Valeriana species and insomnia: multi-organ mechanisms and translational perspectives

Abstract

Context

Insomnia is a common sleep disorder that substantially impairs quality of life. Conventional treatments, including cognitive behavioral therapy and pharmacological agents, are often limited by side effects and insufficient long-term safety data. Valeriana species, such as Valeriana officinalis L. and Valeriana jatamansi Jones, have been traditionally used for their sedative and neuroprotective properties.

Objective

This review evaluates the therapeutic potential of Valeriana species for insomnia, emphasizing their pharmacological mechanisms, multi-organ effects, and evidence from preclinical and clinical studies.

Methods

A systematic literature search was performed in databases including PubMed and Web of Science. Studies addressing Valeriana-induced sleep regulation, neurotransmitter modulation, oxidative stress reduction, and neural, hepatic, and gastrointestinal interactions were included to assess efficacy and safety.

Results

Valeriana species modulate neurotransmission, mitigate oxidative stress, and influence hepatic and gastrointestinal functions. Preclinical studies support their sedative and neuroprotective effects, while clinical outcomes vary with formulation, dosage, and individual response. Overall, safety profiles are favorable, though inconsistencies remain.

Conclusion

Valeriana species represent a promising multi-target strategy for insomnia, integrating neural and peripheral pathways. Future research should clarify the mechanisms underlying multi-organ effects, optimize formulations, and conduct rigorous clinical trials to establish standardized, effective, and safe interventions.

Introduction

The increasing prevalence of insomnia among adults, particularly in aging populations, is significantly diminishing quality of life. Many individuals struggle not only with falling asleep but also with maintaining sleep throughout the night. Others awaken prematurely and are unable to return to sleep promptly. These nocturnal difficulties are frequently accompanied by pronounced daytime impairments that impede optimal functioning, including fatigue, mood instability, and reduced concentration. To be diagnosed with “insomnia disorder”, these difficulties must occur several times per week for at least three months (Riemann et al. 2023). Approximately 10% of adults are affected by insomnia disorder, while an additional 20% experience intermittent insomnia symptoms (Morin and Jarrin 2022). Insomnia can present as a standalone condition or co-occur with other medical and mental health disorders, posing a risk for their progression or exacerbation if untreated (Perlis et al. 2022; Riemann et al. 2022). It may promote a state of allostatic overload that impairs brain neuroplasticity and stress-immune pathways, thereby contributing to mental disorders (Palagini et al. 2022). Insomnia affects approximately 50% of individuals with anxiety (Chellappa and Aeschbach 2022). Current treatment modalities for insomnia include CBT-I and pharmacotherapy. A systematic review and meta-analysis have demonstrated that CBT-I exerts a positive effect on quality of life (Alimoradi et al. 2022). Although some medications are effective for treating acute insomnia, many approved options, including benzodiazepines, zaleplon, zolpidem, and eszopiclone, are associated with poor tolerability and limited data regarding their long-term effects (De Crescenzo et al. 2022).

Valeriana species have a long history of medicinal use (Mulder et al. 2023). Several commonly used species include Valeriana officinalis L., Valeriana jatamansi Jones, and Valeriana fauriei Briq. (Das et al. 2021). Their relevant characteristics are presented in Table 1. Valeriana species possess neuroprotective, anti-inflammatory, sedative, and antitumor properties (Li et al. 2022). Research on the sedative effects and sleep-promoting properties of Valeriana officinalis L. and Valeriana jatamansi Jones is relatively abundant. These species share several bioactive components, including iridoids, flavonoids, lignans, sesquiterpenes, and triterpenes (Orhan 2021; Wang et al. 2024). Evidence suggests that Valeriana officinalis L. may serve as a safe and effective herb for promoting sleep and preventing associated disorders (Baek et al. 2014; Shinjyo et al. 2020). However, one report found no evidence of efficacy for the treatment of insomnia (Valente et al. 2024). A consensus has also emerged that Valeriana officinalis L. has a limited risk-benefit profile and should not be recommended for the treatment of insomnia (Zhao et al. 2023). This discrepancy may be attributable to the low quality of the available studies and the heterogeneity of outcome measures across studies (Kim et al. 2018; Ell et al. 2023).

Table 1.

The efficacy and active ingredients of valeriana species related to sleep.

Latin Name	Common English Name(s)	Functions	Representative Bio-active Constituents	References
Valeriana officinalis L.	European valerian, Garden valerian	Sedative–hypnotic, anxiolytic, antispasmodic	Volatile oils (VA, valerenol, bornyl acetate); valepotriates (valtrate, didrovaltrate); lignans, flavonoids	(Patočka and Jakl 2010)
Valeriana jatamansi Jones (syn.  Valeriana wallichii)	Indian valerian, Tagar	Sedative–hypnotic, antidepressant, neuroprotective, anti-inflammatory	Sesquiterpenoids (jatamansone / valeranone, patchouli alcohol); valepotriates; iridoids; lignans	(Ngo et al. 2022; R. Wang et al. 2021)
Valeriana fauriei Briq.	Korean valerian	Sleep-onset improvement, anxiolytic; modulates GABA-Areceptors	VA derivatives; neolignans; iridoids (didrovaltrate); sesquiterpenoids	(Ota et al. 2021)
Valeriana glechomifolia F.G.Mey.	NR	Sedative-hypnotic; antidepressant-like; antinociceptive; anti-inflammatory	Valepotriates (valtrate, isovaltrate, acevaltrate, diene valepotriates); chlorogenic acid; lignans	(Maurmann et al. 2011; Müller et al. 2012; Salles et al. 2000; Silva et al. 2002)

NR, no report. GABA, gamma-aminobutyric acid; VA, valerenic acid.

Recent randomized double-blind placebo-controlled trials and basic research indicate that Valeriana species can effectively improve insomnia, with outcomes dependent on usage and dosage (Tammadon et al. 2021; Zare Elmi et al. 2021; Ota et al. 2022; Kolobaric et al. 2023; Chandra Shekhar et al. 2024). Notably, the existing research has primarily focused on the effectiveness and toxic side effects of Valeriana species in the treatment of insomnia, and most of the studies have been conducted at the neurobiological level. However, the medicinal value of the Valeriana species is multifaceted, with demonstrated activity across multiple organ systems (Jugran et al. 2019; Feng et al. 2022; Tram et al. 2022; Wu et al. 2023). Given that insomnia results from a combination of factors, it can also serve as a precipitating factor for other diseases. These conditions exert reciprocal effects, creating a vicious cycle. In addition to the brain, liver and gut microbiota are also implicated in the development of insomnia. Therefore, it is essential to critically evaluate the existing research on Valeriana species as a treatment for insomnia. Additionally, exploring the potential relationship interrelationships among the brain, liver, and gut in the pathogenesis of insomnia may provide valuable guidance for future research directions.

