Medicinal Plants for Insomnia Related to Anxiety: An Updated Review^{[ # ]}

Abstract

Sleep disorders are common among the general population and can generate health problems such as insomnia and anxiety. In addition to standard drugs and psychological interventions, there are different complementary plant-based therapies used to treat insomnia and anxiety. This review aimed to find and examine the most recent research on the use of herbal medicines for treating anxiety and insomnia as compiled from clinical trials, as well as to assess the safety and efficacy of these medicines and to elucidate their possible mechanisms of action. The process entailed a search of PubMed, Scopus, and the Cochrane Library databases from 2010 to 2020. The search terms included “sleep disorder”, “insomnia”, “sedative”, “hypnotic”, “anxiety”, “anxiolytic”, and “clinical trial”, combined with the search terms “herbs” and “medicinal plants”, in addition to individual herbal medicines by both their common and scientific names. This updated review, which focuses mainly on clinical trials, includes research on 23 medicinal plants and their combinations. Essential oils and their associations have also been reviewed. The efficacy of medicinal plants depends on treatment duration, types of study subjects, administration route, and treatment method. More clinical trials with an adequate, standardized design are necessary, as are more preclinical studies to continue studying the mechanisms of action. As a result of our work, we can conclude that the 3 plants with the most potential are valerian, passionflower, and ashwagandha, with the combination of valerian with hops and passionflower giving the best results in the clinical tests.

Key words

medicinal plants - essential oils - sleep disorders - insomnia - anxiety - clinical trials

Abbreviations

5-HT: 5-hydroxytriptamine, serotonin

ACh: acetylcholine

AChE: acetylcholinesterase

BDNI: brain-derived neurotrophic factor

CNS: central nervous system

DA: dopamine

EPM: elevated plus maze

GABA: gamma-aminobutyric acid

GAD: generalized anxiety disorder

i. p.: intraperitoneally

i. v.: intravenous

ICSD: International Classification of Sleep Disorders

ISI: Insomnia Severity Index

NA: noradrenaline

NREM: nonrapid eye movement sleep

p. o.: per os, orally

PSQI: Pittsburgh Sleep Quality Index

REM: rapid eye movement sleep
 

Introduction

Sleeping is necessary for life, like eating or breathing, and can be described as a reversible state that is easily affected both by the physical environment (even though it does not interact with it) and by age [1]. Different mediators are implicated in the physiology of sleep. Of these, NA, histamine, DA, glutamate, and GABA play a relevant role in the process, but other neurotransmitters are also implicated, such as orexins A and B, adenosine, glycine, ACh, serotonin (5-HT), and melatonin [1], [2], [3], [4], [5], [6]. NA is synthesized in different regions of the brain, one of which is the locus coeruleus, where it is produced during wakefulness as well as during the sleep cycle; interestingly NA decreases partially in NREM sleep and is absent in REM sleep. In contrast, histamine, which is synthesized in the posterior area of the hypothalamus, specifically in the tuberomammillary nucleus, plays an important role in wakefulness and decreases during NREM sleep [2]. Glutamate, the most important stimulant in the CNS, is the third most relevant stimulant neurotransmitter implicated in wakefulness; its activity occurs after stimulation of the ionotropic and metabotropic receptors [3]. The orexins A and B are related to the maintenance of wakefulness; they are synthesized in the hypothalamus and also trigger other systems, such as the noradrenergic, dopaminergic, and histaminergic pathways [4].

Inhibitors of the neurotransmitter system include GABA, adenosine, and glycine. Of these, GABA is the most important because it exerts inhibitory control over both the monoaminergic systems and the orexin system during sleep [5]. The GABA system is implicated in a relevant series of neurophysiological events, including anxiety and sleep, with impairments in GABA modulations producing different neurological and psychological disorders, including insomnia and anxiety [6], [7]. In the case of adenosine, it induces NREM sleep when present in the preoptic area and hypothalamus, whereas glycine favors atonic over REM sleep. ACh plays an important role during REM sleep because anticholinergic activity increases in this phase. In contrast, 5-HT inhibits REM sleep; thus, when the brain stem nucleus is activated, REM sleep decreases [7]. The last neurotransmitter implicated is melatonin, which is released in the absence of light and is essential for sleep regulation and circadian rhythm [2].

Sleep Disorders and Insomnia

Sleep disorders are common in the population and can generate problems with both sleep quality and overall health [8]. The ICSD-3 classifies these problems into 7 categories: insomnia, sleep-related breathing disorders, central disorders of hypersomnolence, circadian rhythm sleep-wake disorders, sleep-related movement, parasomnias, and other sleep disorders. One of the most common disorders is insomnia, which is defined as “difficulty in falling asleep or maintaining the sleep state during the night” and affects a significant percentage of the general population [9]. The condition is considered chronic when insomnia occurs at least 3 times per week for at least 3 mo. This type of chronic insomnia is estimated to affect 5 – 10% of the population and is associated with numerous adverse effects on function, health, and quality of life. On the other hand, short-term insomnia manifests itself for less than 3 mo and affects a greater percentage of people–approximately 30% to 50% of the general population [10].

Relationship between Insomnia and Anxiety

Sleep disturbances, especially insomnia, are quite common in people suffering from anxiety, especially GAD, which is a persistent state of anxiety lasting for at least 6 mo and is often a consequence of different psychiatric disorders (e.g., depression or post-traumatic stress disorder). Patients with GAD commonly present with nonspecific somatic symptoms such as insomnia [11]. Based on the available scientific and medical evidence, the sleep disorders linked to mild-moderate GAD are maintenance sleep insomnia and, to a lesser degree, early sleep insomnia [12], [13]. GAD has a prevalence of 4 – 7% in the general population and is characterized by excessive worry and other physiological symptoms ranging from muscle tension to restlessness and insomnia [14]. Schanzer et al. described GAD as a disabling psychiatric condition encompassing several concurrent disorders, including social phobia, other specific phobias, panic disorder, and major depressive disorder. The pathophysiology of GAD is significantly affected by low levels of GABA and excitatory glutamate neurotransmission. GABA_A receptors are especially concentrated in the medial prefrontal cortex, the amygdala, and the hippocampus, all of which are involved in anxiety and fear responses [15]. Other authors have suggested that there is a bidirectional relationship between anxiety/depression and insomnia, with anxiety and depression being related to future insomnia and insomnia being related to future high anxiety and future high depression [11], [16]. In a recent study by Bragantini et al., difficulties initiating sleep were found to be related to increased anxiety levels [17].

