathologies, such as Alzheimer Disease (AD) and Parkinson Disease (PD) that Active compounds behavior modifiers: oleuropein compromise memory, cognition, sociality, gait, and and hydroxytyrosol (probably). motor coordination and interfere heavily with the everyday life. These, and other neurodegenerative Effects on human behavior and animal models: diseases, both in the sporadic and, when present, in anxiolytic and antidepressant effects the familial forms, are characterized by the presence of intracellular and/or extracellular (amyloid plaques) Olive is used throughout the world especially in the deposits of an intricate mesh of fibrillar aggregates Mediterranean region. It is full of nutriments and arising from the aberrant polymerization of specific vitamins. It has the most delicate flavor and peptides/proteins, typically Aβ peptides and tau antioxidant benefit (Aguilera & Ramirez-Tortosa, protein in AD, tau protein in other tauopathies (e.g. 2001). is rich in monounsaturated fatty acids frontotemporal dementia), α-synuclein in PD, (MUFAs) and has excellent health benefits (Alarcón huntingtin in Huntington disease and various ataxins et al, 2001). It is composed mainly of mixed in several ataxias (Selkoe, 2003). triglyceride esters of oleic acid, palmitic acid, and other fatty acids, along with the traces of squalene (up At micromolar concentrations, Olive Leaf Extract to 0.7%) and sterols (about 0.2%; phytosterol & (OLE) has been shown to interfere in vitro with tocosterols). It also contains group of antioxidants amyloid aggregation of the Aβ 42 peptide (Rigacci et that are esters of tyrosol and hydroxytyrosols, al., 2011), amylin (Rigacci et al., 2010), and including , oleuropein, vitamin E and transthyretin (Leri et al., 2016) ; moreover, carotenoids. Oleuropein is a chemical that prevents oleuropein, OLE, and hydroxytyrosol (HT) have been the oxidation of LDL (low-density lipoproteins) reported to hinder in vitro amyloid aggregation of tau particles (Coni et al., 2000). It has been reported that protein into fibrillary tangles. A similar behavior has omega-3 fatty acid, docosahexaenoic acid (DHA), also been reported for oleocanthal; it was shown to plays an adaptive role during stress and shows a interact covalently with tau inducing conformational significant reduction in perceived stress (Bradbury et modifications that interfered with protein aggregation. al., 2004) by increasing secretion of adrenal Oleocanthal was also reported to interfere with Aβ corticosterone in rats loaded with single repetitive aggregation favoring the growth of oligomers with stress (Condo et al., 2000). altered structure, modified immunoreactivity, and reduced binding to synapses and synaptotoxicity (Pitt It must be underlined that repeated administration of et al., 2009). Olive polyphenols can also interfere extra-virgin olive oil produces anxiolytic and indirectly with Aβ40/42 aggregation. antidepressant effects via neurochemical alterations in brain 5-HT,DA,and their metabolites (Perveen et al., BLACK ESSENTIAL OIL (Nigella sativa 2013) .Role of 5-HT in anxiety is well documented. L.) Increased 5-HT produces anxiogenic effect while decreased level of 5-HT produces anxiolytic effect Taxonomy: Family: Ranunculaceae - Subfamily: (Gupta and Chopra, 2010). It has been observed that Ranunculoideae - Tribe: Nigelleae - Genus: Nigella- repeated administration of extra-virgin olive oil Specie: N. sativa. produce significant antidepressant effects as the struggling time of rats taking olive oil was Active compounds behavior modifiers: significantly increased as compared to control rats. thymoquinone. (Perveen et al., 2013) This indicates that olive oil has great potential to reduce depression which may be Effects on human behavior and animal models: due to presence of linoleic acid; a polyunsaturated anxiolytic and antidepressant effects omega-3 fatty acid that makes up 1.5% of extra-virgin olive oil (Sirtori et al., 2007). Nigella Sativa (NS) also known as Black Cumin is an annual native to south and southwest Morever, data on bioavailability indicate that, in spite Asia (Botanical Society of Britain and Ireland, 2007). of extensive metabolism by microbiota and The seeds of the plant have a long history of use in physiological modifications by the organism, plant, different frameworks of medicines and food. In notably olive, polyphenols are, at least in part, Islamic literature, it is considered as one of the

