Neuropsychiatric effects and safety of Salvia species: A critical narrative review of preclinical and clinical evidence

Abstract

Salvia species (sage) are medicinal plants that are used in several pathological conditions due to their anti-inflammatory, antioxidant, antimicrobial, anticancer, and healing properties. Therefore, their traditional clinical uses are broad and lack specificity, and some species showed characteristic effects. Salvia species showed variable beneficial effects in depression, anxiety disorders, and mental health. Other species may aggravate mental symptoms or lead to addiction, as with Salvia divinorum. Some authors believed that the effects of Salvia on the central nervous system are related to their active ingredients; others believed that the sage would counteract the pathological changes or the risk factors that are associated with neurological or psychiatric illnesses, e.g., low-grade inflammation. This narrative review investigates the psychiatric outcomes of using different species of Salvia by attributing their effects on the neurotransmitters and on the oxidative or nitrosative stress species, the inflammatory markers in different experimental models (preclinical studies), and on healthy humans and patients with psychiatric illnesses. The search strategy had no time limit, and the data extracted from several databases using specific Medical Subheadings that are relevant to the objectives of the review.

Key Words: Sage; Anxiety; Depression; Cognitive function; Psychoactive; Alzheimer’s disease

Core Tip: There are many species of sage that are used as traditional medicines for psychiatric problems because they have effects on cognitive function and have sedative and anxiolytic effects. Salvia divinorum has a psychoactive property, producing hallucinations and amnesia, while Salvia miltiorrhiza and other sages have many beneficial neuropsychiatric effects. The majority of research is preclinical, and randomized double-blind controlled studies are needed to show the significant effects of the sage. Encouraging the synthesis of the active ingredient could lead to innovative advancement in medications for psychiatric illnesses.

INTRODUCTION

Sage is one of the medicinal plants containing a higher content of total flavonoids that are released by the hydrolysis process from ester and glycosidic derivatives, which are its constituents: 19.38 ± 0.13 mg of glucoside and ester/g in the sage leaf[1]. It has been estimated that the antioxidant activity of the sage leaves is 69.88 ± 2.22 μmol Trolox/g, which is higher than other medicinal plants[1]. In an experimental study, ethanolic extract of sage attenuates the cisplatin-induced hepatotoxicity via its antioxidant, anti-nitrative, lipid peroxidation-inhibiting, and anti-inflammatory [decreasing the interleukin (IL)-6 and tumor necrosis factor (TNF)-α] properties[2]. The anti-inflammatory property was investigated in the experimental and clinical studies. In humans, a topical preparation of sage gel (Salvizan) was found to be effective in relieving the pain and speeding the wound healing in patients with recurrent aphthous stomatitis, and this effect is significantly better than triamcinolone acetonide gel[3]. The chemotherapeutic effects of sage against microorganisms and tumor cells have been demonstrated, and they are attributed to its inhibitory effect against topoisomerase I[4]. The protective effects of the sage were reported in the many preclinical studies. The protective effects and the pharmacological properties of sage are related to its species, as it may have antioxidant, anti-inflammatory, antidiabetic, cardioprotective, or neuroprotective[5] and cardioprotective effects. The cardioprotective effect of sage was demonstrated in the ischemic-reperfusion injury in the isolated perfused heart of the rat by reducing the size of the infarcted area associated with increased peroxisome proliferator-activated receptor gamma coactivator1-alpha phosphorylation and decreased caspase-3[6]. The potential favorable impact of sage on cognitive function was related to pleiotropic effects on the brain, summarized by having activity on cholinergic neurotransmission, amyloid β-peptide, oxidative stress, low-grade inflammation, and possessing anxiolytic and antidepressant effects[7]. It is necessary to take into consideration that each sage species has a distinct pharmacological property that differs from other species, and the preclinical studies could be applicable or not applicable for clinical studies; in addition, the extracted active constituents are involved in neuroprotection. Therefore, the place of using sage in psychiatric clinical practice is discussed from three aspects: (1) The species of sage; (2) The presence of active ingredients; and (3) Reported evidence-based studies. Figure 1 illustrates the main pharmacological actions of Salvia species or their ingredients that could be applicable in the treatment of psychiatric illnesses.