Pharmacological Treatment of Insomnia

Treatment of chronic insomnia often involves prescription drugs such as benzodiazepines and hypnotics, but these have many adverse side effects such as dependency, headaches, nightmares, daytime fatigue, nausea, confusion, and a loss of balance resulting in falls [18]. Other pharmacological treatments such as antipsychotics and antidepressants likewise have significant adverse effects. Even so, they are commonly prescribed “off-label” for chronic insomnia, particularly in later life [19]. In addition, various nonpharmacological approaches are common, including cognitive-behavioral therapy. Having so many options allow people seeking treatment for insomnia to combine pharmacological and nonpharmacological therapies to achieve better sleep [10]. Treatment for GAD is similar; patients can use drugs such as benzodiazepines, antidepressants, and pregabalin (an anticonvulsant), but there are also effective psychological therapies such as behavioral therapy, relaxation response training, mindfulness meditation training, and cognitive behavioral therapy, which is the most studied and most commonly used [14].

Medicinal Plants in the Treatment of Insomnia

Although pharmacotherapies and psychological interventions are the main treatments for insomnia and sleep disorders, compounds employed in complementary, alternative, and folk medicine have also been used to treat these disorders, albeit mostly by herbalists and indigenous communities. Here it is important to distinguish between the different types of assessments used when discussing these compounds. Thus, for example, whereas traditional knowledge about the historical use of medicinal plants provides valuable insight into their effects, preclinical studies focus on the in vitro and in vivo (animals) effects to understand and modify the potential applications of these compounds for use in humans. In the case of clinical trials with medicinal plants and their extracts, such studies, along with reviews like this one, provide evidence about how these plants may be used as supplements in humans to induce and maintain sleep during the night [20], [21]. The results obtained to date indicate that the active principles of sedative medicinal plants generally have effects on the GABA system, but other mechanisms are also implicated, including the dopaminergic pathway [6], [22].

This review aimed to find and examine the most recent research on herbal medicines studied for their effects on anxiety and insomnia in human clinical trials, as well as to evaluate their safety and efficacy in treating these pathologies. The methodology involved a language-restricted (English) search of PubMed, Scopus, and the Cochrane Library databases from 2010 to 2020, but certain highlighted papers were also included, mainly preclinical studies. The review centers on clinical data for medicinal plants studied specifically for insomnia and anxiety. The search terms included “insomnia”, “sleep disorders”, “sleep”, “sedative”, “hypnotic”, “anxiety”, “anxiolytic”, and “clinical trial” combined with the search terms “herbs”, “plants”, and “medicinal plants”, in addition to both the common and scientific names of individual herbal medicines. Several preclinical studies were also included to clarify the mechanisms of action of some relevant species. To avoid repetition, the official botanical names [23] of all the plants that appear in this review, as well as the doses and types of tests used, have been included as tables. Thus, [Table 1] compiles all the protocols and tests used in the clinical trials cited in the text while Table 1S (Supporting Information) compiles all the protocols and tests used in the clinical trials cited in Tables 2S to 6S (Supporting Information). [Table 2] summarizes the species cited in this review, including the binomial botanical name, family, and common names, whereas Table 2S (Supporting Information) compiles the principal studies of sedative and anxiolytic-like plants in animals. Table 3S (Supporting Information) lists the principal clinical trials cited in the text, including all the experimental data. Table 4S (Supporting Information) shows the trials in which a mixture of plants was used and Table 5S (Supporting Information) summarizes the trials with only essential oils. Finally, Table 6S (Supporting Information) compiles the studies that included mixtures of essential oils.

Table 1 Rating scales and tests used for clinical studies and cited in this review.

BAI	Beck Anxiety Inventory
BDI	Beck Depression Inventory
Bf-S	Befindlichkeitsskala (sensitivity scale)
DISS	Defined Intensity Stressor Simulation
DSM	Diagnostic and Statistical Manual of Mental Disorders
HAM-A	Hamilton Anxiety Rating Scale
ICSD	International Classification of Sleep Disorders
ISI	Insomnia Severity Index
LSEQ	Leeds Sleep Evaluation Questionnaire
MENQOL	Menopause-Specific Quality of Life Questionnaire
PSQI	Pittsburgh Sleep Quality Index
PSS	Perceived Stress Scale
SMHSQ	St. Maryʼs Hospital Sleep Questionnaire
STAI	Spielberger State-Trait Anxiety Inventory
VAS	Visual Analogue Scale

Table 2 Species cited in the present review: botanical names, family [23], and common names.