Abnormalities of brain, liver and gut in insomnia

Circadian rhythm and sleep-wake cycle disruptions in the brain

Disruptions in the circadian rhythm and sleep-wake cycle are key contributing factors to insomnia. Imbalances in neurotransmitter activity and hormonal fluctuations contribute to sleep disturbances. These functional alterations are illustrated in Figure 1.

Figure 1.

Insomnia-related brain areas and neurons. The figure was created by figdraw (ID: IPWWW000e9). DLPFC, dorsolateral prefrontal cortex; mPFC, medial prefrontal cortex; SCN, suprachiasmatic nuclei; GABA, gamma-aminobutyric acid. Schematic representation of key brain regions and neurotransmitter systems involved in insomnia. The SCN coordinates circadian rhythms and interacts with cortical and subcortical regions, including the DLPFC, mPFC, thalamus, amygdala, hippocampus, parahippocampal gyrus, putamen, and pallidum. Insomnia is characterized by disrupted functional connectivity among these regions and an imbalance between inhibitory GABAergic neurons and excitatory glutamatergic, dopaminergic, and orexin neurons, contributing to hyperarousal and sleep–wake cycle disturbance.

Sleep-related brain functional regions

In mammals, the central circadian clock located in the suprachiasmatic nuclei (SCN) of the hypothalamus synchronizes innate circadian rhythms with the external 24-hour light-dark cycle to optimize internal temporal organization (Zisapel 2018; Collins et al. 2020; Rahimi et al. 2024). This process is facilitated by a complex network of transcription-translation feedback loops involving clock genes (Maywood et al. 2021; Pandi-Perumal et al. 2022). The SCN exhibits increased activity during the day and decreased activity at night, thereby modulating various physiological functions, including sleep and wakefulness, through the regulation of neurotransmitters and hormones (Blume et al. 2019; Pevet et al. 2021).

Patients with chronic insomnia disorder exhibited increased resting-state functional connectivity (rsFC) between the SCN and the left dorsolateral prefrontal cortex (DLPFC), alongside reduced rsFC between the SCN and the bilateral medial prefrontal cortex (mPFC) (Yu et al. 2024). Moreover, connectivity between the SCN and both the locus coeruleus (LC) and the raphe nucleus (RN) was disrupted (Yu et al. 2024). In individuals predisposed to insomnia, the LC appeared more sensitive to or received greater input from the salience network and related circuits, even during rapid eye movement (REM) sleep (Van Someren 2021). Additionally, insomnia disorder patients displayed reduced thalamic connectivity with the left amygdala, parahippocampal gyrus, putamen, pallidum, and hippocampus. This reduction was observed during wakefulness and all non-REM sleep stages (Zou et al. 2021). Intriguingly, the severity of insomnia was correlated with the centromedial right amygdala, whereas anxiety was associated with the basolateral nuclei (Gong et al. 2019). Dysfunctions in the nucleus accumbens (NAc)-mPFC circuit were also observed in insomnia disorder patients (Shao et al. 2020).

Imbalance in the function of excitatory and inhibitory neurons

Insomnia is linked to reduced gamma-aminobutyric acidergic (GABAergic) neuron function and increased excitability of glutamatergic neurons (Machado et al. 2022). GABAergic neurons, particularly those in the preoptic area (POA) and ventral tegmental area (VTA), are crucial (Oishi et al. 2023). These neurons may restrict wakefulness by suppressing the activity of the arousal-inducing VTA glutamatergic and/or dopaminergic neurons and by projecting to the lateral hypothalamus (Yu et al. 2019). Additionally, glutamatergic neurotensin (NTS) neurons in the posterior thalamic region innervate central amygdaloid nucleus (CeA) GABAergic NTS neurons. Both of them promote non-rapid eye movement (NREM) sleep (Ma et al. 2019). Excitatory neurons in the mPFC have been found to facilitate REM sleep by projecting to the lateral hypothalamus and regulating phasic events (Hong et al. 2023). The calcium activity of glutamatergic ventral pallidum neurons is heightened during transitions from NREM sleep to wakefulness. This heightened activity is also observed during behaviors indicative of depression and anxiety in mice (Luo et al. 2023). Orexin neurons help sustain arousal by indirectly inhibiting GABAergic neurons in the ventrolateral preoptic nucleus (De Luca et al. 2022). Orexin receptors can modulate the influence of orexin on both sleep regulation and motivation pathways (Fragale et al. 2021; Sun et al. 2021).

Abnormal release of neurotransmitters and hormones

Gamma-aminobutyric acid (GABA) and glutamate (Glu) are recognized as the primary inhibitory and excitatory neurotransmitters, respectively (Hyland and Cryan 2010). The Glu/GABA-glutamine (Gln) metabolic cycle regulates the synthesis and breakdown of these neurotransmitters. Disruptions in this cycle have been linked to insomnia (Bak et al. 2006). Activation of GABAA receptors promotes sleep (Kim et al. 2019). Moreover, abnormal hormone secretion contributes to insomnia. Melatonin, an endogenous hormone produced by the pineal gland, is essential for regulating the sleep-wake cycle (Kennaway 2022). This hormone is controlled by a complex neural pathway involving sympathetic innervations, the SCN, pre-ganglionic neurons, and post-ganglionic fibers from the superior cervical ganglion (Moore 1996). Insomnia is sometimes accompanied by insufficient secretion of endogenous melatonin (Xie et al. 2017; Lack et al. 2023). Furthermore, evidence indicates a significant correlation between elevated blood corticotropin-releasing hormone (CRH) levels and the severity of insomnia. Anterior inferior hypothalamus hypertrophy has been identified as a mediator in this association (Luo et al. 2024).

Metabolic disorder and impaired function in liver

A higher prevalence of short sleep duration and poor sleep quality has been observed patients with nonalcoholic fatty liver disease (NAFLD) (Marin-Alejandre et al. 2019; Ezpeleta et al. 2023). In female patients, the risk of depression increases as steatosis worsens, and severe NAFLD is significantly associated with both state and trait anxiety (Choi et al. 2020). These sleep disturbances are associated with metabolic factors such as body mass index (BMI) and age (Zarean et al. 2023). However, some reports suggest that the relationship between shorter sleep duration, poor sleep quality, and adverse lipid profiles may be confounded by factors such as BMI and sleep apnea. These associations may not reflect a direct effect of sleep on lipid metabolism (Bos et al. 2019). Additionally, hepatic lipid overload triggers Piezo2/transient receptor potential vanilloid 1 vagal afferents to the NTS, linking lipogenesis with anxiety circuits. Removal of this pathway alleviates both steatosis and anxiety (Hwang et al. 2025). Anxiety, in turn, can precipitate insomnia (Kirwan et al. 2017).

