Mood disorders are affective mental disorders characterized by significant and persistent changes in emotion or state of mind (Marvel and Paradiso, 2004; Hasler, 2020). They can originate from psychological disorders, organic damage, nerve injury, side effects of medications used to treat physical or mental disorders, and chronic stress (Jorge and Arciniegas, 2014; Sanacora et al., 2022). The COVID-19 pandemic has severely aggravated the occurrence of mental illness and contributed significantly to the global increase in the prevalence of morbidity and disability (Vigo et al., 2016; COVID-19 Mental Disorders Collaborators, 2021). Studies on the global disease burden have revealed the severity of this ailment (Yun et al., 2016; Feigin et al., 2019). The pathogenesis of which are related to gene-environment interactions. In addition, they are multifactorial illnesses triggered by particular environmental variables in genetically vulnerable people, which can impact their capacity to relate to others and function (Cenit et al., 2017; Briguglio et al., 2020). Severe mood disorders could have serious negative consequences extending to family members (Fekadu et al., 2021). Moreover, the International Classification of Diseases (ICD-11) published by the World Health Organization (WHO) reveals that mental disorders include diseases of depression, bipolar illness, anxiety (e.g., panic attacks and phobias), mood-related sleep disorders, and other mood disorders (e.g., compulsive overeating) and conditions associated with post-traumatic stress disorder and more (Krawczyk and Święcicki, 2020). In most cases, mild symptoms can be relieved with a combination of medications and psychotherapy.

It has long been speculated that some essential oils derived from natural aromatic plants can help improve sleep quality and mood disorders by inhalation (Ko et al., 2021). In the early 20th century, aromatherapy was first defined as a medical treatment by a French chemist, René-Maurice Gattefossé (Koyama and Heinbockel, 2020). In 1975, Pierre Franchomme, a pharmacologist and aromatologist, proposed the concept of the “chemotype,” the true chemical identity of a plant, and listed the critical aromatic compounds that characterize each plant and their influence on its properties—made breakthroughs in aromatherapy. In recent years, use of natural aromatherapy as adjuvant therapy for mental disorders, especially anxiety and depression has increased steadily, and increasing research is being done on the treatment mechanism (Lizarraga-Valderrama, 2021). And furthermore, it has been proven to produce pharmacological effects via the use of high-quality essential oils entering the body by the nasal inhalation (through the respiratory system or olfactory nerves), through topical absorption (skin), or through oral administration (digestive system) (Martinec, 2012; Gnatta et al., 2016; Acimovic, 2021). It is important to note that systemic administration of essential oils via intraperitoneal injection is often used in animal studies. The results of an animal experiment showed that systemic administration of essential oils induced antioxidant, anti-inflammatory, and γ-aminobutyric acid (GABA) changes to alleviate anxiety-like behavior in rats (Cui et al., 2020). Essential oils used in aromatherapy are hydrophobic liquids containing volatile aromatic molecules extracted in concentrated form from herbs, flowers, and other plant parts (Wang and Heinbockel, 2018). Researchers have analyzed the physiological effects of volatile aromatic molecules from pharmacological and aromatherapy perspectives and suggested that aromatherapy be a natural therapy for patients suffering from anxiety or depression (Tsang and Ho, 2010; Saiyudthong and Marsden, 2011; Amsterdam et al., 2012). Specifically, a significant reason for aromatherapy’s effectiveness in treating mood disorders is the presence of desirable chemical components and biological activities in essential oils such as limonene, linalool, linalyl acetate, geraniol, citronellol, and more. These chemicals have been extensively studied and have shown anxiolytic and antidepressant properties (Setzer, 2009; Vieira et al., 2018; Zhang and Yao, 2019; Agatonovic-Kustrin et al., 2020; Soares et al., 2021).