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Tropical and Subtropical Agroecosystems, 21 (2018): 69 – 89 Castillo et al., 2018 greatest forms of therapeutics (Aftab Ahmad, 2013). orally) 5 days before ischemia and continuing it It has been widely used to treat nervous system during the reperfusion time, prevented brain damage diseases such as memory impairment, epilepsy, in a model of transient forebrain ischemia in the rat neurotoxicity, pain, etc. Additionally, this is hippocampus (Al-Majed et al., 2006). The study also uncovered that the majority of therapeutic properties showed that TQ stimulated resistance to oxidative of this plant are due to the presence of thymoquinone stress by decreasing the elevated levels of MDA, (TQ) which is a major bioactive component of the glutathione (GSH) contents, CAT and SOD (Al- essential oil. Pharmacological studies have been done Majed et al., 2006). to evaluate the effects of NS on the central nervous system (CNS) (Hosseinzadeh, 2004). The present A protective effect for TQ was also reported in 1- review is an effort to provide a detailed scientific methyl-4- phenylpyridinium (MPP)-treated primary literature survey about pharmacological activities of cultures and a primary Parkinson’s the plant on nervous system. The essential oil contain disease model involving rotenone and 48 compounds, the most interesting psychoactive neuroinflammatory mechanisms. In this study, compound is Thymoquinone (TQ). rotenone, a well-known insecticide, following both short (20 nmole on day 10 i.v. for 48 h) and long-term Concerning anxiety and depression, a study where (1 nmole on day 6 i.v. for 6 consecutive days) was following four weeks of daily administration of treatment reduced the number of tyrosine hydroxylase NS oil (NSO) to mices, it showed an increment in immunoreactive which was prevented by TQ (Radad open field activity. The animals also had a better et al., 2009). performance when tested in elevated plus maze. An oral administration of NSO raised brain levels of 5- VALERIAN ESSENTIAL OIL ( hydroxytryptamine (5-HT), but the levels of brain officinalis L.) hydroxyindole acetic acid (5-HIAA) significantly reduced. Likewise, brain and plasma levels of Taxonomy: Family: - Subfamily: increased after repeated oral - Genus: Valeriana - Specie: V. administration of NSO (Perveen, 2009). TQ has also officinalis. shown an anti-anxiety-like effect in mice through modulation of γ-aminobutyric acid (GABA) and nitric Active compounds behavior modifiers: valerenic oxide (NO) levels in the brain or plasma (Gilmore, acid, valerenal. 2011). In another study, mice were subjected to 6h immobilization in order to experience stressed Effects on human behavior and animal models: conditions and the role of GABAergic and nitriergic anti-depressant, anxiolytic, sedative effects, improves modulation in the anti-anxiety effect of TQ has been sleep quality and decreases sleep latency. investigated. TQ (10 and 20 mg/kg) produced significant anti-anxiety effects in unstressed mice The root of Valerian officinalis, a pink-flowered without altering nitrite levels, but only the higher perennial that grows wild in temperate areas of the dose (20 mg/kg) of TQ increased the GABA content Americas and Eurasia, has been a popular calming in unstressed mice. and sleep-promoting agent for centuries. German health officials have approved valerian for use as a In stressed mice, TQ (20 mg/kg) showed anxiolytic mild sedative and sleep aid, based on several effects with a significant reduction in plasma nitrite European clinical trials that demonstrate these effects and brain GABA content. Pre-treatment with (Kamm-Kohl et al., 1984). Because