Figure 1 Some of the central and peripheral pharmacological properties of sage and its active ingredients that suggested their potential effectiveness in treating psychiatric illnesses (anxiety, depression, and Alzheimer’s disease). These properties are extracted from preclinical and clinical studies.

METHODS

This narrative review summarized the published literature on investigating the effects of sage (Salvia species) on psychiatric illness. This narrative review addressed a broad question; therefore, the PRISMA guidelines were not followed because this review is not a systematic review. The research question was, “What are the Salvia species that showed central effects and benefit in the treatment of psychiatric illness or the production of specific neuropsychiatric signs or symptoms?” The relevant evidence on their effects on anxiety, depression, memory, mania, schizophrenia, cognitive function, Alzheimer’s disease, addiction, dependence, and hallucination is found by looking for the human interventional and observational evidence, animal evidence, in vitro evidence, and in silico evidence. The literature search was conducted through MEDLINE (via PubMed), European PMC, Semantic Scholar, Dimensions, Scopus, and Web of Science. Medical Subheadings terms used for the search were “Salvia species”, “sage”, “memory”, “cognitive function”, “anxiety”, “depression”, “schizophrenia”, “Alzheimer’s disease”, “dependence”, “hallucination”, “clinical trial”, “toxicity”, “active ingredients”, clinical trials”, “animal models”, “in vitro”, “in silico”, and “network pharmacology.” Any related articles (experimental, or on human, or molecular docking), reviews, abstracts, or data in books were included, and there is no time limit for publication, with up to 2026 research included. The collected information addressed the effects of sage or its derivatives on psychiatric diseases or experimental models, the search for the dosage or concentration, and the benefits and drawbacks of utilizing sage during treatment. Retracted articles or articles published in predatory journals were excluded. Salvia species free from central nervous system effects are excluded, and only the studies in English were considered. One of the important limitations of this review is that the studies for each specific sage are concerned with the antioxidant, anti-inflammatory, and antimicrobial properties. In addition, the clinical studies on healthy humans or patients with psychiatric illnesses are so deficient.

Salvia apiana (white sage; bee sage; sacred sage)

The natives of this medicinal plant are Southern California and parts of Mexico, and its extract is used to treat the signs and symptoms of upper respiratory tract infections. The bioassay of the active ingredients in the sage extract showed that sageone (IV) displaced the cannabinoid type 1 (CB1) and type 2 receptors by 72.5% and 79.8% at a concentration of 33 μmol, respectively[8]. The CB1 regulates mood, memory, learning, and pain, while the CB2 is expressed in undesirable psychotropic conditions, e.g., tendency to addiction[9,10]. Therefore, Salvia apiana could have a role in the management of psychiatric diseases, but at the time, the literature survey does not disclose experimental or clinical studies concerning the use of crude extract or its active ingredients. Traditionally, Salvia apiana has a powerful aroma, and for that reason, it is used for meditation and relaxation to create peaceful environments.

Salvia azurea (azure sage; blue sage; pitcher sage)

The native of this medicinal plant is central and eastern North America, and it is traditionally used to relieve toothache pain and migraine headaches[11]. In addition, as with any sage, it is used to create relaxation and enhance spiritual awareness. The academic research does not disclose the extracted essential oils of blue sage for clinical uses.

Salvia buchananii (Buchanan’s sage)

The native of this sage is Mexico. The antiproliferative effects of Salvia buchananii Hedge have been attributed to the triterpene compounds isolated from the roots rather than from the flowers or leaves in an experimental study done on the cancer cell lines[12]. It is known that triterpenoid compounds have a broad spectrum of pharmacological properties, including neuroprotection in terms of improving cognitive function and the process of neurogenesis, which pointed to using these medicinal plants in the management of neurodegenerative diseases, e.g., Alzheimer’s disease[13-16]. It has been found that the essential oils of buchanan’s sage have anticholinesterase activity, which explains their positive impact on cognitive function[17]. The literature survey does not show any evidence that Salvia buchananii, as an extract or its active compounds, has been studied experimentally or in clinical practice in the management of psychiatric-related diseases.