Botanical name	Family	Common name
Aloysia polystachya (Griseb.) Moldenke	Verbenaceae	“Burrito”, “ka á jaguá”
Caralluma adscendens var. fimbriata (Wall.) Gravely & Mayur.	Apocynaceae	“Maakada singi”, “Mangana kodu”
Centella asiatica (L.) Urb.	Apiaceae	Gotu cola
Citrus × aurantium L.	Rutaceae	Bitter orange, Neroli oil
Citrus limon (L.) Osbeck	Rutaceae	Lemon
Citrus limon (L.) Osbeck (syn: Citrus × bergamia Risso & Poit.)	Rutaceae	Bergamot
Citrus sinensis (L.) Osbeck	Rutaceae	Sweet orange
Crataegus rhipidophylla Gand. (syn: C. oxyacantha L.)	Rosaceae	Hawthorn
Crocus sativus L.	Iridaceae	Saffron
Eschscholzia californica Cham.	Papaveraceae	California poppy
Eucalyptus globulus Labill.	Myrtaceae	Eucalyptus
Foeniculum vulgare Mill.	Apiaceae	Fennel
Galphimia glauca Cav.	Malpighiaceae	Goldshower, “calderona amarilla”
Glycine max (L.) Merr.	Leguminosae	Soya
Humulus lupulus L.	Cannabaceae	Hops
Lactuca sativa L.	Compositae	Lettuce
Lavandula angustifolia Mill.	Lamiaceae	Lavender
Lavandula dentata L.	Lamiaceae	French lavender
Lavandula × heterophylla Viv. (syn: Lavandula × hybrida Balb. ex Ging.)	Lamiaceae	Lavender (hybrida)
Lavandula × intermedia Emeric ex Loisel	Lamiaceae	Lavandin super
Lippia alba (Mill.) N. E.Br. ex Britton & P.Wilson	Verbenaceae	Bushy matgrass
Matricaria chamomilla L.	Compositae	Chamomile
Melaleuca alternifolia (Maiden & Betche) Cheel	Myrtaceae	Tea tree
Melissa officinalis L.	Lamiaceae	Lemon balm
Mentha × piperita L.	Lamiaceae	Peppermint
Nepeta menthoides Boiss. & Buhse	Lamiaceae	“Ostokhodus”
Passiflora edulis Sims (syn: Passiflora incarnata L.)	Passifloraceae	Passionflower
Petasites hybridus (L.) G.Gaertn., B.Mey., & Scherb.	Compositae	Butterbur
Piper methysticum G.Forst.	Piperaceae	Kava
Rosmarinus officinalis L.	Lamiaceae	Rosemary
Scutellaria baicalensis Georgi	Lamiaceae	Baikal skull
Scutellaria lateriflora L.	Lamiaceae	American skullcap
Sedum roseum (L.) Scop. (Syn: Rhodiola rosea L.)	Crassulaceae	Golden root
Valeriana officinalis L.	Caprifoliaceae	Valerian
Viola odorata L.	Violaceae	Wood violet or sweet violet
Withania somnifera (L.) Dunal	Solanaceae	Ashwagandha
Ziziphus jujuba var. spinosa (Bunge) Hu ex H. F.Chow	Rhamnaceae	Sour date
Species not declared: possible species used are listed
Botanical name of species was not cited	Geraniaceae	Geranium
Cananga odorata (Lam.) Hook.f. & Thomson or Cananga odorata var. fruticosa (Craib) J.Sinclair	Annonaceae	Ylang ylang
Cinnamomum verum J. Presl	Lauraceae	Cinnamon
Citrus paradisi Macfad.	Rutaceae	Grapefruit
Pelargonium hybrids	Geraniaceae	Rose-scented geranium

Relevant Species Used to Treat Insomnia

A limited number of species were tested for their sedative and anxiolytic effects in animals. While the results provide some insight into the plantsʼ active compounds and their potential mechanisms of action, they are inconclusive because some of the tests were carried out with isolated compounds and others with various extracts. Of these, valerian, passionflower, kava, goldshower, ashwagandha, and lemon balm gave the best results, as compiled in Table 2S (Supporting Information). In the following paragraphs, medicinal plants are classified according to the relevance of the preclinical and clinical studies performed with them; we then discuss the species cited for their clinical studies only.

Valeriana officinalis

Valerian is probably the species that has been studied the most for its effects on different types of nervous alterations, especially insomnia and anxiety [24]. Previous in vivo studies have established the plantʼs anxiolytic and antidepressant activities in both mice and rats but not its sedative or myorelaxant properties [25]. Researchers have also elucidated specific pharmacological activities for different compounds from the plant, including the synergistic interactions of different valepotriates [26], along with the allosteric modulation of GABA_A receptors (but not of its analogs and derivatives) by valerenic acid [27] ([Fig. 1]). This latter compound is also responsible for the increase observed in BDNF levels in vitro [28]. These results indicate that valerenic acid could be considered the principal active compound of valerian.

Fig. 1 Chemical structure of active component of valerian (valerenic acid), kava (kavain), and goldshower (galphimine A and galphimine B).

Different clinical studies have demonstrated the positive effects of valerian on both the sleep structure and sleep perception of insomnia patients, making this a compound of interest for treating patients with mild psychophysiological insomnia. Indeed, Donath et al. [29] analyzed its effects on this disorder using both objective and subjective sleep parameters and found that only patients who had received multiple doses showed a significant increase in sleep. In another clinical trial with patients with nonorganic insomnia, Ziegler et al. demonstrated a similar effect when patients received valerian or oxazepam [30]. Other studies did not obtain positive results with similar doses, but these were conducted on a reduced number of patients [31], [32]. In a controlled trial with menopausal women, Taavoni et al. found that valerian had a positive effect on sleep quality in comparison to a placebo [33], but Barton et al. observed no significant improvement in sleep [34]. In patients with obsessive-compulsive disorders, valerian significantly ameliorated anxiety and various other psychiatric symptoms including insomnia, but the effects were not significantly greater than those of the placebo [35]. Another clinical trial evaluated the activity of valerian in patients of both genders, with the results unequivocally demonstrating the remarkable effects of valerian in providing patients with the necessary comfort and relaxation without sedation and with less somnolence than midazolam, which was used as a reference drug [36]. Taking the results of all these clinical trials together, it seems clear that valerian has an anxiolytic effect and, as a consequence, improves both the quality and time of sleep, although more studies are needed before this plant can be recommended in a clinical setting.

Passiflora edulis

The aerial parts of passionflower are widely used to treat sleep disorders and anxiety [37]. Preclinical studies confirmed the anxiolytic and sedative properties in both mice [38], [39] and rats [40]. In the first case, in which the EPM test was used, researchers proposed an anxiolytic-like effect through a GABA_A/benzodiazepine receptor antagonist rather than a specific 5-HT_1A-antagonist, concluding that passionflower activity in mice may be due to a GABAergic mechanism rather than a serotonergic effect [39]. The same test in rats demonstrated a significant increase in slow-wave sleep and a reduction of REM sleep, along with a decrease in the total time spent in wakefulness [40].

Different clinical trials have confirmed the anxiolytic and sedative effects of passionflower. For example, Akhondzadeh et al. evaluated the efficacy of passionflower in the treatment of GAD, demonstrating that passionflower was indeed an effective treatment therapy [41]. In another study, the results were not significant for anxiety, probably because the dosage was inferior to the adequate dose, but they were positive for sleep quality [42]. In contrast, another trial with pre-operatory patients showed that subjects who took passionflower had a reduction in anxiety levels but experienced no sedation effects [43]. In the case of patients undergoing dental extraction, passionflower had a similar effect to midazolam as an anxiolytic [44]. In the specific case of sleep disorders, Lee et al. demonstrated the positive effects of passionflower on objective sleep parameters in adults with insomnia, with improvements in both sleep efficiency and waking after sleep onset [45]. Although the dosages varied in these studies, making comparisons difficult, it seems that passionflower could be useful for treating both anxiety and sleep disorders.