Insomnia is also correlated with liver function markers, including total protein and bilirubin levels. Genes such as uridine diphosphate glucuronosyltransferase, krüppel-like factor 15, and docking protein 7 are implicated in insomnia (Chu et al. 2021). Chronic liver injury has also been shown to induce depressive-like behaviors in mice (Zhu et al. 2020), which may represent an additional contributing factor to insomnia. In individuals with chronic hepatitis B, at least one form of insomnia affects 64.2% of cases (Guo et al. 2017). Disruptions in liver function can alter gut microbiota composition, which in turn impacts brain function and emotional well-being (Breit et al. 2018).

However, current evidence primarily explores the correlation between liver metabolism, inflammation, liver dysfunction, and insomnia; the underlying pathological mechanisms remain poorly understood. Although links between liver dysfunction and sleep disturbances have been reported, the specific molecular pathways potentially involving neuroinflammatory processes and neurotransmitter imbalance in insomnia remain incompletely understood. Further investigation is needed to uncover how liver dysfunction contributes to insomnia and identify potential therapeutic targets.

Disturbance of gut microbiota

Chronic insomnia has been linked to alterations in gut microbiota and bile acid metabolism (Jiang et al. 2022). Specific gut microbiota, such as Prevotella, Dorea, and Lachnoclostridium, have been associated with insomnia, suggesting their potential involvement in its pathogenesis through the modulation of metabolic processes, immune responses, and inflammation (Li et al. 2023). Prevotella may affect sleep by reducing serum amino acids and short peptides. It may also exacerbate sleep disturbances through immune mediators such as ‌interleukin-1 beta (Q. Wang et al. 2022). Fusicatenibacter influences the immune system by producing anti-inflammatory short-chain fatty acids, whereas Oscillibacter may affect sleep via mechanisms analogous to those of GABA (Zhou et al. 2022). An increased abundance of Bacteroides has been positively correlated with improved sleep quality (Tanaka et al. 2023). Modulating the abundance of Porphyromonadaceae, Lactobacillus, and Escherichia, and enhancing the levels of 5-hydroxy-L-tryptophan—a crucial metabolite in serotonin metabolism—can ameliorate insomnia symptoms. These effects are mediated through the modulation of arachidonic acid metabolism and serotonin synapse pathways in the serum, hypothalamus, and hippocampus (Si et al. 2022).

Stress-induced dopamine (DA) activation, gut dysbiosis, and systemic inflammation are recognized as contributing factors to sleep disorders, particularly insomnia. Probiotic P72 mitigates these disturbances by elevating levels of GABA and serotonin and enhancing receptor expression, and downregulating the tumor necrosis factor-α and nuclear factor kappa-B pathways, thereby alleviating depression and sleep disturbances (D.-Y. Lee et al. 2025). Moreover, the regulation of metabolites such as 5-hydroxytryptamine (5-HT), L-3,4-dihydroxyphenylalanine, and L-glutamine influences the gut-brain axis and neurotransmitter pathways, thereby improving sleep quality (Du et al. 2024). Normalization of gut microbiota in rats with insomnia was achieved by increasing the relative abundance of Lachnospiraceae, Ruminococcaceae, and Saccharimonadaceae, thereby restoring the altered gut microbial ecosystem (Yao et al. 2022). Multi-omics analysis has revealed correlations between adenosine and Lachnospira, as well as between phenol and Coprococcus, indicating that gut microbiota and their metabolites may influence sleep regulation by affecting sleep quality and insomnia severity (Lin et al. 2024). Nonetheless, current research predominantly focuses on alterations in gut microbiota and their metabolites in insomnia, primarily manifested as changes in microbial diversity and abundance. Research on how gut microbiota affect the neuroimmune system remains limited. The relationship between gut microbiota and insomnia is illustrated in Figure 2.

Figure 2.

Gut microbiota alterations associated with insomnia. The figure was created by figdraw (ID: RWOYU60d08). Microbial taxa positively associated with insomnia or increased insomnia severity include Prevotella, Dorea, lachnoclostridium, oscillibacter, Escherichia, lachnospira, and coprococcus. Taxa negatively associated with insomnia or positively correlated with sleep improvement include Fusicatenibacter, bacteroides, Porphyromonadaceae, Lactobacillus, Lachnospiraceae, Ruminococcaceae, and Saccharimonadaceae.

Valeriana species can effectively improve sleep in clinical evidence

Accumulating clinical studies suggest that various Valeriana species may improve sleep parameters in individuals with insomnia or sleep disturbances, although the magnitude and consistency of these effects vary across populations and formulations. Evidence derives from randomized controlled trials and exploratory clinical investigations assessing both subjective and, in some cases, objective sleep outcomes. The clinical findings are summarized in Table 2, which provides an overview of study populations, formulations, administration regimens, and key outcomes.

Table 2.

Clinical applications of Valeriana species in the treatment of insomnia.

Subjects	Composition	Intervention	Results	References
80 adults	VE capsules (contained 200 mg of valerian extract)	One capsule 1 h before bedtime, at the same time every day for 8 weeks	↑Actual sleep time, sleep efficiency, total sleep time, NREM ↓PSQI total score, sleep latency, anxiety score, daytime sleepiness, waking up refreshed feeling, sleep latency	(Chandra Shekhar et al. 2024)
100 women	Each supplement capsule (Sedamin) contained 530 mg of VE	Orally twice a day for 4 weeks	↑Quality of sleep	(Taavoni et al. 2011)
16 women	The product used was Nature’s Resource® valerian root extract, 100 mg softgels (Pharmavite, LLC., San Fernando, CA), and standardized by HPLC to contain 0.8% valerenic acid per 100 mg extract.	Nightly 300 mg 30 min pre-bed for 2 weeks	↑WASO	(Taibi et al. 2009b)
34 patients	Tagara Churna (powder of Valeriana wallichii rhizome)	Tagara Churna (powder of V. wallichii rhizome) in the dose of 4 gm with milk was administered 3 times a day after food for a period of 1 month	↑Initiation of sleep, duration of sleep, disturbed sleep, disturbances in routine work	(Toolika et al. 2015)
	Jatamansi Churna (powder of N. jatamansi rhizome)	Jatamansi Churna (powder of N. jatamansi rhizome) in the dose of 4 gm with milk was administered 3 times a day after food for a period of 1 month	↑Initiation of sleep, duration of sleep, disturbed sleep, disturbances in routine work
5 children	Valerian tablets contained 500 mg (100%) of dried and crushed whole root from Valeriana edulis plants. Each tablet contained 5.52 mg of valtrate/isovaltrate.	A pro rata dosage of 20 mg/kilogram of body weight to their child, in a single nightly dose at least one hour before preferred bed-time for 8 weeks	↑Total sleep time, sleep quality	(Francis and Dempster 2002)
			↓Sleep latencies, nocturnal time awake
20 patients	Valeriana edulis rhizomes deter + mined the concentration of the main valepotriate compounds as follows: 0.03 % valtrate; 0.05% isovaltrate; 0.20 % dihydrovaltrate, and 0.26% dihydroisovaltrate.	Orally (three capsules, 450 mg total dose) and provided directly by the researcher in the laboratory 60 min prior to lights out and recording on	↑REM sleep ↓The number of awaking episodes, morning sleepiness	(A et al. 2001)
	Valeriana officinalis L. hydroalcoholic extract contained 66.1 mg of valerenic acid in 100 g extract)		↑REM sleep, Delta sleep ↓NREM sleep, morning sleepiness

VE, Valeriana officinalis L. extract; NREM, non-rapid eye movement; PSQI, Pittsburgh Sleep Quality Index; WASO, wake after sleep onset; REM, rapid eye movement.