Salvia cacaliifolia Benth. (Blue vine sage; Guatemalan sage)

This sage is native to Chiapas, Mexico, Guatemala, and Honduras. The essential oils of this sage were reported to have anti-inflammatory effects by inhibiting the activities of cyclooxygenase and inducible nitric oxide synthase and have anti-aging properties via their effect on the cellular senescence marker β-galactosidase[18]. The anti-aging properties could be utilized to show their effect on cognitive functions, which deteriorated with advancing age. Among the traditional uses of different types of sage in Mexico, Salvia cacaliifolia was not reported despite its being native to Mexico, indicating that this medicinal plant is not considered despite its acting on specific enzymes that are involved in neuroinflammation and aging.

Salvia candelabrum (candelabrum sage)

The native of this herb is southern Spain. Different active ingredients are isolated from different parts of the plant, including diterpenes, β-sitosterol, nepeticin, candelabrone, etc. It contains large amounts of ursolic and oleanolic acids as well as sugol. β-sitosterol is a nutraceutical compound with biological activities such as antimicrobial, antidiabetic, immunomodulatory, and antiproliferative[19]. A study based on a compound-target network identified that sitosterol strongly binds to genes that are expressed in schizophrenia[20]. A network pharmacology analysis study revealed that β-sitosterol potentiates the traditional Chinese medicines in improving the schizophrenic symptoms and sleep rhythm[20]. In another study, β-sitosterol inhibits monoamine oxidase, indicating that it has a role in improving the mood and cognitive function and offers neuroprotection via acting on the neurotrophic factors[21]. A network pharmacology analysis of traditional Chinese medicines that are effective in the treatment of depression contains β-sitosterol[22]. In a rat model of iodine deficiency in pregnant females, their “offsprings” showed abnormal histopathology (neuronal disruption, reduction in myelination, and a decrease in the synaptic density), indicating impairment in the development of the brain. β-sitosterol supplementation improved the abnormalities in the histological changes in the brain, indicating its role in brain development[23]. This sage contains a large amount of ursolic acid, which has many pharmacological properties, including antioxidant, antidiabetic, anti-obesity, promoting the growth of skeletal muscle, and anticancer[24]. Its effect on cognitive function is indirect via modulating the neuroinflammation and scavenging the free radicals or improving the activity of antioxidant enzymes[24]. The psychiatric effects of sage decoction or crude extract on humans are not carried out.

Salvia coccinea (scarlet sage, blood sage, tropical sage, and Texas sage)

The native of this sage is in many countries in North and South America (Central America, Mexico, Peru, Colombia, and Brazil). This sage has wide pharmacological actions, including antioxidant and free radical scavenging activity and hypoglycemic, antimicrobial, and anti-inflammatory [suppressing the levels of TNF-α, cyclooxygenase 2, lipoxygenase, C-reactive protein, IL-6, and nuclear factor kappa B (NF-κB)], and wound healing effects[25]. Its action on several pathways, including caspase 3, poly (ADP-ribose) polymerase cleavage, extracellular signal-regulated kinase, cyclin-dependent kinase 1, Janus kinase 2/signal transducer and activator of transcription 3, Bcl 2-associated X protein/B cell lymphoma 2, AMP-activated protein kinase, and Wnt/β-catenin, suggests using this sage in a wide variety of diseases, including neurological and psychiatric illnesses. In schizophrenia, downregulation of the Wnt/β-catenin pathway is associated with neuroinflammation and upregulation of peroxisome proliferator-activated receptor-γ, which can be attenuated (theoretically) by using scarlet sage[26]. In Alzheimer’s disease, the activation of the Wnt/β-catenin pathway results in activation of glutamate transporter expression, leading to the removal of the excess glutamate, which is significantly elevated at higher levels in Alzheimer’s disease[27]. Therefore, any herbal medicine that acts on the regulation of Wnt/β-catenin will result in an improvement in the symptomatology of psychiatric illnesses. The caspase-3 gene is involved in the pathophysiology of psychiatric diseases; it is significantly expressed in schizophrenia and substance abuse, suppressed in depression, and altered in Alzheimer’s disease[28-31]. Therefore, the inappropriate use of scarlet sage will result in the deterioration of psychiatric health, as it has a dual effect on one pathway or gene expression, and its effects on the other pathway will complicate pathological psychiatric conditions. Therefore, its uses should be limited whenever there is strong evidence of neuroinflammation and oxidative stress.