Piper methysticum

Kava is used for treating anxiety, stress, and insomnia and in elevated doses also has anesthetic and hypnotic properties [46], [47]. The preclinical assays reviewed here were carried out principally with kavain ([Fig. 1]), which, when tested for its effects on the GABAergic system, was found to improve GABA_A activity. Moreover, the combination of kavain and diazepam produced an even greater enhancement of GABA activity compared to their actions alone [48]. Shinomiya et al. demonstrated that kava improves delta activity during sleep at stages 2 – 3 and 3 – 4 [49], while Tsutsui et al. confirmed the hypnotic effect of kavain, finding that, compared to rilmazafone and diphenhydramine, it enhanced sleep quality in sleep-disturbed rats during the sleep-wake cycle. The combination of kavain and rilmazafone reduced sleep latency and awake time and increased NREM sleep time; in contrast, when combined with diphenhydramine, it affected sleep latency but not awake time or NREM sleep [50].

Clinical studies have further demonstrated kavaʼs potential for treating anxiety and sleep disorders in humans. Lehrl, for example, studied the effect of kava on sleep disorders in patients with anxiety, measuring the results with various scales such as the HAM-A, the Bf-S (a self-rated scale of well-being), and the CGI scale. In the first 2, the authors observed a reduction in psychic anxiety and an increase in general well-being [51]. Sarris et al. demonstrated a decrease in the anxiety levels of patients with GAD, above all in participants with high-level anxiety according to the DSM. The results, as measured with HAM-A, showed that the effect in the kava group was associated with GABA transporter polymorphisms [52]. Kutcha et al. likewise demonstrated the efficacy of kava in the treatment of anxiety as measured with HAM-A on volunteers with anxiety disorders, observing a significant enhancement in the high-dose group compared with the low-dose group [53]. Unfortunately, Sarris et al. were unable to confirm this effect in a clinical trial with a longer duration and a larger sample size [54]. Taken together, however, these studies demonstrate that kava generally has anxiolytic and hypnotic effects and can improve sleep quality, especially when the problem is due to anxiety issues.

Galphimia glauca

Goldshower or “calderona amarilla” is a tropical plant of Central America used for treating anxiety and sleep disorders [55]. Many preclinical studies have been performed with enriched extract and with the plantʼs nor-seco-triterpenes, some of which (galphimines A, B [Fig. 1], and E) have been described as inhibitors of dopaminergic activity. However, these compounds may also interact with the serotonergic system, which could partly explain their previously described anxiolytic effects [55]. In this context, Herrera-Ruiz et al. tested the anxiolytic properties of goldshower using the EPM test with different sets of mice. They found that the galphimine-rich fraction, galphimine A, and galphimine B showed a higher anxiolytic effect than the placebo, but this effect was modest compared to the standard drug [56]. These same authors [57] studied the effects of a standardized extract using the EPM, the light-dark test, and the forced swimming test in mice and observed an anxiolytic-like effect in the EPM and the light-dark tests; however, no effect was observed in the forced swimming test. This could be due to an interaction of galphimine B with the serotonergic system in the dorsal hippocampus, which modulates the induced response of 5-HT_1A receptors in an allosteric manner without affecting the GABAergic system [58]. Avilés-Montes et al. performed another preclinical trial using galphimine A on mice and observed an anxiolytic-like effect with no accompanying sedative effect [59]. The mechanism was elucidated by Santillán-Urquiza et al., who noted that galphimines act in the dopaminergic system but not in the GABAergic system [60]. These same authors also established that the administration route should be oral, although Garige et al. had previously used i. p. administration with similar results [61]. Taken together, these results indicate that Galphimia glauca has anxiolytic properties due to its nor-seco-triterpenes and galphimines A and B via the serotonergic and dopaminergic systems but not by the GABAergic one.

In addition to the preclinical assays, some relevant trials have also been performed in humans. Especially noteworthy are those carried out by Herrera-Arellano et al., who performed 2 clinical trials comparing goldshowerʼs anxiolytic effects with those of lorazepam but under different conditions. The results for both treatments, as measured with the HAM-A, demonstrated that Galphimia glauca exerted anxiolytic effects in patients with GAD, even at different doses and with different treatment times, although the age range was similar [62], [63]. In another study, Romero-Cerecero et al. demonstrated the same anxiolytic effect in a study with patients who received either extract or sertraline. Using various scales to measure anxiety, they established that there were no significant differences between groups as measured by the BSPS, which indicates that anxiety decreased in both treated groups [64]. In a second study, these same authors developed a trial comparing the efficacy of a standardized extract of Galphimia glauca with that of alprazolam. The results were measured with the Health Scale. The authors observed that the extract of Galphimia glauca reduced anxiety levels but did not produce sleepiness during the day, thereby confirming the dopaminergic hypothesis as the mechanism of action for galphimine B [65]. In conclusion, Galphimia glauca is an effective anxiolytic that reduces anxiety through a dopaminergic mechanism without causing drowsiness.

Withania somnifera

Ashwagandha is a classic herb used in Ayurvedic medicine [66]. It was evaluated in a previous study by Andrade et al., who investigated its efficacy against anxiety and observed a positive effect vs. placebo [67]. In a subsequent study, Chandrasekhar et al. designed a trial to see if ashwagandha could reduce stress and anxiety and observed similar beneficial results, including improvements in the quality of life, but with no reductions in cortisol levels [68]. Lopresti et al. performed a clinical trial for assessing ashwagandhaʼs effects on stress, anxiety, and hormone production, among other outcomes, in healthy adults. The results of the HAM-A scale showed a beneficial anxiolytic effect. Likewise, the DASS-21 measure indicated a strong positive trend, with decreases in cortisol and dehydroepiandrosterone levels but no significant increase in testosterone in men [69]. Fuladi et al. suggested that ashwagandha could be used as a complement to selective serotonin reuptake inhibitors in patients with GAD [70]. In the case of patients with schizophrenia, Gannon et al. indicated that ashwagandha could help in the treatment of depression and anxiety [71]. Salve et al. carried out a clinical trial in which patients who received treatment showed improvements in their stress levels and sleep quality as measured by the PSS and HAM-A, as well as in their cortisol levels [72]. A similar trial performed by Langade et al. confirmed that ashwagandha can be used as an anxiolytic as well as for treating insomnia and enhancing sleep quality compared to a placebo [73]. Kelgane et al. studied whether an extract of ashwagandha could be used in the elderly for general health and sleep quality, with the outcomes, as measured with different scales, demonstrating that ashwagandha supplementation could be an effective alternative to counter issues associated with aging, including sleep quality and mental alertness [74]. Deshpande et al. showed improved sleep quality in healthy patients suffering from nonrestorative sleep after treatment with a standardized extract of ashwagandha [75]. In a recent clinical study, Langade et al. verified the use of an extract of ashwagandha both as an anxiolytic and to improve symptoms of insomnia as compared to a placebo [76]. Taken together, these studies show that ashwagandha can be used as an anxiolytic, as well as for treating insomnia and enhancing sleep quality.