of valerian's methylene blue improved the anti-anxiety effect of historical use as a sedative, antiseptic, anticonvulsant, TQ in both unstressed and stressed mice. Hence, an migraine treatment, and pain reliever, most basic association between NO-cGMP and GABAergic science research has been directed at the interaction pathways in the anxiolytic-like activity of TQ has of valerian constituents with the GABA receptor been proposed (Gilhotra and Dhingra, 2011). The (Boullata et al., 2000). Many studies remain results of the previous study also showed that inconclusive and all require clinical validation. The injection of 200 and 400 mg/kg of hydro-alcoholic mechanism of action of valerian in general, and as a extract of NS prevented lipopolysaccharide-induced mild sedative in particular, has not been fully depression-like behavior in rats (Hosseini et al., elucidated. However, some of the GABA-analogs, 2012), which confirmed the anti-depressive effects of particularly valerenic acids as components of the the plant and suggested that the effects might be due essential oil along with other semivolatile to its anti-inflammatory properties. It is also sesquiterpenoids, generally are believed to have some concluded that NS, NSO and TQ improve anxiety and affinity for the GABAA receptor, a class of receptors depression. It seems that the effects are related to the on which benzodiazepines are known to act. (Holzl, effects of GABA, NO and 5-HT. It has also been 1989) (Mennini et al., 1993) Valeric acid, which is reported that administration of TQ (5 mg/kg/day, responsible for the typical odor of mostly older

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Tropical and Subtropical Agroecosystems, 21 (2018): 69 – 89 Castillo et al., 2018 valerian roots, does not have any sedative properties. CONCLUSIONS Valeric acid is related to valproic acid, a widely prescribed anticonvulsant; valproic acid is a The use of essential oils in their various forms of derivative of valeric acid. administration either inhaled (aromatherapy), topical application or ingested emerges as an alternative tool Valerian also contains isovaltrate, which has been in the conventional therapy of many problems shown to be an inverse agonist for adenosine A1 associated with mood, behavior and sleep disorders. receptor sites. This action likely does not contribute to The studies mentioned in this review have shown the the herb's possible sedative effects, which would be efficacy and stability of different essential oils. It is expected from an agonist, rather than an inverse important to establish the optimal dosage of the EO to agonist, at this particular binding site. Hydrophilic use it as an adjuvant of treatment for different extractions of the herb commonly sold over the disorders. Many of these plants share the property of counter, however, probably do not contain significant having anxiolytic effects, being anxiety the core amounts of isovaltrate (Lacher et al., 2007). Valerenic symptom observed in emotional problems, acid in valerian stimulates serotonin receptors as a developmental disorders such as ADHD, ASD, partial agonist (Patočka, 2010) including 5-HT5A psychiatric disorder such as schizophrenia, which is implicated in the sleep-wake cycle (Dietz et neurodegenerative diseases, neoplasms, metabolic al., 2005). In 2 randomized sutides, (Leatherwood, diseases and even on people with typical 1982) (Lindahl and lindwell, 1989); blind, and development. placebo-controlled crossover trials (n=27 and n=128), valerian (400-450 mg before bedtime) resulted in REFERENCES significantly improved sleep quality and decreased sleep latency, with no residual sedation in the Abuznait, H.A., Qosa, H., Busnena, B.A., El Sayed, morning. In vitro, constituents of valerian mediate the K.A., Kaddoumi, A. 2013. Olive-oil-derived release of -aminobutyric acid (Leuschner et al., 1993) oleocanthal enhances βamyloid clearance as and bind the same receptors as benzodiazepines, but a potential neuroprotective mechanism with less affinity and milder clinical effects. (Mennini against Alzheimer’s disease: in vitro and in et al., 1993) Habituation or addictions have not been vivo studies. ACS Chem Neurosci. 