Salvia columbariae (chia sage, golden chia, or desert chia)

The native of this sage is in the United States (California, Nevada, Utah, Arizona, New Mexico, Sonora, and California), and it is an important food for Native Americans. A variety of Salvia columbariae is named Ziegler’s sage. Tashinones are the active ingredients of Salvia columbariae, which is found to be effective in alcohol abuse, as they prevent relapse[32]. Tashinone IIA was experimentally found to ameliorate the fear behavior in the post-traumatic stress disorder model of mice[33]. Another experimental study reported that tashinone IIA upregulates the expression of the gamma-aminobutyric acid (GABA) transporter 1, which counteracts the depression-like behavior and impairment of cognitive function induced by a chronic mild unpredictable stress test for four weeks in rats[34]. The antidepressant effect of tashinone is mediated via different mechanistic pathways, and it is not specific for certain signaling pathways. It inhibits the monoamine oxidase-A (IC₅₀ < 10 μM) and monoamine oxidase-B (< 25 μM)[35].

Salvia dianthera Roth (Bengal sage)

The natives of this sage (Meriandra dianthera) are Eritrea, Ethiopia, Saudi Arabia, Yemen, and India. The pharmacological spectrum of this sage extended from antimicrobial activity to the cytotoxic effect in an experimental study using leaf extracts[36]. The crude aqueous leaf extract produced anticoagulant activity in an in vitro experimental study, as evidenced by prolonging the partial thromboplastin time, indicating a selective inhibition of the intrinsic coagulation mechanism[37]. The antidiabetic effect and lipid-lowering property were observed in mice treated with crude extract at doses ranging between 500 mg/kg and 2000 mg/kg[38]. Direct effects of the crude extracts or the active compounds of Meriandra dianthera on psychiatric illnesses were not mentioned.

Salvia divinorum (diviner’s sage, magic mint, mystic sage, ska Maria, and ska Pastora)

The native of this sage is Southwest Mexico. It is a popular recreational herbal medicine or a substance of abuse due to its hallucinogenic effects induced by its active compound, salvinorin A[39]. The onset and duration of the hallucinogenic effect differ with the route of administration. The onset and duration of smoked Salvia divinorum are 15-60 seconds and 15-90 minutes, and when placed under the tongue, they are 10-20 minutes and 30-90 minutes, respectively. Figure 2 showed the main central and systemic effects of Salvia divinorum. The central and peripheral pharmacological properties of Salvia divinorum are as follows[40]: (1) Activation of central kappa-opioid receptors; (2) Modulation of CB1 receptors; (3) Modulation of the norepinephrine, dopamine, and serotonin release; (4) It has no effect on the 5-hydroxytryptamin A2 serotonin receptor; and (5) Suppression of the activity of leukotrienes and proinflammatory cytokines

Figure 2 The somatic and central effects, including the positive and negative impacts of using Salvia divinorum. These clinical signs and symptoms are reported in observational clinical studies.