Melissa officinalis

Lemon balm is used in folk medicine as a sedative-hypnotic agent for treating insomnia and stress [77], with volatile compounds, triterpenes, and phenolics as the principal active constituents [78]. In one preclinical study, its anti-anxiety effects were associated with the inhibition of GABA transaminase and the consequent increase in cerebral availability of GABA, without impairment to normal activity [79]. This study was complemented with an open-label prospective study performed by the same authors. Indeed, Cases et al. [80] studied the anxiolytic effect of one standardized extract (Cyracos) in healthy volunteers and described its positive effects on symptoms of anxiety and insomnia for patients with mild-to-moderate anxiety. However, this clinical study has severe limitations due to the absence of a placebo or positive control, the low number of volunteers, and the broad age range of the subjects. In another study, Haybar et al. performed a clinical trial in patients with chronic stable angina, observing that treated patients showed significant reductions in their scores for depression, anxiety, stress, and total sleep disturbance in the DASS-21 and PSQI [81]. While more clinical studies with lemon balm are needed to establish clear conclusions about its effects, other studies have examined the potential of mixtures of lemon balm with other plants. These will be discussed below in the section on “Effects of Medicinal Plants in Combination”.

Matricaria chamomilla

Chamomile has long been used around the world as a medicinal plant to treat different pathologies and their symptoms, including anxiety and insomnia [82]. In their study of this plant, Amsterdam et al. [83] demonstrated its anxiolytic effect on patients with mild to moderate GAD. Keefe et al. confirmed these anxiolytic properties in patients with moderate GAD but not in patients with severe GAD symptoms [84]. Mao et al. investigated these effects in a similar trial but over a longer period and using different indexes and scales to measure the results. They concluded that chamomile can be used for reducing anxiety in patients with moderate-to-severe GAD without modifying the rate of relapse [85]. Moreover, in an exploratory study, Keefe et al. measured cortisol levels in patients with GAD and demonstrated that an increase in morning salivary cortisol and the diurnal cortisol slope are both related to symptom improvement in chamomile treatment of GAD [86]. Concerning insomnia, chamomile can enhance sleep quality in elderly subjects as demonstrated by Adib-Hajbaghery et al. using the PSQI [87]. Likewise, after drinking a cup of chamomile tea, postnatal women with sleep disorders and symptoms of depression showed an increase in sleep quality and an improvement in their symptoms; however, these effects did not last over an extended period [88]. Chamomile can also be used to ameliorate symptoms of depression, as demonstrated by Amsterdam et al. in a clinical trial that included volunteers with comorbid anxiety and depression [89]. The results suggested that chamomile may be used as an antidepressant in anxious patients with depression to ameliorate the negative symptoms of the disease, including insomnia. In conclusion, chamomile could be a good complementary treatment for sleep disorders, including those due to comorbidities such as anxiety and depression.

Humulus lupulus

Hops, traditionally used for anxiety and mood disorders, were studied by Kyrou et al. in a clinical trial using young subjects that included 2 intervention periods separated by a wash-out period. The researchers noted improvements in the subjectsʼ symptoms of anxiety, stress, and depression, along with the insomnia associated with them [90]. Erkkola et al. performed a clinical trial in healthy postmenopausal women, who often suffer sleep disorders. Although the results were not significant after 8 weeks, at 16 weeks, the treatment was shown to reduce all outcome measures [91]. Nonetheless, the best results were obtained in association with valerian (see the section, “Effects of Medicinal Plants in Combination”).

Other species of interest

Carmona et al. performed a phase-2 clinical trial with Aloysia polystachya and observed a reduction in anxiety symptoms as measured by HAM-A [92]. Centella asiatica, another species that could be used for the treatment of GAD, was tested in patients with this disorder by Jana et al. [93], who observed improvements in levels of anxiety, stress, and depression. Sedum roseum was evaluated in a pilot study by Bystritsky et al., who found an anxiolytic effect in volunteers with GAD as demonstrated by reductions in their HAM-A scores; however, it must be noted that the number of participants was exceptionally low [94]. Edwards et al. studied the effects of Sedum roseum on students, and the results showed improvements in symptoms of stress [95]. In a similar study, Cropley et al. confirmed the effects of golden root for decreasing stress and anxiety in subjects with mild anxiety [96]. Different preparations of Scutellaria laterifolia were used in a trial conducted by Wolfson et al., who observed an anxiolytic effect, but more studies are needed to confirm this property [97]. In the case of Scutellaria baicalensis, no clinical trials have been carried out, but flavonoids (baicalein and wogonin) have previously been cited as being responsible for its anxiolytic and sedative effects [98], [99]. Nepeta menthoides was studied by Firoozabadi et al. in a clinical trial with patients suffering from anxiety and symptoms of depression; the results showed a decrease in anxiety symptoms and a significantly lower rate of short-term recurrence of these symptoms after cessation of the intervention [100]. Rosmarinus officinalis (rosemary) was studied by Nematolahi et al. in university students to treat memory performance, anxiety, depression, and sleep quality; improvements in all areas were observed [101]. Finally, Caralluma adscendens var. fimbriata was investigated for the first time by Kell et al. to assess its efficacy in reducing anxiety and stress in patients with mild to moderate anxiety. It is noteworthy that while there were no significant changes in males, the female subjects experienced changes in their cortisol levels [102].

In conclusion, although the number of trials on these plants is quite low, several species have yielded interesting results. These data can thus be considered preliminary, with those studies having positive results pointing the way for future research.

Effects of Medicinal Plants in Combination

Some authors have found that it is possible to obtain better results with a combination of medicinal plants than with only one, an idea also held by practitioners of herbal medicine and phytotherapy (the experimental data are compiled in Table 4S, Supporting Information). In this context, Morin et al. performed a study comparing the effects of a mixture of valerian and hops to those of diphenhydramine in patients with mild insomnia vs. a placebo. The combination of medicinal plants improved insomnia as measured by sleep latency, sleep efficiency, and total sleep time and provided enhancements in quality of life [103]. Koetter et al. evaluated the efficacy of a dry extract combination of valerian and hops in patients with nonorganic insomnia and observed that the results were markedly better with the mixture than with valerian alone [104]. Dimpfel et al. demonstrated that a valerian-hops combination improves sleep in patients after receiving only 1 administration [105].