Inhalation aromatherapy via brain-targeted nasal delivery is one of the most common methods of administration in trials of aromatherapy and has evolved from the inhalation of essential oils, in which simple inhalation benefits the emotional wellbeing, tranquility, relaxation, or renewal of the human body (Ali et al., 2015). In clinical applications, transnasal inhalation of essential oils can be used nasal inhaler, vapor diffuser, spraying into the air, vapor balms, or direct inhalation by evaporation using tissue or cotton round (Acimovic, 2021). Notably, inhalation of essential oils or aromatic plant volatile oils can send signals directly to the olfactory system and trigger the brain to produce neurotransmitters e.g., serotonin [5-hydroxytryptamine (5-HT) and dopamine], influence the neuroendocrinological system, neurophysiological brain activity, sympathetic and parasympathetic nervous system, biomarkers changes, psychological and behaviour effects, and to modulate mental disorders further (Masago et al., 2000; Hongratanaworakit, 2004; Lahlou, 2004; Watanuki and Kim, 2005; Strous and Shoenfeld, 2006; Tanida et al., 2008; MPham et al., 2012; Lv et al., 2013; Angelucci et al., 2014). From this, it can be seen that inhalation aromatherapy on mental disorders is due to the pharmacological effect caused by systemic absorption or act on the nervous system, but not only due to the psychological perception of the scent (Scuteri et al., 2019). A potential mechanism for the effects of inhalation aromatherapy on brain function is the activation of nasal olfactory chemoreceptors and subsequent olfactory signaling. Olfaction is not only the oldest and the most vital sense for survival, it is also the only one unaffected by psychological processes (Cook and Lynch, 2008; Schneider et al., 2018; Cha et al., 2021). In humans, ∼300 genes are dedicated to detecting thousands of distinct scent molecules through a vast family of olfactory receptors (Sowndhararajan and Kim, 2016). In recent years, the mechanism of inhaled essential oils delivered to brain targets is being intensively studied. According to neurobiological studies, the olfactory nerve links the olfactory system to the central nervous system, which allows odor information processing. Moreover, higher-order (prefrontal) processes mediate the “smell experience.” If odor molecules contact the nasal mucosa, first-order neurons transmit the odor-evoked response to the olfactory bulb (Schneider et al., 2018). The olfactory tract is a complex system comprising sensory axons and second-order dendrites (mitral and tufted cells) located in the olfactory sulcus of the basal forebrain, and conveys information to several locations within the frontal and dorsomedial lobes (Nagayama et al., 2014; Smith and Bhatnagar, 2019). Olfactory perception starts with the binding of odorant molecules with suitable receptor proteins, and terminates in higher cerebral cortex, making us consciously aware of an odor. Odorous compounds can elicit chemo-electrical transduction pathways to modulate the excitability of the sensory neurons through converting the chemical stimulus into electrical impulses (Buck and Axel, 1991; Breer, 2003). Following that, olfactory sensory neurons convey electrical impulses to the limbic and hypothalamic regions of the brain through the olfactory bulb and upper olfactory cortex. These projections together comprise the primary olfactory cortex. Then, these olfactory areas produce higher-order projections to the orbital prefrontal cortex, amygdala, hypothalamus, basal ganglia, and hippocampus (Figure 1) (Angelucci et al., 2014; Lie et al., 2021). Another potential mechanism is that the essential oil molecules inhaled via steam enter the blood circulation by the alveoli of the respiratory system, and subsequently small lipophilic molecules easily cross the blood-brain barrier (BBB) to affect the brain (Faturi et al., 2010; Selvaraj et al., 2017). However, whether this pathway of nasal/respiratory system/circulation system/brain produces pharmacological effects is highly dependent on the drug properties, dose and concentration of the administration (Illum, 2003). In recent years, based on the limitations of dosages and amount of activity in inhalation administration, researchers have focused on the use of nanocarrier technology for transnasal targeting of drugs to the brain to improve drug utilization.

This review summarizes the aromatic oils that may be used to treat mood disorders, assesses the efficacy of inhaled aromatherapy in treating anxiety, depression and sleep disorders (Table 1), and delves into their mechanism of action. In addition, we discuss recent data on the impact of inhalation aromatherapy on the brain and the pathways involved (Figure 1). Further, we summarized animal and clinical data and analyzed transnasal brain-targeted inhaled aromatherapy in anxiety, depression, and sleep disorders. Inhalation aromatherapy holds promise for preventing or treating mood disorders, but additional study is required to grasp the fundamental mechanisms involved. We argue for further clinical and scientific studies on inhalation aromatherapy to treat mental disorders, especially anxiety, depression, sleep disorders.