Valeriana officinalis L

Supplementation with Valeriana officinalis L. extract (VE) significantly improved both subjective and objective sleep parameters in young individuals with mild insomnia symptoms (Chandra Shekhar et al. 2024). The prominent role of Valeriana officinalis L. in post-operative sleep disturbances highlights its potential efficacy, especially for women, the elderly, those with chronic illnesses, and long-term hospitalized patients (Taavoni et al. 2011; Winter et al. 2022). However, one study indicated that Valeriana officinalis L. may not significantly improve sleep quality in older women with insomnia (Taibi et al. 2009b). Valeriana officinalis L. supplementation did not significantly improve sleep quality in cancer patients, although exploratory analyses suggested potential benefits for fatigue and mood-related outcomes (Barton et al. 2011). It also did not significantly improve sleep in individuals with arthritis-related sleep disturbances (Taibi et al. 2009a).

Magnetic resonance imaging studies have revealed that insomnia, depression, and anxiety share common neural signatures within the insula–anterior cingulate salience network (Peng et al. 2025). In hemodialysis patients, Valeriana officinalis L. enhanced sleep quality, alleviates depression, and reduces anxiety (Tammadon et al. 2021). VE is also shown to modify brain connectivity in association with anxiety in nonclinical volunteers experiencing psychological stress (Roh et al. 2019). While Valeriana officinalis L. may benefit patients with comorbid anxiety and depression, further research is needed to elucidate its neurobiological mechanisms and long-term effects on sleep.

Other Valeriana species

Compared with Valeriana officinalis L., clinical evidence for other Valeriana species remains relatively limited but suggests potential sleep-promoting effects in specific populations. Valeriana wallichii DC. and Nardostachys jatamansi DC. notably enhanced sleep onset and sleep duration, reduced disturbed sleep, and improved routine work disturbances in patients with primary insomnia (Toolika et al. 2015). Valeriana spp. treatment significantly reduced sleep latency and nocturnal wake time, extended total sleep duration, and enhances overall sleep quality in children with hyperactivity-related sleep issues (Francis and Dempster 2002). Valeriana edulis ssp. procera, commonly known as “Valeriana mexicana”, improved sleep architecture and reduced morning sleepiness in insomnia patients (Herrera-Arellano et al. 2001).

Although initial findings are promising, most studies have small samples sizes, lack detailed methodology, and employ insufficient phytochemical standardization. Differences in extract composition, dosage, and assessment instruments complicate interspecies comparisons. Therefore, larger, well-designed trials with standardized preparations and objective sleep measurements are necessary to confirm the clinical efficacy and safety of other Valeriana species for insomnia.

Valeriana species may exert their effects on insomnia through mechanisms involving the brain, liver, and gut in experimental animals

The effects of Valeriana species on sleep-related brain functions are directly supported by experimental evidence, but the roles of the liver and gut in insomnia are still being explored. While Valeriana species have demonstrated effects on liver and gut pathways, their direct contribution to sleep improvement remains speculative, requiring further research to fully understand these mechanisms. All the potential effects and direct influences of Valeriana species are depicted in Figure 3, and the experimental evidence for its effects on insomnia is presented in Table 3.

Figure 3.

Multi-organ mechanisms of Valeriana species in insomnia involving the brain, liver, and gut. The figure was created by figdraw (ID: OSWWW03f55). GABA, gamma-aminobutyric acid; 5-HT, 5-hydroxytryptamine; GABA-A, gamma-aminobutyric acid receptor; MAOB, monoamine oxidase B; BDNF, brain-derived neurotrophic factor; akt, protein kinase B; TrkB, tropomyosin receptor kinase B; NE, norepinephrine; USP9X, ubiquitin-specific protease 9; NLRP3, NOD-like receptor protein 3; PPAR-α, peroxisome proliferator-activated receptor alpha; SREBP-1c, sterol regulatory element-binding protein 1c; C/EBP-α, CCAAT/enhancer-binding protein alpha; ZO-1, zonula occludens-1; CRF, corticotropin-releasing factor; SP, substance P; DA, dopamine. In the brain, Valeriana officinalis L., Valeriana jatamansi Jones, and Valeriana glechomifolia modulate GABAergic, serotonergic, dopaminergic, and noradrenergic neurotransmission, regulate monoamine turnover, enhance receptor expression, and influence BDNF–TrkB and related signaling pathways, thereby improving sleep, anxiety, and depressive behaviors. In the liver, Valeriana species exert anti-inflammatory, antioxidative, and lipid-regulatory effects by modulating oxidative stress, endoplasmic reticulum stress, inflammasome activation, autophagy, and key metabolic transcription factors, contributing to systemic metabolic homeostasis. In the gut, particularly for Valeriana jatamansi Jones, regulation of intestinal microbiota composition, neurotransmitter levels, metabolic pathways and intestinal barrier integrity, supports gut–brain axis modulation.

Table 3.

Experimental studies of valeriana species for improving insomnia.

Model	Composition	Administration	Results	References
ddY mice	Valeriana fauriei Briq. root ethanol extract	Oral 5 g/kg	↑ Sleep duration, GABA A receptor ↓ Sleep latency	(Ota et al. 2022)
Wistar rats	The solution is a hydroalcoholic extract of Valeriana officinalis L. with a specific gravity of 0.824–0.994 and a concentration of 0000/200 ml.	Oral 400 mg/kg	↑ NREM sleep, sleep spindle density and spindle frequency	(Soltani et al. 2021)
			↓ REM sleep
Fruit flies	Valeriana officinalis L. 20 µg/mL + Hop 10 µg/mL (Cascade)	Dietary exposure	↑ Sleeping time, GABA receptors, serotonin receptor, GABA-R binding ↓ Total activities	(Choi et al. 2017)
ICR mice & SD rats	Valeriana officinalis L. 160 mg/kg + Cascade 40 mg/kg	Single oral dose before test	↑ NREM, total sleep time, delta wave, GABA A receptor, binding capacity to GABAA-BZD receptor ↓ Sleep latency	(Choi et al. 2018)
Wistar rats	Valeriana officinalis L. essential-oil inhalation	Inhalation exposure at 2.0 l/m n us ng a flow meter	↑ Total sleep, GABA activity ↓ Sleep latency, GABA-transaminase	(Komori et al. 2006)
SD rats	Volatile oil of Valeriana officinalis L.	1% Tween 80 aqueous solution containing valerian volatile oil (20, 50, 100 mg/ml) by gavage	↑ Sleep duration, 5-HT1AR receptor, 5-HT, couple 5-HT with a G protein coupled receptor, cAMP	(W. Wang et al. 2022)
			↓ Insomnia-induced tension and anxiety
Kunming mice	Valeriana officinalis L. Volatile Oil	Gavage 0.1 mL/10 g	↑ Sleep duration	(H et al. 2025)
			↓ Autonomous activity, sleep latency, MAOB