Another typical combination of medicinal plants is valerian and lemon balm. Kennedy et al. studied the effects of this mixture on healthy volunteers suffering from stress induced in a laboratory setting and observed improvements, notably a dose-dependent reduction in anxiety as measured by the DISS [106]. In another study, menopausal women who received essential oil of valerian and lemon balm vs. a placebo presented up to a 5-point reduction in their PSQI scores [107].

Abdellah et al. demonstrated the beneficial effect of a mixture of California poppy and valerian extracts on sleep disorders and anxiety in patients in a primary health care setting [108]. Wheatley studied the effects of kava followed by administration of valerian in patients being treated for stress-induced insomnia, noting improvements in both stress levels and insomnia [109]. Ranjbar et al. carried out a clinical trial in which subjects took lemon balm and Nepeta menthoides. The authors found that this combination improved the symptoms of anxiety and depression and reduced insomnia as measured with ISI, BAI, and BDI scores [110].

Maroo et al. demonstrated that administration of NSF-3 (a mixture of valerian, passionflower, and hops) in patients with primary insomnia enhanced total sleep time and latency and decreased both the number of nightly awakenings and the ISI scores [111]. Ze185 (a mixture of valerian, passionflower, lemon balm, and butterbur) reduced the self-reported anxiety response to stress in male test subjects but without affecting any physiological parameters, including salivary cortisol levels due to stress [112]. Hanus et al. combined hawthorn and California poppy to evaluate the effect in patients with mild-to-moderate anxiety disorders associated with functional disturbances. Anxiety levels decreased in both the treatment and placebo groups, but the improvement was greater in the treatment group, as indicated by the HAM-A (both total and somatic) and VAS scores [113]. Scholey et al. demonstrated that LZComplex3, which contains lactium (hydrolyzed milk protein, α-capsazepine enriched), sour date, hops, magnesium, and vitamin B₆, improved sleep quality somewhat, but there were no significant differences between the baseline and endpoint of the primary outcome in patients with insomnia as measured with the PSQI [114]. Dietary supplementation with polyunsaturated fatty acids and hops improved neither sleep quality nor the sleep-wake cycle as measured by the LSEQ in participants with moderate to severe sleep disorders [115]. Finally, in a single-center, single-arm, open-label study in which Lemoine et al. used a combination of medicinal plants (extracts of California poppy, passionflower, and lemon balm) with melatonin and vitamin B₆ in patients with mild-to-moderate insomnia, the results showed improvements in sleep quality [116]. These results justify the use of some combinations of these plants, such as mixtures of valerian and hops or of valerian and passionflower, as sedative agents.

Essential Oils

The essential oil of lavender has been widely used for treating insomnia and anxiety (see experimental data, compiled in Table 5S, Supporting Information). Previous reports have suggested that this is mainly due to the regulation of GABAergic neurotransmission, especially with regard to GABA_A receptors, which enhance the inhibitory response of the nervous system [117], [118]. Various clinical trials have confirmed the anxiolytic properties of lavender, as well as its sedative effect. In several of these studies, researchers have opted to use a preparation made from lavender called Silexan. This was the case for Woelk et al., who compared this preparation with lorazepam and observed similar outcomes in subjects with GAD; however, this study did not confirm lavenderʼs sedative properties [119]. Kasper et al. carried out another trial with Silexan, noting that the results demonstrated a clear reduction in the PSQI scores in the Silexan group vs. the placebo group [120]. In another clinical trial, subjects with neurasthenia, post-traumatic stress disorder, or somatization disorder were treated with Silexan, which led to improvements in anxiety levels, sleep disorders, and restlessness [121]. Kasper et al. confirmed the anxiolytic effect of Silexan in patients with GAD and also demonstrated that Silexan can act as an antidepressant [122]. Kasper et al. performed a clinical study on the ability of Silexan to improve anxiety levels, restlessness, and disturbed sleep patterns with volunteers. They verified the anxiolytic effects as measured with HAM-A; however, no sedative effects were observed (PSQI). These results indicate that Silexan may be administered orally as a treatment for anxiety but not for sedation [123]. Inhalational administration may also be of interest. Indeed, in a study carried out by Chien et al. on midlife premenopausal and postmenopausal women with insomnia who underwent ultrasonic ionizer aromatherapy with essential lavender oil, the authors found that lavender aromatherapy decreased the heart rate while increasing high-frequency standard deviation of the normal-to-normal intervals, along with the square root of the mean-squared differences of successive normal intervals for 30 min in comparison to controls [124]. Another clinical trial was performed by Karan et al. with patients unable to undergo general anesthesia. When these subjects inhaled lavender oil before dental surgery, it reduced anxiety and even decreased the need for antipsychotics [125]. Otaghi et al. performed a similar clinical trial on patients undergoing angiography. Those who received treatment with lavender essential oil and peppermint essential oil before angiography presented no differences in sleep quality [126]. Jokar et al. carried out a clinical trial in menopausal women to assess the effects of lavender oil on menopausal symptoms, especially insomnia, and observed a reduction of symptoms [127]. Another clinical trial with type 2 diabetes patients suffering from insomnia showed that lavender aromatherapy led to an increase in the quality of life through the reduction of insomnia and an increase in mood status [128].

Aromatherapy with lavender essential oil could also be a potential treatment for regulating melatonin levels, especially in older people with various sleep disorders. Velasco-Rodríguez et al. carried out a clinical trial with geriatric patients who inhaled essential lavender oil; the results confirmed that lavender increased blood melatonin levels, thus regulating the circadian cycle in both older adult men and women, which is relevant for treating insomnia. Another possibility for improving sleep disorders and anxiety may be the application of this oil through massage [129]. Ayik et al. demonstrated this in patients undergoing colorectal surgery. Before the operation, patients received a back massage with lavender essential oil (Lavandula × heterophylla) twice daily. They noted a decrease in both sleep disorders and anxiety as compared to the control group, who received standard nursing care [130].