The essential oils used for aromatherapy have been extracted from aromatic plants and herbs to treat various ailments for centuries. About 17,500 plants have an aromatic scent (Tu et al., 2020). Because of their specific pharmacological functions, essential oils can be used in various ways to stimulate specific physiological responses for symptom relief. For instance, some scents (e.g., Mentha × piperita L. peppermint oil) can change the endogenous opioid pathways of the brain to alleviate pain and anxiety (Zarzo, 2007; Angelucci et al., 2014). Moreover, aromatic herbal preparations have long been a mainstay for treating anxiety and depression. Volatile oils are active chemicals derived from aromatic herbal remedies that often possess a broad spectrum of biological actions (Wang et al., 2014). Recent research indicates that the chemically active components in essential oils or volatile oils have neuroprotective effects, which may help alleviate depression and anxiety symptoms. Table 1 summarizes the properties of aromatic herbs or essential oils for the treatment of mood disorders.

Anxiety disorders are the most frequent mental ailment, with a global prevalence ranging between 2.4 and 20% per nation. According to the WHO, 3.6% of the world’s population—around 264 million people—suffer from anxiety (Baxter et al., 2013; Bandelow and Michaelis, 2015; Munir and Takov, 2021). It is a type of dread that emerges in response to potentially dangerous or stressful events, and results from a complex interaction of biological factors, as well as psychological, temperamental, and environmental elements (Thibaut, 2017).

Anxiety disorders include (but are not limited to) panic disorder/agoraphobia (PDA), GAD, social anxiety disorder (SAD), and obsessive-compulsive disorder (OCD) (Giacobbe and Flint, 2018). Panic disorder (with or without agoraphobia) is the most common, accounting for 6.0% of all types, followed by social phobia (2.7%) and GAD as the most common phobias (2.2%) (Craske et al., 2017). Each subcategory of anxiety disorders has its own set of symptoms and diagnostic criteria, but ICD-11 identifies the common symptoms apprehension, motor overactivity, and autonomic overactivity (Reed et al., 2019). Several biological anomalies have been implicated in the pathophysiology of anxiety disorders. The gamma-aminobutyric acid (GABA), norepinephrine, and 5-HT systems have critical roles in modulating the emotional circuitry that underlies anxiety and depression, which are closely connected (Romana et al., 2020).

For anxiety disorders, various treatment options, such as medication and psychotherapy, are available. These treatments may exert their advantages by top-down or bottom-up regulation of abnormal brain activity, respectively (Bandelow et al., 2017; Giacobbe and Flint, 2018). Mild anxiety disorder, in general, does not require excessive treatment, but treatment is indicated if patients manifest significant discomfort or experience disorder-related consequences. For example, subsequent depression, suicidal thoughts, or alcohol misuse are possible outcomes (Bandelow et al., 2017). First-line therapies for anxiety include lifestyle modifications, cognitive behavioral therapy, selective serotonin reuptake inhibitors (SSRIs), or serotonin-norepinephrine reuptake inhibitors (SNRIs) (Bandelow et al., 2015; Mangolini et al., 2019; Garakani et al., 2020). Since the 1980s, researchers have conducted upwards of 10,000 animal studies of nearly 1,500 medications for anxiety, and the number of such studies has shown a marked increase in recent years. However, many studies have not yielded satisfactory results. In many cases, severe adverse drug reactions, dependence, and poor treatment outcomes have persisted (Griebel and Holmes, 2013). There is an immediate need for safe and efficacious treatments and medications for anxiety. The number of studies on inhalation aromatherapy for anxiety disorders has been increasing recently. In general, chamomile, lavender, bergamot, clary sage, rosemary, ylang-ylang, frankincense, and damask rose are used commonly as “anti-anxiety oils.” Essential oils to treat anxiety have been used throughout Europe for many years (Seol et al., 2010). Also, the chemical and biological properties of essential oils have resulted in the development of crucial treatment strategies for anxiety disorders (Fernandes et al., 2021). Essential oils have fewer side effects and more administration methods than traditional anti-anxiety medications. Among them, inhalation has been the most common method of administration in trials of aromatherapy, and the most efficacious (Zhang and Yao, 2019).