ICR, Institute of Cancer Research mice; SD, Sprague-Dawley rats; GABA R, gamma-aminobutyric acid receptor; BZD, benzodiazepine; NREM, non-rapid eye movement sleep; 5-hydroxytryptamine; cAMP, cyclic adenosine monophosphate; MAOB, monoamine oxidase B.

Brain

Valeriana officinalis L

In a model of neuropathic pain, Valeriana officinalis L. enhanced sleep quality by increasing NREM sleep, spindle density, and spindle frequency, despite reducing REM sleep (Soltani et al. 2021). The co-administration of Valeriana officinalis L. with other herbal compounds, such as the valerian/cascade mixture, appears to augment the expression of mRNA for GABA and serotonin receptors in fruit flies (Choi et al. 2017). This combination is also associated with the enhancement of NREM sleep in a rodent model (Choi et al. 2018). Inhalation of Valeriana officinalis L. in conjunction with rose enhanced GABA activity through the inhibition of GABA transaminase in rats (Komori et al. 2006). Combining Eschscholtzia californica Cham. with VE resulted in a 30% reduction in insomnia severity and a 50% decrease in anxiety after four weeks (Abdellah et al. 2020). Valerenic acid (VA) was shown to modulate 5-HT and norepinephrine (NE) turnover in the hippocampus and amygdala (Jung et al. 2015). Furthermore, caryophyllene, a key component of Valeriana officinalis L. essential oil, upregulates the 5-HT1A receptor, thereby enhancing serotonin activity and release (W. Wang et al. 2022). VE produced anxiolytic effects through allosteric modulation of GABA-A receptors, primarily driven by VA (Becker et al. 2014; Borrás et al. 2021; Khan et al. 2022; Ghasemzadeh Rahbardar and Hosseinzadeh 2024). VE also mitigates physical and psychological stress by reducing the ratio of monoamine neurotransmitters to their metabolites in the hippocampus and amygdala (Jung et al. 2014). Additionally, Valeriana officinalis L. improved depression-like behaviors in chronic unpredictable mild stress-induced mice, likely through its antioxidative effects on the brain (Gavzan et al. 2023). High-dose (100 mg/kg) Valeriana officinalis L. volatile oil (VVO) significantly reduced autonomous activity, prolonged sleep duration, and decreased sleep latency in mice. This effect was mediated through interaction with monoamine oxidase B (MAOB), leading to decreased MAOB expression in the cerebral cortex (Muhetaer et al. 2025).

Valeriana jatamansi Jones

The aqueous root extract of Valeriana jatamansi Jones improved sleep quality in Sprague-Dawley (SD) rats through modulation of monoamine levels in the frontal cortex and brain stem (Sahu et al. 2012). In addition, Valeriana jatamansi Jones exerted anti-anxiety effects by regulating neuroactive ligand-receptor interactions, cholesterol metabolism, and the advanced glycation end-products/receptor for advanced glycation end-products signaling pathway (S.-N. Wang et al. 2021).11-Ethoxyviburtinal, an iridoid from Valeriana jatamansi Jones, alleviated anxiety-like behaviors in a gender-specific manner by modulating the phosphoinositide 3-Kinase/protein kinase B (Akt) and estradiol 2/estrogen receptor beta signaling pathways (Lyu et al. 2023).

Valeriana glechomifolia

Diene valepotriates from Valeriana glechomifolia exhibit antidepressant properties through the modulation of dopaminergic and noradrenergic neurotransmission (Müller et al. 2015). This effect is attributed to the activation of the tropomyosin receptor kinase B (TrkB) signaling pathway mediated by brain-derived neurotrophic factor (BDNF) (Müller et al. 2020).

Liver

Valeriana officinalis L

VE has been found to inhibit key impede crucial enzyme activities associated with obesity, hypertension, and type 2 diabetes (Wu et al. 2023). VA demonstrated significant protective effects against oxidative and endoplasmic reticulum stress in liver cells (Kara et al. 2021b). Valtrate (Val), a natural compound derived from Valeriana officinalis Jones attenuates NLRP3 inflammasome activation by disrupting the ubiquitin-specific protease (USP9X)-NLRP3 axis. This promotes NLRP3 ubiquitination and proteasomal degradation without impairing USP9X’s catalytic activity. These effects were demonstrated in murine models of acute liver injury induced by acetaminophen (APAP) and lipopolysaccharide (Su et al. 2025). These findings highlight anti-inflammatory and stress-modulating properties that may be relevant to insomnia associated with systemic inflammation.

Valeriana jatamansi Jones

The iridoid-rich fraction of Valeriana jatamansi Jone (IRFV) significantly regulated lipid metabolism in hyperlipidemic rats by improving serum and liver lipid profiles and enhancing lipoprotein lipase and hepatic lipase activity (Zhu et al. 2016). It also modulated key proteins such as apoprotein A5, peroxisome proliferator-activated receptor α, sterol regulatory element binding protein 1c (SREBP-1c), and liver X receptor α (Zhu et al. 2016).

Valeriana fauriei

Iridoids from Valeriana fauriei were found to reduce oleic acid-induced lipid accumulation in an autophagy protein 5-dependent manner and to improve fatty liver by enhancing autophagy-mediated lipid droplet degradation (Lee et al. 2020). These compounds also exhibited significant inhibition of fat accumulation in 3T3-L1 murine adipocytes (Yuki et al. 2015). These metabolic effects may contribute to improved systemic homeostasis relevant to sleep-related metabolic disturbances.

Valeriana dageletiana Nakai ex F. Maek

Valeriana dageletiana Nakai ex F. Maek, significantly inhibited the expression of adipogenic genes, including peroxisome proliferator-activated receptor γ (PPAR-γ) and CCAAT/enhancer-binding protein α (C/EBP-α), as well as lipogenic genes including SREBP-1c, fatty acid synthase, and stearoyl-CoA desaturase in both epididymal adipose and hepatic tissues (Wang et al. 2017). These results further support the capacity of Valeriana species to modulate hepatic and adipose lipid metabolism, potentially contributing to systemic metabolic balance relevant to insomnia pathophysiology.