Neroli oil was tested in pregnant women suffering sleep disturbances; the results showed a reduction of anxiety symptoms [131]. Heydari et al. confirmed that this essential oil can also improve premenstrual syndromes, including insomnia and anxiety, among others [132]. Pimenta et al. showed that bitter orange essential oil (inhalational administration) reduced blood pressure in patients with chronic myeloid leukemia while modifying the excitation of the CNS, thereby reducing insomnia [133]. A similar study carried out by Moslemi et al. showed improvements in patients with acute coronary syndrome who were treated with essential oil [134]. Another recent trial confirmed the anxiolytic effect of bitter orange essential oil in patients undergoing coronary angiography, with a reduction of STAI scores, systolic blood pressure, diastolic blood pressure, and both respiratory and pulse rates [135]. In a clinical trial in elderly patients with heart failure, neroli oil improved sleep quality as measured with SMHSQ [136]. Moreover, aromatherapy with neroli oil can be used in type 2 diabetes patients for decreasing anxiety and fatigue. This same effect was described by Abdollahi et al. in volunteers who inhaled an extract of bitter orange (20% concentration) [137]. The essential oil of sweet orange was studied by Goes et al. in male volunteers subjected to an anxiogenic situation, obtaining positive results [138]. Mirghafourvand et al. carried out a clinical trial with postpartum women and the outcomes, as measured by PSQI, indicated that treatment with orange essential oil increased sleep quality [139].

Ylang-ylang was evaluated in a pilot study, but no differences were observed between groups for either anxiety levels or physiological parameters [140]. Wood violet essential oil was studied in patients with chronic insomnia and the outcomes, as measured by ISI, indicated a reduction in symptoms after treatment [141]. In a subsequent trial, volunteers with chronic insomnia demonstrated that this essential oil is more effective than a placebo in severe insomnia [142]. Another clinical trial in which Shirzadegan et al. studied the effects of geranium aroma on anxiety in subjects with acute myocardial infarction showed a reduction in anxiety levels; unfortunately, there are no other clinical trials on this species reported in the literature [143]. Afrasiabian et al. performed a clinical trial with lemon verbena and observed improvements in insomnia [144]. The essential oil of bushy matgrass may also be a potential treatment for decreasing anxiety. In a preclinical trial carried out by Hatano et al., the authors hypothesized that the component responsible for the plantʼs anxiolytic effects was carvone [145]. Soto-Vásquez et al. also investigated this plant, noting a reduction in anxiety levels when subjects inhaled the plantʼs essential oil [146].

Several other clinical trials have examined the potential of various combinations of different types of essential oils for improving sleep disorders and anxiety (Table 6S, Supporting Information). In one study, Lee et al. tested the effects of inhalation of an essential oil mixture (lemon, eucalyptus, tea tree, and peppermint) and observed that this aromatherapy reduced stress and depression while improving sleep quality but did not affect the stress index scores [147]. Stevens et al. used a specific mixture (Serenity softgel) containing lavender essential oil, L-theanine, and a blend of lemon balm, passionflower, and chamomile in a group of volunteers and observed significant differences in the treated group as measured with LSEQ [148]. Hur et al. investigated a mixture of essential oils (lavender, geranium, cinnamon, grapefruit, neroli, and ylang-ylang), administered by both inhalation and abdominal massage. The outcomes were satisfactory, with reductions in subjective stress and fatigue, and improvements in sleep quality [149]. Gürler et al. studied the same properties in menopausal women, who inhaled a combination of 2 different oils (lavender and lemon). The results were positive, with a reduction in the total median scores of the PSQI and MENQOL for the aromatherapy group [150]. A combination of lavandin super, bergamot, and ylang-ylang was tested for its effects on the sleep quality of patients in cardiac rehabilitation and found to have significant positive results in the PSQI [151]. Another study compared the effect of lavender and peppermint essential oils (by inhalation) on the sleep quality of cancer patients; the mean PSQI scores were lower in the lavender and peppermint groups than in the controls, but no differences between the effects of the individual essential oils were observed [152]. Polonini et al. studied the intranasal effect of Pinetonina (a mixture of French lavender and fennel) on stress and chronic stress-induced sleep disorders in volunteers and observed improvements in sleep quality as measured by the PSQI [153]. Lavender and bitter orange improved the sleep quality of postmenopausal women vs. a placebo [154]. The combination of various oils from wood violet, saffron, and lettuce also led to significant reductions in the ISI and PSQI scores in a trial on patients with chronic insomnia [155].

Discussion

Insomnia and anxiety are 2 closely related diseases that affect a large portion of the population, especially in elderly people and women. According to the literature consulted, insomnia is more common in the elderly than in young adults because it is associated with other disorders they tend to suffer from, albeit not with age. Other causes include changes in circadian rhythm or certain medications [156]. Insomnia is more prevalent in women than men (1.5 times), perhaps due to different biological, psychological, and social factors. In fact, 14 to 27% of women have sleep disorders during pregnancy while 40 to 56% of menopausal women suffer sleep disturbances [157]. This explains the greater number of clinical trials carried out on these 2 population groups to evaluate the use of various medicinal plants for treating insomnia and anxiety.

At first glance, the results of the different clinical trials seem to disagree on the benefits of these treatments for insomnia and/or anxiety. This is due to various factors, including the use of different types of extracts, the nature of the population group studied, the size of the population sample used in the trial, and the study design. For example, in the various studies on valerian, the protocols used are quite different, and the results vary accordingly. Thus, while valerian improved sleep quality in menopausal women [33], no beneficial effects on insomnia were observed in elderly adults [31], [32]. This could be because different research groups used different specific extracts (see Table 3S, Supporting Information). Moreover, Taibi et al. evaluated sleep in the laboratory using self-reported data [32]. In the case of kava, it was shown to improve symptoms of anxiety but only in the elderly [53]. In population groups other than the elderly and menopausal women, similar studies have been carried out with different medicinal plants; for example, both passionflower and goldshower have been tested against these pathologies. Thus, several clinical trials have been carried out with these species to evaluate their efficacy in reducing anxiety and sleep disorders, with 3 specific studies–2 using passionflower [43], [44] and 1 using valerian [36]–assessing the use of these plants to treat anxiety before an intervention. Another widely studied species is chamomile, which can improve moderate GAD, but seems to have little effect on the severe form of the pathology [84]. Still, it showed beneficial results in treating anxiety in postnatal women. Ashwagandha is another species that could be used as an anxiolytic or to improve sleep quality [66].