Among anxiety-related research items, the lavender essential oil has received the most attention. Franco and others evaluated the reduced anxiety effect of lavender aroma on women before breast surgery. Inhalation of lavender-fragrance aromatherapy treatments reduced anxiety before surgery (Franco et al., 2016). A randomized, double-blind, placebo-controlled clinical study by Farshbaf-Khalili and others focused on anxiety in postmenopausal women. They compared the effects of inhaling oils of lavender or bitter-orange, and found them to have a beneficial impact on anxiety in this population (Farshbaf-Khalili et al., 2018). A randomized controlled study investigating the effect of lavender-oil inhalation on vital signs and anxiety revealed that inhalation aromatherapy was favorable for anxious individuals about to undergo surgical procedures under local anesthesia (Karan, 2019). Guo and others analyzed the efficacy of inhalation aromatherapy on preoperative anxiety. They discovered evidence to support using aromatherapy to alleviate preoperative anxiety in adults. Their results suggested that aromatherapy inhalation was the most practical and feasible mode of administration, and had the advantage of a short duration of administration (20 min for each session). Hence, recent research suggests that lavender oil, preparations of citrus species, and rose oil are the most common and efficacious fragrance preparations for anxiety disorders (Guo et al., 2020). With regard to using essential oils to treat anxiety, initially researchers examined the direct effects of scent on the brain through EEG and functional imaging. They found that the essential oils of rose, lavender, lemon, and peppermint had anti-anxiety effects, and more in-depth research has been conducted in recent years (Lehrner et al., 2005; Bradley et al., 2007; Zhang et al., 2013). Inhaled aromatherapy could reduce preoperative anxiety, but data from primary studies are needed to improve evidence quality (Men et al., 2021).

Animal experiments have shown that inhalation of essential oils can prevent or relieve anxiety symptoms. These beneficial effects may result from modulation of monoamine levels, induction of neurotrophic factors expression, regulation of the endocrine system, and promotion of neurogenesis (Fung et al., 2021). However, an animal experiment has shown that olfactory deficit induced by zinc (zinc gluconate + zinc acetate) did not impair the anxiolytic effects of lavender essential oil inhalation in the marble-burying test. This study demonstrated that the active compounds of lavender oil might enter the systemic circulation and central nervous system through the respiratory system in the absence of olfaction, ultimately activating the relevant receptors to improve anxiety symptoms (Chioca et al., 2013). In future studies, researchers can evaluate the importance of the olfactory system through pharmacological and physiological alterations induced by inhaled essential oils in olfactory impairment animal models. In another animal study, the authors reported that the sedative effect of inhaling a lavender-Roman chamomile oil mixture was impaired by reduced olfactory function (Kagawa et al., 2003). It can be concluded that the olfactory system has an essential role in inhalation aromatherapy, and olfactory impairment on the effects of inhalation is also related to the different types and active ingredients of the essential oils. We can synthesize that the mechanism of transnasal inhalation of essential oils in psychiatric disorders is a function of multiple factors. Researchers should undertake more rigorous animal studies to gain more insight into the mechanisms of inhalation aromatherapy.

Depression is a prevalent mental illness and “mood illness” that manifests via a mix of emotional (sadness and anhedonia), cognitive (thinking problems and inability to focus), and somatic symptoms (changes in appetite and insomnia). Approximately 280 million people worldwide suffer from depression. The incidence of depression varies significantly according to geographic location, and depression may increase dramatically in the next decade (Wang, 2021). It is characterized by the profound emotions of melancholy, hopelessness, despair, and an inability to find pleasure in routine activities, as well as changes in sleep and food habits, fatigue, and suicidal thoughts (Sánchez-Vidaña et al., 2019).