The pharmacological effects of this sage are the following: (1) Psychoactive signs and symptoms. Intake of an aqueous preparation of sage produced headache, dysphoria, a sensation of depersonalization, and visual and auditory perceptions[41]. The hallucinogenic effects appeared after taking salvinorin A at a concentration of 250-500 μg[42]. It differs from other hallucinogenic compounds, e.g., lysergic acid, by having a short action, as its effect appeared immediately and lasted for 15 minutes[43,44]. Salvinorin A induces rapid desensitization of the kappa opioid receptor, transient functional plasticity, and dissociative effects as a result of thalamocortical disruption and downregulation of the activity of mesolimbic dopaminergic neurons[45]. In a survey that included 581 psychedelic users, the participants did not prefer to use Salvia divinorum or salvinorin due to their adverse reactions and their intense effect on the physical and mental[46]. Another study was carried out on educated young participants and found those participants preferred using Salvia divinorum in combination with alcohol, cannabis, or ecstasy[47]. Salvinorin is found naturally in many species of Salvia and in different concentrations as follows: Salvia divinorum (0.89 mg/g to 3.70 mg/g); Salvia recognita (212.9 μg/g); Salvia cryptantha (51.5 μg/g) and Salvia glutinosa (38.9 μg/g)[48,49]; (2) Neuropathic pain. Preclinical studies demonstrated the antinociceptive, anti-inflammatory, and antineuropathic effects, suggesting that salvinorin A could be applicable in the treatment of trigeminal neuralgia[50]; and (3) Substance abuse. Consumption of Salvia divinorum constitutes 66% of patients admitted to detoxification for illicit drug use[51]. Salvia users are characterized by a higher perception score and a lower volition rate compared with non-salvia users[51]. In an experimental animal model, it has been reported that Mesyl B attenuates the behavior changes induced by cocaine, with a limited antinociceptive effect[52]. Like other psychedelics, Salvia divinorum does not produce dependence.

Salvia elegans (pineapple sage, tangerine sage, mitro)

The native of this sage is Mexico. It has interesting pharmacological properties, including antihypertensive via inhibiting the angiotensin-converting enzyme[53], antimicrobial[54], antioxidant (rich in caffeic acid)[55], and antidiabetic via inhibiting a-glucosidase[55]. The antidepressant and anxiolytic effects were investigated in mice subjected to the forced swimming test, elevated plus maze test, and open field test, and it was found that the active ingredients of Salvia elegans interact with serotonergic drugs in activating the serotonergic receptor (5-hydroxytryptamine 1A)[56]. Salvia elegans is rich in caffeic acid, and there is an experimental study that showed a pharmaceutical preparation of a venlafaxine-caffeic acid salt to be useful in the treatment of depression in type 2 diabetes mellitus[57]. Such evidence may indicate the use of a crude extract or decoction of S. elegans in combination with other antidepressants for the reasons of increasing the consumption of glucose (hypoglycemic effect) and potentiating the activity of antidepressants. In addition, caffeic acid experimentally increases the levels of monoamine neurotransmitters that are related to the depressive disorder by attenuating the norepinephrine and decreasing the levels of tryptophan and 3-methoxy-4-hydroxyphenylglycol in depressed rats using a chronic unpredictable mild stress model for 6 weeks[58].

Salvia fruticosa (Greek sage)

The native of this sage is the eastern (southern Italy, The Canary Islands, and North Africa). It is especially abundant in Palestine, Israel, and Lebanon. As a traditional herbal medicine, it is used to produce a calming effect, but there are no experimental and clinical studies proving it to have anxiolytic effects. In vitro, an experimental study shows its constituents (α-humulene and α-pinene) have neuroprotective effects, as they protect the astrocytes from reactive oxygen species[59]. In addition, α-humulene activates the neurotransmitters, e.g., dopamine, serotonin, and norepinephrine, which explains the antidepressant effects of Greek sage[60]. Another study demonstrates that α-humulene interacts with GABA_AR and 5-hydroxytryptamin 3 receptors channels, suggesting that this active ingredient possesses anxiolytic and antidepressant effects[61].