Another factor affecting the results in this field of study is the complex formulations of the extracts assessed. Because several clinical trials have used a combination of different medicinal plants [104], [107], the results may have been affected by a pharmacokinetic and/or pharmacodynamic synergy, which could lead to both positive and negative interactions between the components [158], [159]. In some cases, synergistic effects can improve the solubility and bioavailability of different active ingredients in plants [160], [161]. For example, the increase in the bioavailability of curcumin in the presence of piperine is well-documented [162].

Concerning the principal mechanisms responsible for the effects of medicinal plants, various studies have implicated the GABAergic pathway as the principal system involved. Indeed, some authors have proposed valerenic acid as the active principle of valerian because it regulates the allosteric GABA_A receptors. In the case of kava, it has a clear active compound, kavain, which enhances the receptor activity of the subunit composition of GABA, especially at receptors α4β2δ [48].

Another group of relevant principles on sleep activity and anxiety is flavonoids, which play an important role as GABA_A receptor ligands in the CNS [163]. Of these, amentoflavone (Ginkgo biloba), apigenin (Matricaria chamomilla), or baicalein (Scutellaria baicalensis) is most likely responsible for the sedative properties of these species [163] through a mechanism by which these flavonoids, especially apigenin, act as a noncompetitive antagonist of GABA_A receptors while also enhancing the modulatory action of diazepam on the activation by GABA of GABA_A receptors [164] or that of chrysin (Passiflora edulis) as a partial agonist at the benzodiazepine binding site [6]. Other flavonoids, such as kaempferol and quercetin, are transformed into their active metabolites, including hydroxyphenylacetic acid, by the intestinal microflora [6], [165]. The anxiolytic and sedative-like effects of flavonoids such as quercetin, rutin, and isoquercitrin reinforce these studies, but in this case, not only the GABA/benzodiazepine receptors are implicated because the 5-HT_1A serotonergic receptors are also involved in this case [166], effects ratified for other flavonoids, such as quercitrin, rutin, kaempferol and tiliroside, which can modify the serotonergic system for inducing their anxiolytic effects by acting directly on the postsynaptic 5-HT_2A/2C receptors and also on 5-HT_1A [167]. However, the anxiolytic-like effect of rutin in the basolateral amygdala involves GABA_A, but the effect was not associated with benzodiazepine receptors [168].

In the case of essential oils, they have also been described as regulators of GABAergic neurotransmission–acting especially on GABA_A receptors–because they seem to enhance the inhibitory response of the nervous system. Still, no specific principles have been described as being responsible for these effects, although several trials have used isolated compounds from essential oils, such as linalool and its oxides [117], [118].

Another interesting aspect of medicinal plants for treating insomnia and anxiety is the potential synergy between synthetic drugs and plant extracts. Indeed, Carrasco et al. described a possible synergy between the active principles of valerian and passionflower with benzodiazepines because these species can enhance the inhibitory activity of benzodiazepines by binding to GABA receptors. Although this causes an interesting enhancement, it can also lead to severe secondary effects [169]. For this reason, Tweddell et al. [170] emphasize the importance of evaluating the efficacy of treatment with medicinal plants in patients treated with benzodiazepines beforehand to avoid adverse interactions.

While studies so far indicate that the GABAergic pathway is the main system affected by different medicinal plants [6], another group of principles has been found to act via the serotonergic and dopaminergic pathways. These include Galphimia glauca, which has anxiolytic properties due to galphimines A and B [60], [61], [62], [63], [64], [65].

When comparing clinical trials, the study design and the characteristics and size of the population sample are all extremely relevant as they can modify and condition the results obtained, making comparisons between various studies difficult. In the trials analyzed, we observed a great variation in the number of subjects included, as well as the doses employed and the duration of the studies (see Table 3S, Supporting Information); also noteworthy is the age range of the subjects in different clinical trials. For example, in one study with only 16 participants, the ages ranged from 22 to 55 years old [29], whereas in another study with 202 patients, the range varied from 18 to 73 years old [30]. Other authors modified their own projects and performed assays first with 34 subjects [64] but then used a greater number of subjects (n = 167) in a second trial [65]. The duration of the studies also varied greatly, with some lasting only 2 weeks [45] whereas others lasted up to 16 weeks [54]. This variability can modify the results because treatments for insomnia and anxiety are not generally short. Likewise, various dosages and routes of administration also need to be highlighted, both in preclinical and clinical studies. For example, the possible routes of administration for preclinical studies in animals are p. o., i. p., or i. v. (see Table 2S, Supporting Information), while for clinical studies the administration route is generally oral (see Table 3S, Supporting Information).

Another highly relevant aspect of these studies is which plant part and what kind of extract were used in the trials. Indeed, some studies used essential oils to treat insomnia and anxiety, including lavender oil and neroli, along with commercial products such as Silexan (capsules with essential oil of lavender) [119], [120], [121], [122], [123]. This influenced the via of administration, with some oils administered by inhalation (lavender oil and neroli) [124], [125], [126], [127], [128], [131], [132], [133], [134], [135], [136] or intranasal application (a drop of violet essential oil) [141]. Other studies combined aromatherapy with massages, using essential oils in some cases [130], [149].

Taking into account the results found in the literature, the efficacy of medicinal plants, their extracts, and the essential oils obtained from them to treat insomnia and anxiety largely depends on the duration of treatment, the patients involved (number and characteristics), the route of administration, and the treatment method. It is thus necessary to conduct more clinical studies with an adequate study design and more homogeneous trial protocols to compare the results and make a more realistic assessment. More preclinical studies are also of interest because the mechanisms of these plants are mostly unknown. This would also help clarify other relevant aspects, such as appropriate dosages, routes of administration, and safety.

Contributorsʼ Statement

The 3 authors have participated in the preparation of the document jointly. Data collection: S. Borrás; design of the study: I. Martínez, J. L. Ríos; analysis, interpretation and drafting: S. Borrás, I. Martínez, J. L. Ríos; critical revision of the manuscript: I. Martínez, J. L. Ríos.

Conflict of Interest

The authors declare that they have no conflict of interest

Acknowledgements

The authors would like to thank Laura Gatzkiewicz for her contribution in the process of improving the language of the text.

^# Dedicated to Professor Arnold Vlietinck on the occasion of his 80th birthday.

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Publication History

Received: 07 January 2021

Accepted after revision: 09 May 2021

Article published online:
11 June 2021