4: 973– reported. 982. DOI: 10.1021/cn400024q Addae, J.I., Pingal, R., Walkins, K., Cruickshank, R., Anxiolytic or Sedative/Hypnotic activity: In mice, Youssef, F., Nayak, S.B. 2017. Effects of intraperitoneal injections of valerenic acid, valerenal Jasminum multiflorum leaf extract on rodent and whole herb extracts produced significant models of epilepsy, motor coordination and sedation, ataxia and anticonvulsant effects (Veith et anxiety. Epilepsy Res.131: 58-63. DOI: al., 1986). Intraperitoneal injections of 100 mg/kg 10.1016/j.eplepsyres.2017.02.012 had sedative effects as strong as barbiturates; doses of Aggarwal, S.K. 2013. Cannabinergic pain medicine: 400 mg/kg led to death. In comparison with diazepam A concise clinical primer and survey of and chlorpromazine, valerian extract had weak randomized-controlled trial results. Clin J anticonvulsive properties. Valerian root extract Pain. 29:162-171. DOI: (Valdispert) reduced motility and increased 10.1097/AJP.0b013e31824c5e4c. thiopental-induced and pentobarbital-induced Aguilera, C.M., Ramírez-Tortosa, M.C., Mesa, D., sleeping time. Gil, A. 2001. Protective effects of monounsaturated fatty acids and Even the aroma of valerian root exerted sedative polyunsaturated fatty acids in the effects in mice (Buchbauer et al., 1992). Other development of cardiovascular disease. Neurologic activity: Unlike diazepam, valerian did Nutricion Hospitalaria. 16(3):78–91. not affect spontaneous ambulation and rearing or Agurell, S., Halldin, M., Lindgren, J., Ohlsson, A., approach-avoidance conflict in mice in a water-lick Widman, M., Gillespie, H., Hollister, conflict test. On the other hand, valerian and L.1986. Pharmacokinetics and metabolism significantly inhibited immobility of delta-9-THC and other cannabinoids with induced by a forced swimming test in rats and emphasis on man. Pharmacol. Rev. 38: 21- significantly reversed reserpine-induced hypothermia 42. in mice, leading researchers to conclude that valerian Alarcón de la Lastra, C., Barranco, M.D., Motilva, V., may be a useful antidepressant (Sakamoto et al., Herrerías, J.M. 2001. Mediterranean diet and 1992). health: biological importance of olive oil. CurrentPharmaceuticalDesign, 7 (10): 933– In the annex (Table 1) shows studies conducted with 950. other essential oils of other plants not addressed in Alhebshi, A.H., Gotoh, M., Suzuki, I. 2013. this review. Thymoquinone protects cultured rat primary

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Table 1. Annex; a summary of studies based in other plants essential oils.

Essential oil Participants (diagnosis, n) Results References Significant anxiolytic effect at a dose that does not affect Jasmine (Jasminum multiflorum) Murine Model Addae et al. (2017) motor co-ordination. Feverfew (Tanacetum parthenium) Murine Model Anxiolytic- and antidepressant-like effects. Cárdenas et al. (2017) Reduces depressive-like behavior and modulates Frankincense or Murine Model hippocampal BDNF and CRF expression of submissive Moussaieff et al. (2012) (species of Boswellia) animals Depression 35= Mild to moderate major In week 4, the extract showed a significant superiority Borage (Echium amoenum) Sayyah and Kamalinejad (2006) depressive disorder. over placebo in reducing depressive symptoms. These results confirmed the antidepressant-like effect of Roseroot (Rhodiola rosea) Hyperactivity Depression (murine model) rhodioloside, which might be primarily based on its up- Zhang et al. (2016) regulation of the monoaminergic system activity. Anxiety Hamilton rating scale for anxiety total scores decreased Ginkgo (Ginkgo biloba) Woelk et al. (2007) 107= anxiety disorder and anxious mood. after the treatment. Blue skullcap (Scutellaria Attenuated anxiety and tension on a numerical rating Healthy Wolfson and Hoffmann (2003) lateriflora) scale. Ginger (Zingiber officinale) Murine Model Anti-stress. Moon et al. (2017) Passionflower (Passiflora Significant reduction of anxiety in favor of the herb on a Surgery patients Movafegh et al. (2008) incarnata) numerical rating scale. Lemon (Citrus medica limonum) Palliative patients 10= control group Increase in respiration rate, heart rate and diastolic blood Goepfert et al. (2017) Lemon (Citrus limon) 15= conscious Patients pressure in all groups. 