Salvia fulgens (cardinal sage, Mexican scarlet sage)

The native of the sage is Mexico, and as a traditional folk medicinal herb, it is used to treat insomnia and restlessness, but there is no basic evidence for this use.

Salvia guaranitica (hummingbird sage, anise-scented sage, black and blue sage)

The native of this sage is South America. As early as 1997, this sage was investigated in mice by injecting its active constituent, cirsiliol, which produced hypnotic and sedative effects, proposing that this effect is mediated via the benzodiazepine receptor because it was observed that cirsiliol displaced ³H zolpidem binding in the rat cortex[62]. A synthetic cirsiliol has been found to inhibit Aβ aggregation, indicating a possible effectiveness in Alzheimer’s dementia[63].

Salvia hispanica

Its native area is Southern Mexico and Northern Guatemala. The seeds contained higher percentages of fatty acids, which are responsible for their antioxidant and antimicrobial activities[64]. In addition, the seeds contained vitamins (A, D, E, C, B1, B2, and B3) and phenolic compounds. It has been found that its constituent omega-3 fatty acid is responsible for its cardioprotective effect[65], while its contents of B1, B2, and B3 as well as its inhibitory effect on acetylcholinesterase may offer neuroprotective effects and improve cognitive functions[66]. The high ω-3 content of chia seed oil could be utilized as a nutraceutical in the management of psychiatric diseases.

It may act as an adjunctive treatment with other antidepressant treatments because its effect on depression is inconsistent[67].

Its potent antioxidant activity suppressed the neuroinflammation in the experimental animal model via different pathways (downregulated the neuropeptide Y, leptin receptor, and nuclear factor kappa-light-chain-enhancer of activated B cells gene expression and upregulated the nuclear erythroid-2-related factor), making it a neuroprotective agent[68]. In the in vivo worm model of juglone-induced Huntington’s disease, chia protects the worms from developing chorea and increases survival as it attenuates the basal reactive oxygen species levels in the worms (by upregulating the superoxide dismutase-3 and downregulating the heat shock protein 16.2 expression)[69].

Experimental evidence of streptozotocin-induced diabetes in rats: Chia attenuates the neurodegenerative process causing encephalopathy via its effect on the release of neurotransmitters (serotonin, noradrenaline, dopamine, and acetylcholine)[70]. These neurotransmitters play a role in the functions of memory, learning, mood, and protection against neurodegenerative diseases.

The antinociceptive effect of chia was reported in an experimental animal study using 1% acetic acid-induced writhing[71]. This effect can potentiate the antinociceptive effect of another herbal medicine, indicating that each herbal medicine produces analgesia via a different mechanism.

Salvia lavandulaefolia (Spanish sage)

Its native region is Spain and southern France. This sage seems to act on the central nervous system. In an in vivo experimental animal study, it improves the cognitive functions, which are assessed by Y-maze and Morris-water maze models. This effect is extended to improve the neural plasticity, neurogenesis, and neurotrophins that are demonstrated by histochemistry studies when it is used in combination with Salvia officinalis[72]. In healthy humans, the essential oil of Spanish sage improves the cognitive function in terms of improving the immediate word recall using the Cognitive Drug Research computerized test battery[73]. In another study on healthy humans, the oral dosing of the essential oils of sage improved the performance of secondary memory and attention tasks as well as decreased mental fatigue, possibly by inhibiting the activity of acetylcholine esterase[74-76]. A systematic review summarized the beneficial effect of using Salvia officinalis and Salvia lavandulaefolia in patients with dementia or cognitive impairment with a limitation, which is that the natural source is effective, the crude extracts, or the constituents of the essential oils[77]. In a crossover-controlled double-blind randomized clinical trial carried out on 26 volunteers, supplementation of Salvia officinalis and Salvia lavandulaefolia significantly and positively impacts cognitive function by improving the working memory assessed by the digit span memory test[78]. Hydroalcoholic extract and essential oil of Salvia lavandulaefolia are reported to have a positive impact on the memory of young healthy subjects and to be beneficial in mild-moderate Alzheimer’s dementia as they halt the disease progression[79]. The Salvia lavandulaefolia aroma was investigated on the healthy subjects using Bond-Lader mood scales, and it was found that the swinging in the mood that followed consumption of Spanish sage is related to the aroma of the essential oils[80].