Gut

Valeriana officinalis L

Contrary to earlier assumptions that valerian may directly modulate gut microbial metabolites, one study reported that extracts of Valeriana officinalis L., alone or combined with Hypericum perforatum (St. John’s wort), did not significantly alter short-chain fatty acid production or bacterial viability in vitro (Chauveau et al. 2023). These findings suggest that short-term exposure may not substantially impact microbial metabolic output, and that gut-mediated central effects, if present, may require longer treatment duration or involve indirect mechanisms rather than direct antimicrobial activity.

Valeriana jatamansi Jones

The potential antidepressant properties of total iridoids from Valeriana jatamansi Jones extract (TIV) may be attributable to its influence on Firmicutes and the regulation of neurotransmitters such as 5-HT, NE, substance P, and corticotropin-releasing factor in the brain and intestines (L. Wang et al. 2020). Improvements in insomnia symptoms were observed in association with adjustments in neurotransmitter levels—specifically GABA, 5-HT, dopamine (DA), and NE—as well as alterations in gut microbiota composition (H. Wang et al. 2020). Modulating the gut microbiota has been shown to enhance the expression of zona occludens 1 (ZO-1) and occludin proteins, thereby strengthening the blood-brain barrier (BBB) and contributing to the antidepressant effects of TIV (Zhang et al. 2021). TIV may also modulate the intestinal flora, thereby inducing the expression of ZO-1 and occludin, protecting the BBB and exerting an antidepressant effect (Zhang et al. 2021). Valeriana jatamansi Jones may treat depression by repairing intestinal damage, thereby restoring vitamin B12 levels and preventing homocysteine infiltration into the central nervous system (Lv et al. 2025). IRFV exerted an antidepressive effect by regulating multiple metabolic pathways, including the tricarboxylic acid cycle, neurotransmitter synthesis, and amino acid metabolism (Zhang et al. 2018; Li et al. 2020). In addition, the optimized anxiolytic compounds group from Valeriana jatamansi Jone ethanol extract exerted anti-anxiety effects by modulating neurotransmitters and hypothalamic–pituitary–adrenal (HPA) axis hormones (Zhao et al. 2022). Collectively, these findings support a more pronounced gut–brain modulatory role for Valeriana jatamansi Jones compared with other species, although direct clinical validation in insomnia remains limited.

Efficacy and safety concerns of Valeriana species in insomnia

Adverse effects have been reported for several commonly used Valeriana species, including Valeriana officinalis L., Valeriana jatamansi Jones, and Valeriana fauriei. These effects appear to be influenced by factors such as individual physiological differences, insomnia severity, dosage, and product composition. The lack of standardized dosing protocols is a critical limitation, as it complicates the establishment of a universally safe and effective treatment for insomnia. The variability in active compound concentrations across different Valeriana species products further contributes to this inconsistency, undermining its reliability as a treatment option. This inconsistency poses a significant challenge for both clinicians and patients.

Side effects

Valeriana officinalis L

Valeriana officinalis L. shows considerable promise as a sleep aid (González-Parejo et al. 2024; Sahin et al. 2024). At recommended concentrations, Valeriana officinalis L. appears to be safe, as it does not induce oxidative stress (Kara et al. 2021a). An effective dose typically requires at least 2–3 grams of dried root (Ali et al. 2021). The aqueous extract of Valeriana officinalis L. root is considered non-genotoxic, with no observed adverse effects at doses up to 14 g/kg, supporting its potential use as a safe food resource (Bao et al. 2024). In particular, at a dose of 12 mg/kg, Valeriana officinalis L. produced anxiety reduction comparable to diazepam (Pinder et al. 2024). Despite these promising results, concerns remain regarding the efficacy and safety of Valeriana officinalis L. can cause significant adverse effects when misused or taken in excessive doses (Yeom and Cho 2024). Long-term memory impairment has been observed in female offspring at doses of 1000 mg/kg/day, highlighting potential risks associated with Valeriana officinalis L. use during lactation (Carvalho et al. 2021). Other toxic effects at high doses include fatigue, abdominal cramps, mydriasis, somnolence, and, in severe cases, cognitive decline and autonomic instability (Freitas et al. 2021). As a positive allosteric modulator of the GABA receptor, Valeriana officinalis L. may directly activate the receptor at high concentrations, potentially leading to delirium (Burke et al. 2020). Blended essential oils, combining Valeriana officinalis L. with lavender and chamomile in specific ratios may offer complementary therapies with fewer side effects (Lee et al. 2023).

Valeriana jatamansi Jones

Valeriana jatamansi Jones has side effects similar to those of Valeriana officinalis L., primarily causing sedation, drowsiness, and mild digestive upset. It may also lower blood pressure and heart rate owing to its hypotensive constituents (Irshad et al. 2024). In vitro studies suggest potential genotoxicity at high doses, with DNA damage observed in HepG2 cells (Etebari et al. 2012). However, IRFV is considered extremely safe at clinical doses, showing no significant acute or sub-chronic toxicity in mice and rats, even at doses far exceeding typical human use (Xu et al. 2015).

Valeriana fauriei Briq

Early human studies demonstrated that healthy volunteers taking 10 g/day of Valeriana fauriei ethanol extract for 4 weeks reported only mild daytime drowsiness, with no serious laboratory abnormalities (Ota et al. 2023). High doses enhanced barbiturate-induced sleep, indicating a sedative synergy. The essential oil exhibited immunotoxicity in insect models, although this finding is likely of limited relevance to humans (Chung et al. 2011; Ota et al. 2022).

Insomnia study quality, outcome heterogeneity, and placebo effects

Clinical findings on the effectiveness of Valeriana species for insomnia are inconsistent and methodologically heterogeneous. Some randomized controlled trials show improvements in sleep and anxiety, whereas others, especially in older adults or those with chronic insomnia, do not show significant benefits. Many studies are underpowered, have small sizes, and employ short treatment durations, limiting their ability to detect sustained effects. Variability in species, extract preparation, dosage, and active constituent standardization further complicates cross-study comparisons. Most studies rely on subjective measures such as the Pittsburgh Sleep Quality Index, with fewer incorporating objective assessments including polysomnography, rendering cross-study interpretation difficult and overall conclusions less robust.