5= unconscious Murine model Anxiolytic activitity. Khan and Riaz (2015) The concentration of 2 mg of hop extract effectively Hops (Humulus lupulus) 15= animal models (coturnix coturnix) decreased nocturnal activity in the circadian activity Franco et al. (2012) rhythm. Objective effects on cognitive performance, as well as Mark Moss et al. Rosemary (Rosmarinus officinalis) Healthy Patients subjective effects on mood. (2009) Is a brain-active, with moderate triple reuptake inhibitory Oregano (Origanum vulgare) Murine model activity, and exhibits positive behavioural effects in Mechan et al. (2011) animal models. Myrtle (Myrtus communis) Murine Model The anxiolytic, myorelaxant and hypnotic effects. Hajiaghaee et al. (2016) Spikenard (Nardostachys Anti- schizophrenic. jatamansi) Murine Model Janardhanan et al. (2016) Grapefruit (Citrus paradise) Murine model Anxiolytic and antidepressant activitity. Mallick and Khan (2016) Pinus (Pinus pinaster) Murine model Ameliorates depression-like behavior. Mei et al. (2014) Orange (Citrus sinensis) Patients waiting for dental treatment. Helpful in reducing anxiety. Lehrner et al. (2005)

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Table 1. Continuation

Essential oil Participants (diagnosis, n) Results References Roman chamomile (Chamaemelum Alteration of depressive- like behavior Antidepressant effect. Yingying KOng et al. (2017) nobile) WKY rats (genetic depressive model) Sandalwood (Santalum Murine model Sedative effect but not anxiolytic-like activity. Tadaaki et al. (2015) paniculatum) Bitter Orange (Citrus aurantium) Murine model Improve anxiety and obsessive-compulsive disorder. Moraes Pultrini et al. (2006) Influence of binasal and uninasal The binasal inhalation of Abis koreana increases the Korean fir (Abies koreana) inhalations in EEG activity in humans relaxation and the uninasal increases the alertness and Min Seo et al. (2016) (n=20) attention state of human brain. Both acute and chronic ylang-ylang essential oil Ylang-Ylang (Cananga odorata) Murine model Zhang et al. (2016) exposure showed anxiolytic effect on the mice. Tuberose or Azucena (Polianthes tuberosa) Anxiety among students (n=54) Effective in reducing test anxiety among students. Fereshteh et al. (2016)

Basil (Ocimum basilicum) Murine model of depression. Antidepressant-like effect. Ali et al. (2017) Angelica (Angelica sylvestris) Murine model Anxiolytic-like effect. Si et al. (2004) Indian cassia (Cinnamomum Murine model Anxiolytic, antidepressant, and antistress activitity. Upadhyay et al. (2016) tamala) Coriander (Coriandrum sativum) Murine Model of anxiety Anti-anxiety activity. Mahendra and Bisht (2011) Mugwort (Artemisia indica) Murine Model Anxiolytic and Antidepressant Activities. Khan et al. (2016) Japanese Spicebush Murine model Antidepressant-Like Effects. Lim et al. (2016) (Lindera obtusiloba) The results confirm previous observations of the Healthy young participants. (n=30). cholinesterase inhibiting properties of S. officinalis, and Sage (Salvia officinalis) Double-blind, placebo-controlled, improved mood and cognitive performance following the Kennedy et al. (2006) crossover study. administration of single doses to healthy young participants. Anxiolytic properties of Vetiver essential oil might be Vetiver Anxiety-related behavioural murine associated with altering neuronal activation in central Saiyudthon et al. (2015) (Chrysopogon zizanioides) Model. amygdaloid nucleus. Postmenopausal women (n=90) Triple- Reduce menopausal symptoms. Rahimikian et al. (2017) Fennel (Foeniculum vulgare) blind, placebo-controlled trial. Murine Anxiolytic properties. Mesfin et al. (2014) model

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