Salvia leucantha (Mexican bush sage, wooly sage)

Many essential oils are separated from Salvia leucantha from the fresh leaves, and it has been found that these essential oils inhibit butyrylcholinesterase with an IC₅₀ of 32.60 µg/mL[81]. In a transgenic Caenorhabditis elegans model (CL4176) of Alzheimer’s dementia, the bioactive compound, 2,4-Di-tert-butylphenol, exhibits a neuroprotective effect in the nematode by extending the lifespan and delaying the paralysis of the nematode by up-regulating the gene gst-5, indicating that this sage has a potential value in treating Alzheimer’s dementia[82]. The synthetic 2,4-Di-tert-butylphenol experimentally showed an antianxiety behavior effect, and a network pharmacology analysis demonstrates that this active compound modulates the neurotransmitters (dopamine, serotonin, and GABA), which explains the neurobehavioral effect[83]. Synthetic 2,4-Di-tert-butylphenol supplementation attenuates the development of amphetamine-induced neurotoxicity as a result of decreased omega-3 fatty acids[84]. These results indicate that the bioactive compounds of wooly sage differed from the identical synthetic compounds in their effects on the central nervous system, which needs extensive research to disclose the differences.

Salvia limbate

The natives of this sage are Turkey and Iran. The sedative-hypnotic effect of this sage was demonstrated in the experimental animal study using phenobarbital-induced loss of righting reflex, while the anxiolytic effect was investigated using an open-field test. It has been proposed that S. limbate produces central nervous effects via modulating the GABA-A receptor[85]. This assumption is based on its oil, rosmarinic acid, which is documented to inhibit glutamate release and activate the GABA-A receptors in the 4-aminopyridine-induced glutamate release model[86]. In addition, the antinociceptive (analgesic) effect of this sage was demonstrated in the hot-plate test as well as attenuated the development of withdrawal syndrome in a morphine-induced dependency[87]. These findings are not explained on the basis of neurotransmitters that are involved in these pathological conditions.

Salvia longispicata

Oral dosage of Salvia longispicata (300 mg/kg) extract showed an antinociceptive effect, as with Salvia cinnabarina and Salvia lavanduloides, in a dose-response effect, and up to 2000 mg/kg, there is no evidence of toxicity[88].

Salvia microphylla (baby sage)

The bioactive compounds of the baby sage have antioxidant and antibacterial effects, as with other sage species[89]. In an experimental model of scopolamine-induced Alzheimer’s dementia in rats, the ethanolic extract of baby sage attenuates the scopolamine effects, including histopathological findings in the prefrontal cortex and hippocampus brain regions, deposition of β-amyloid plaque, oxidative stress species, and acetylcholinesterase activity, and it has been suggested that these neuroprotective effects are related to salvianolic acid K, rosmarinic acid, and salvianolic acid C[90]. The bioactive compounds, including rosmarinic acid and salvianolic acid C, are suggested to have anti-dementia effects by inhibiting glycogen synthase kinase 3β, an enzyme involved in the pathogenesis of Alzheimer’s dementia, as it dysregulates tau hyperphosphorylation and production of amyloid-beta protein[91,92]. Furthermore, rosmarinic acid is involved in hippocampal neurogenesis via modulating the glucocorticoid signaling on that site, which results in antidepressant-like behavior[93]. The antiferroptosis effect of rosmarinic acid inhibits the iron-induced α-synuclein aggregation via upgrading heme oxygenase-1 in a mouse model of Parkinson’s disease using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine[94-96].