Mainstream interventions for depression have relied primarily on medication, such as antidepressants, which may have unacceptable side effects, such as headache, insomnia, nausea, potential drug interactions, or the danger of overdose (Bauer, 2007). Antidepressant medicines may be used as first-line therapy for depressive disorder and are classified into several types. The antidepressants used most often are SSRIs, SNRIs, TCAs, and monoamine oxidase inhibitors (Ramachandraih et al., 2011; Hillhouse and Porter, 2015; Kok and Reynolds, 2017; Zanos and Gould, 2018; InformedHealth.org, 2021). The American College of Physicians advises that practitioners treat individuals with major depressive disorder using cognitive behavioral therapy or second-generation antidepressants (Qaseem et al., 2016). However, ∼30% of persons who use SSRIs for depression experience no response. In addition, the first-line drugs used to treat depression (SSRIs) often have severe side-effects, which stops patients taking them or to lose confidence in treatment. As a result, many people suffering from depression do not achieve remission of symptoms and have to endure relapses and more functional impairment (Adell et al., 2005; Arroll et al., 2005). This phenomenon has pushed patients and researchers to seek more efficacious alternative medicines, particularly in the early phase of treatment. Due to the limitations of those traditional methods and antidepressants, there is a growing interest in using aromatic naturopathy as an alternative therapy. As a complementary approach, inhalation aromatherapy is used widely for treating depression (Koo, 2017; Liang et al., 2021). Numerous studies have indicated that some of the critical constituents of essential oils may reduce depressive symptoms markedly via nasal–brain pathways, including those in patients with severe depressive disorder, postpartum women, postmenopausal women, and cancer patients (Chan et al., 2015; Han et al., 2017). In addition, the researchers discovered that citrus scents containing 95% citral were often more appealing and pleasant to people who felt sad (Pause et al., 2001). Inhalation of aromatic molecules through the nose is mild and has few adverse effects, which makes it an attractive option for treating depression (Yim et al., 2009; Lv et al., 2013). And they work more quickly than other methods because the blood-brain barrier does not interfere with the effects. In this way, aromatherapy looks to be a straightforward, cost-effective, and low-risk adjuvant approach for treating depression (Sánchez-Vidaña et al., 2017).

The use of animal models has enabled elucidation of different molecular pathways for treating depression by essential oils, such as the hypothalamic-pituitary-adrenal axis, sympathetic nervous system, cyclic adenosine monophosphate response element-binding protein signaling pathway, and neurotransmitter systems (e.g., serotonergic, dopaminergic, and GABAergic pathways) (Guillemain et al., 1989; Tafet et al., 2001; Raison et al., 2006; Chung et al., 2011; Slavich and Irwin, 2014; Chen et al., 2016; Xiong et al., 2018). de Sousa and others used a rodent model of depression and demonstrated the antidepressant activity of the essential oils of several plants: Acorus tatarinowii Schott, Asarum heterotropoides F. Schmidt, Litsea glaucescens Kunth, Mentha × Piperita L, Citrus limon (L.) Osbeck, Eugenia uniflora L, Lavandula angustifolia Mill, Perilla frutescens (L.) Britton, Salvia sclarea L, Rosmarinus officinalis L, Schinus terebinthifolius Raddi, and Syzygium aromaticum (L.) (de Sousa et al., 2017). A behavioral experiment in a rat model of depression using the FST examined the antidepressant effects of the essential oils of chamomile (A. nobilis), clary (Salvia sclarea), rosemary (Rosmarinus officinalis), and lavender (L. angustifolia) in rats. They showed that these oils improved depressive-like behavioral effectively (Seol et al., 2010). In addition, Bagci and others investigated the positive effects of the scopolamine component of Anthriscus nemorosa essential oil on memory, anxiety, and depression in rats: their behavior improved (Bagci et al., 2016). Notably, one animal study revealed that lemon oil increased the metabolic turnover of 5-HT markedly in the prefrontal cortex and striatum to enhance 5-HT function, which demonstrated a mechanism of action comparable with that of SSRIs (Komiya et al., 2006; Cowen, 2008). Although various animal studies on the treatment of depression with inhaled essential oils, more sophisticated experiments should be designed to investigate the pharmacological effects.

Sleep is vital for sustaining physiological and psychological welfare (Karadag et al., 2017). Numerous mental disorders and sleep disorders show a bidirectional relationship. Patients suffering from anxiety, depression, and other mood disorders have persistent difficulties obtaining a decent night’s sleep. Sleep disturbances can contribute to the risk of mental-health illnesses (Santamaria and Iranzo, 2014; Freeman et al., 2020; Momen et al., 2020). In addition, many antipsychotic agents affect sleep and sleep architecture. Even though sedative-hypnotics may enhance sleep quality significantly, these medications have adverse effects, are addictive, and do not lead to sufficient sleep (Pagel and Parnes, 2001; Hajibagheri et al., 2014). Hence, the application of a less harmful relief method with fewer adverse effects is significant (Hajibagheri et al., 2014; Jodaki et al., 2021).