Placebo effects further contribute to inconsistent findings. Given the subjective nature of insomnia and the psychological components underlying sleep perception, expectancy effects are likely substantial. A meta-analysis reported that placebo responses produce comparable improvements in both objective polysomnography and subjective sleep diary measures of sleep continuity, suggesting that objective endpoints do not necessarily mitigate placebo responses (Muench et al. 2023). Similarly, placebo treatment has been shown to significantly improve sleep quality and quality of life in adults with mild insomnia, with stronger placebo responses observed in individuals with shorter disease duration and higher educational levels (Donath et al. 2000). These findings underscore the importance of carefully interpreting modest treatment effects in valerian trials. Future research should prioritize adequately powered, rigorously designed randomized controlled trials employing standardized phytochemical preparations, clearly defined dosing protocols, objective sleep assessments, and longer follow-up periods. Long-term safety evaluation, particularly in elderly populations and individuals receiving concomitant sedative or metabolically active medications, is also warranted to clarify the true therapeutic value of Valeriana species in insomnia.

Potential drug–herb interactions

Commonly used herbal remedies may interact with prescription drugs by altering pharmacokinetic and pharmacodynamic pathways, particularly through modulation of cytochrome P450 enzymes and drug transporters. Such interactions may reduce therapeutic efficacy or increase toxicity, underscoring the need for greater clinical awareness and systematic research (Jogi et al. 2025). Valeriana officinalis L., widely used for its sedative and sleep-promoting properties in mild nervous tension and insomnia, acts primarily through GABAergic and related neurochemical pathways. However, it may also present potential drug–herb interaction risks (Czigle et al. 2023; Ruver-Martins and Ribas 2024). Valeriana species can enhance central nervous system depression when used concomitantly with benzodiazepines, non-benzodiazepine hypnotics, antidepressants, antihistamines, or other sedatives, potentially causing excessive drowsiness and cognitive or motor impairment. Certain bioactive constituents may affect hepatic enzymes and drug transporters, thereby altering the metabolism and efficacy of concomitant medications. Although evidence remains limited, caution is advised for elderly patients, individuals receiving polypharmacy, and those with hepatic impairment. Further research is needed to comprehensively characterize these interactions.

Discussion and future directions

Existing animal models of insomnia and the potential models applicable to Valeriana species

As shown in Table 4, most studies use p-chlorophenylalanine (PCPA), caffeine, or D-galactose to induce insomnia by interfering with serotonin metabolism or adenosine receptor signaling, which effectively mimics the neurochemical imbalances observed in human insomnia. These approaches provide a well-defined framework for studying neurotransmitters, receptor functions, and related signaling pathways (H. Lee et al. 2025; Ren et al. 2020b, Ren et al. 2020a; Si et al. 2020; Sun et al. 2022; H. Wang et al. 2020). In addition, models are typically evaluated using standardized tests, including pentobarbital-induced sleep, electroencephalography/electromyography recording, the Morris water maze, the open field test, and neurotransmitter quantification. These consistent assessment methods ensure comparability across studies. Coupling these approaches with specific brain region signaling analyses further enriches mechanistic understanding. However, these models still present notable limitations. Most rely on short-term administration of agents such as PCPA or caffeine, which reflect acute neurotransmitter depletion but fail to reproduce the complex, chronic nature of clinical insomnia. Additionally, existing models rarely capture the psychological and cognitive dimensions of insomnia commonly observed in patients, such as anxiety, depression, or age-cognitive decline, thereby narrowing their translational relevance.

Table 4.

Comprehensive comparison of animal models of insomnia.

Classification	Types	Animal modeling	Manifestations	Associated symptoms	Mechanism
Stress Model	CMS	Long-term (2–4 weeks) unpredictable stressors: Food/water deprivation, Day-night reversal, Noise or humidity exposure, Activity restriction	Increased sleep latency, Reduced total sleep time, Disruption in NREM/REM ratio	Increased anxiety-like behavior, Impaired cognitive function	Activation of HPA axis, Circadian rhythm disturbance
Drug-Induced Model	Caffeine Model	Caffeine administration via gavage/injection during active phase (30–100 mg/kg), For several days to weeks	Increased wakefulness, Reduced NREM sleep, Possible REM sleep reduction	Hyperactivity	Blockade of adenosine A1/A2A receptors
	PCPA Model	Single intraperitoneal injection of PCPA (300–500 mg/kg)	Complete insomnia for 48–72 h, Near-total REM sleep suppression	Increased anxiety, Aggressive behavior	Inhibition of serotonin synthesis (tryptophan hydroxylase inhibitor)
Sleep Deprivation Model	Total Sleep Deprivation	Gentle handling, Water tank method, Rotating wheel/platform method, Continuous deprivation for 24–72 h	Increased wakefulness, Rebound sleep during recovery (increased NREM deep sleep)	Metabolic disturbances, Immunosuppression	Forced wakefulness
	Partial Sleep Deprivation (REM Deprivation)	Multiple platform water environment method (platform diameter 5–7 cm)	Marked REM sleep reduction, Fragmented NREM sleep	Impaired learning and memory	REM-related muscle atonia causes fall and awakening

CMS, chronic mild stress; REM, rapid eye movement sleep; HPA axis, hypothalamic–pituitary–adrenal axis; PCPA, para-chlorophenylalanine.

Current Valeriana species studies are limited by their reliance on narrow assays such as pentobarbital-induced sleep and caffeine-induced arousal, which don’t capture the full pharmacodynamic profile. There’s also insufficient integration with pharmacokinetics studies, BBB assessments, and behavioral evaluations, thereby limiting the translational applicability of findings. Research often concludes at the receptor or neurotransmitter level without circuit-level validation through techniques such as functional imaging. Effective animal models that replicate insomnia-related neurophysiological and peripheral changes are needed. Employing genetic tools like CRISPR-Cas9 and advanced methods including calcium imaging and in vivo electrophysiology can help uncover crucial pathways and therapeutic targets. These efforts aim to enhance the understanding of Valeriana pharmacology and its evidence-based application in insomnia treatment.

Decoding the crosstalk between gut, liver, and brain in Valeriana species-based insomnia therapy

Although the brain, liver, and gut originate from distinct embryonic layers, they are interconnected through spatial proximity, shared morphogen gradients, and early neurohumoral signaling during organogenesis (Amadei et al. 2022; Chidiac and Angers 2023). Neural crest cell migration establishes the enteric nervous system, linking the central nervous system with the gastrointestinal tract, while early vagal development enables neurovisceral communication (Nagy and Goldstein 2017; Isabella and Moens 2024). In parallel, liver development from the foregut endoderm occurs within a signaling environment influenced by neighboring tissues (Tanimizu and Miyajima 2007). These developmental findings provide biological plausibility for coordinated neuro–metabolic–immune communication among these organs.