From ancient times, aromatherapy has been an effective natural therapy for sleep problems, through massage and inhalation using essential oils are the main strategies (Bikmoradi et al., 2015; Guadagna et al., 2020; Mahdavikian et al., 2020). Numerous essential oils have been used to treat sleep difficulties, including lavender oils and peppermint oils (Blackburn et al., 2017; Salamati et al., 2017; Mahdavikian et al., 2020; Malloggi et al., 2021). Research has shown that bergamot oil can reduce blood pressure and the heart rate and aid sleep. Moreover, jasmine and frankincense have been shown to aid restless sleep and improve sleep quality. Takeda and co-workers explored the benefits of inhalation aromatherapy on sleep disturbances in elderly dementia patients by placing essential oils on towels wrapped around their pillows each night. They measured sleep latency, total sleep time, sleep effectiveness, duration of the most extended sustained sleep phase, waking time after sleep onset, early-morning awakening, total daytime sleep, and assessed the Neuropsychiatric Inventory. Inhalation aromatherapy had a beneficial impact on sleep-disruption symptoms in that population (Takeda et al., 2017). Moreover, aromatherapy using the oils of sweet-orange and lavender have been suggested to improve sleep quality and reduce tiredness in hemodialysis patients (Muz and Taşcı, 2017). Another comprehensive study and meta-analysis determined that aromatherapy significantly improved sleep quality and was quick-acting, simple to apply, and did not require additional equipment (Hwang and Shin, 2015). Recently, Zhong and others investigated the compatibility of using the essential oils of Compound Anshen with those of lavender, sweet orange, and sandalwood with sedative and hypnotic properties. They demonstrated improved sleep quality by combining essential oils and blends. Overall, aromatherapy has improved sleep quality in healthy and unwell people, especially if used as inhalation rather than massage treatment (Hwang and Shin, 2015; Zhong et al., 2019). The molecules in essential oils entering the limbic system of the brain through the nasal passages simultaneously affect GABA receptors in the hypothalamus, which are crucial for maintaining sleep. Hence, aromatherapy is quite popular and used commonly to manage sleep quality (Tang et al., 2021).

In summary, inhalation aromatherapy via brain-targeted nasal delivery can be an effective option for improving depression, anxiety, and sleep disorders. When used in inhalation aromatherapy, the advantages of essential oils are high permeability, fast metabolism, non-retention, and low toxicity. Since essential oils are bioactive molecules and have a molecular weight of less than 300 Da (Dhifi et al., 2016), considered safe and biocompatible with a great range of therapeutic applications due to their heterogeneous composition of fatty acids, terpenes, triterpenes, and many other lipophilic components. In addition, a few minutes of inhalation of essential oils via the nose can affect the limbic system, and all leave the body by urination, excretion, breathing, and pores in 4–20 h after use (Barradas and de Holanda e Silva, 2021). Notably, the active chemical components of the essential oils or volatile oils used in aromatherapy have fewer side effects than traditional medications for treating mental disorders, but the safety and purity of oils must be considered. Under the supervision of a physician, essential oils of assured quality and demonstrated efficacy should be selected to improve depression or anxiety symptoms. Although the use of volatile essential oils for transnasal administration is common in aromatherapy, inhalation of concentrated forms of essential oils may pose a risk of eye and skin irritation, so direct inhalation of pure essential oils is not recommended. There is an urgent need to clarify the safe dose of inhaled essential oils in clinical applications. One research described a series of methods to assess the efficacy of inhaled essential oils, and clarified that EOs intake dose-relationships with the efficacy of brain function. In general, the inhalation of EOs indicated a dose-dependent relationship with efficacy (Aponso et al., 2020).

Taken together, those data suggest that inhalation aromatherapy may have a more excellent therapeutic range than thought previously, especially in the domain of mental diseases (Perry and Perry, 2006; Ayaz et al., 2017). In the future, more universities, research centers, and medical institutions should conduct qualitative and quantitative analyses of aromatic drugs and extract their components. Also, more multicenter, large-sample, high-quality randomized controlled trials on inhaled aromatherapy for mood disorders are needed. In particular, the use of doses and treatment protocols need to be optimized. We hope that transnasal aromatherapy will lead to further breakthroughs on research into mood disorders.