In adult physiology, evidence shows interactions between organ systems, such as nuclear receptors in GABAergic neurons affecting circadian regulation of liver glucose metabolism (Ding et al. 2021). Liver-microbiota interactions may influence neuroactive metabolite profiles with downstream effects on the central nervous system and emotional regulation (Nguyen and Swain 2023). Although these findings suggest cross-organ connectivity, they don’t confirm a causal brain-gut-liver axis in insomnia. Preclinical studies indicate that Valeriana species can alter gut microbiota and neurotransmitter systems, potentially improving mood in animal models (Korczak et al. 2023). However, these studies don’t directly validate a coordinated axis-level regulation of sleep or insomnia improvement through a brain-gut-liver pathway. The brain-gut-liver axis in Valeriana species-based insomnia therapy should be regarded as a conceptual framework for generating hypotheses, rather than proven pathway. Advances in multi-omics technologies may help bridge this gap. Integrating transcriptomics, metabolomics, microbiomics, and systems modeling may reveal molecular connections across organs and determine whether coordinated modulation of the brain, liver, and gut plays a causal role in sleep regulation (Mukherjee et al. 2025; Wang and Sofer 2025).

Innovative formulations and integrative strategies for enhancing the efficacy of Valeriana species in insomnia treatment

Valeriana species can be formulated into various delivery forms, including patches, sprays, and plasters to improve patient adherence and compliance. Combining these formulations with traditional Chinese medicine approaches that target specific meridians and acupoints for treating insomnia treatment presents innovative therapeutic possibilities. A systematic review identified that the principal acupuncture acupoints for senile insomnia as Shenmen (HT7), Sanyinjiao (SP6), Baihui (GV20), Zusanli (ST36), and Neiguan (PC6) (Lu et al. 2024). Applying hot compress patches composed of Valeriana species to these acupoints may also confer therapeutic benefits for insomnia. Moreover, incorporating Valeriana species into comprehensive treatment protocols could further enhance their efficacy. Such multimodal approaches not only engage different therapeutic mechanisms but also increase treatment flexibility, offering personalized strategies for diverse insomnia subtypes.

Role of nanotechnology in the development of Valeriana species-based treatments for insomnia

Traditional formulations of Valeriana species, such as extracts or essential oils, often face limitations in bioavailability, stability, and targeted delivery. Nanotechnology significantly enhances the bioavailability, stability, and efficacy of herbal medicines, offering promising applications in disease treatment and food preservation, though further research is needed to address safety, scalability, and regulatory challenges (Awlqadr et al. 2025). Lipid nanoparticles, one of the extensively investigated drug delivery systems, not only improve pharmacokinetic parameters, transport, and chemical stability of encapsulated compounds but also provide efficient targeting and reduce the risk of toxicity (Ashfaq et al. 2023).

The integration of nanotechnology with botanical pharmacology is rapidly advancing traditional sleep aids toward precise, personalized therapies (Awlqadr et al. 2025). Nanotechnology enables the delivery of neuroactive phytochemicals to the brain by using specialized nanoparticles that enhance cerebral accumulation and therapeutic efficacy (Mohammed et al. 2025; Sadat Razavi et al. 2025). For transdermal delivery, nano-emulsions and nanogels incorporated into sleep patches improve skin permeability, offering a convenient bedtime solution (Aeschbach et al. 2009). Combination platforms can co-load compounds such as melatonin with other sleep-promoting herbs for synergistic effects (Mirza-Aghazadeh-Attari et al. 2022). Future “smart” nanocarriers could release drugs in synchrony with the body’s circadian rhythm, optimizing insomnia treatment (Le Meur et al. 2025). However, challenges persist regarding toxicology, consistency of plant-based nanomaterials, and evolving regulatory frameworks.

Dose–response relationship and standardization in translating preclinical dosages to clinically relevant human doses

In translating preclinical research to clinical applications, understanding the dose-response relationship and standardizing dosages are essential. Animal models provide valuable insights. But interspecies differences in metabolism, and drug bioavailability necessitate careful adjustment of human doses. Preclinical studies often use higher dosages due to varying metabolic rates between animals and humans. Consequently, clinical trials must incorporate dose-response studies to identify the optimal and safe dose for insomnia treatment. This is particularly crucial for plant-based medicines, in which variations in active compound concentrations can affect efficacy.

The allometric scaling approach accounts for differences in body surface area relative to body weight when extrapolating the doses of therapeutic agents across species (Nair and Jacob 2016). A large-scale comparative analysis of 379 pharmaceuticals demonstrated that rat and rabbit embryo–fetal developmental toxicity responses are broadly similar in systemic exposure sensitivity, with both species providing complementary value in hazard identification (Nair and Jacob 2016). Comparative analysis of embryo–fetal developmental toxicity data across animal species and corresponding human clinical outcomes can improve translational predictability, thereby informing the interpretation of preclinical animal findings should be interpreted to better guide safe and evidence-based drug application in humans (Thakur et al. 2024).

The therapeutic effects of Valeriana species may vary substantially across different formulations, including tinctures, capsules, standardized extracts, and volatile oils (Politi et al. 2009; Shinjyo et al. 2020). Extraction methods such as aqueous extraction, ethanol extraction, and supercritical carbon dioxide extraction can significantly alter the composition and concentration of bioactive constituents, thereby influencing pharmacological activity (Liz Girardi Müller et al. 2012; Ren et al. 2022). In addition, certain compounds, including iridoids and valepotriates, are thermolabile and prone to degradation during processing and storage, which may affect efficacy (Liz Girardi Müller et al. 2012). The pharmacological effects of Valeriana species are likely mediated by synergistic interactions among multiple constituents rather than a single compound, and differences in component ratios across preparations may lead to variability in clinical outcomes. Furthermore, routes of administration may affect absorption and metabolism. Therefore, findings derived from one preparation should not be directly generalized to other formulations without careful consideration of phytochemical composition and pharmacokinetic properties.

Conclusions

Valeriana species, particularly Valeriana officinalis L. and Valeriana jatamansi Jones, have demonstrated potential as effective treatments for insomnia through their neuroprotective, sedative, and anti-inflammatory properties. These species exert pharmacological effects on the brain, liver, and gut, highlighting their multifaceted role in sleep regulation. While existing clinical and preclinical evidence supports their efficacy in improving sleep quality, the underlying mechanisms—especially the interactions among the brain, liver, and gut—remain complex and require further investigation. The variability in formulation, dosage, and active compound concentrations complicates comparisons across studies, underscoring the need for standardized research protocols. Future studies should focus on multi-omics approaches to better elucidate the cross-organ interactions in insomnia pathogenesis and to improve the consistency and reliability of Valeriana species in clinical applications. Additionally, addressing safety concerns, particularly in vulnerable populations, and evaluating long-term effects are critical steps toward the full integration of these species into evidence-based therapeutic practices for insomnia. Enhanced formulations and the incorporation of novel delivery systems such as nanotechnology may further improve the bioavailability and efficacy of Valeriana species, providing promising avenues for the treatment of insomnia.

Funding Statement

This study was supported by the National Natural Science Foundation of China (Nos. 82274634, 82105009).

Disclosure statement

No potential conflict of interest was reported by the authors.

Data availability statement

There are no data associated with this research.