Salvia miltiorrhiza (red sage, Danshen)

This sage is a Chinese medicinal plant with broad-spectrum pharmacological and biological properties (Figure 3). Preclinical and clinical studies demonstrated therapeutic efficacy in different psychiatric illnesses.

Figure 3 Preclinical and clinical evidence of the effects of Danshen on neurological and psychiatric illnesses.

Anxiety and depression: The ethanolic extract is investigated as an anxiolytic in mice using the elevated plus-maze and the hole-board tests; the results showed that significant changes in the mice’s behaviors are observed, similar to those observed with diazepam and buspirone, indicating that the anxiolytic effect is mediated by serotonergic and GABAergic receptors[97]. Another study investigated the extract of Danshen root (100 mg/kg) on stress-induced hyperthermia, and it effectively suppressed the response to stressful situations similar to that observed with diazepam (1.5 mg/kg, i.p.)[98]. In another experimental study using open-field and elevated plus maze tests as a model of anxiety-like behavior and conditioned fear and single-prolonged stress as an experimental model of post-traumatic stress disorder, Danshen induces upregulation of the synaptic plasticity-related proteins and activates the cyclic adenosine monophosphate response element-binding protein/brain-derived neurotrophic factor/tropomyosin receptor kinase B signaling signaling pathway in the hippocampus[33]. An analysis of 121 drugs such as ethanol tinctures from Kampo medicine found that the anxiolytic and sedative effects of Danshen are mediated via activation of GABAergic neurons[99]. A double-blinded randomized placebo-controlled study carried out on 200 participants presented with anxiety and depression following percutaneous coronary intervention found that Guanxin Danshen dripping pill treatment significantly improved the scoring of anxiety and depression as well as the quality of life[100].

Cognitive function: Salvianolic acid B in experimental animal studies improves cognitive function and learning by suppressing neuroinflammation and inhibiting the formation of amyloid-β protein, suggesting it to be useful as an adjuvant therapy to halt the progression of Alzheimer’s disease[101]. A systematic review and meta-analysis demonstrated that tanshinones positively impact cognitive function in 14 studies using different animal models of Alzheimer’s dementia by assessing the behaviors of rodents in terms of decreasing the number of escape latencies, increasing the times of platform crossing, and increasing time in target quadrants[102]. Salvia miltiorrhiza is one of 27 traditional Chinese medicines that positively impact cognitive impairment following post-ischemic stroke, and in combination with other medicinal plants, e.g., Acorus tatarinowii and Polygala tenuifolia, a synergism is observed[103]. In humans, a systematic review and meta-analysis of randomized clinical trials included 656 patients (vascular cognitive impairment) and 660 healthy subjects revealed that Danshen preparations significantly improved the cognitive function and life ability scores with a significant decline in the circulating highly sensitive C-reactive protein and IL-6[104]. Activation of the p38 mitogen-activated protein kinase/NF-κB signaling pathway is the molecular observation that followed stimulation of HMC3 cells by lipopolysaccharide to mimic a model of Alzheimer’s dementia in vitro. Salvianolic acid A modulates this pathway, leading to a decrease in the formation of Aβ-protein and reducing the hyperphosphorylation of tau protein in the hippocampus as well as suppressing the proinflammatory biomarkers[105]. Another activated signaling pathway was linked with impairment of cognitive function and spatial learning and memory in rats injected with the Aβ25-35 peptide intracerebroventricularly, which is downregulated with Danshen, manifested by amyloid precursor protein and presenilin-1[106]. In an ex vivo study, Salvia miltiorrhiza-containing plasma is effective in increasing the viable cell and acetylcholine levels and suppressing the apoptosis process in hydrogen peroxide-induced apoptosis in PC12 cells as an experimental study of cognitive impairment[107].

Depression: Network pharmacology identified Salvia miltiorrhiza as a traditional Chinese medicine, targeting the proteins of ferroptosis in depression, suggesting that the antidepressant effect of Danshen is mediated via downregulation of ferroptosis[108]. Rats exposed to chronic mild stress for 6 weeks lead to depression-like behaviors characterized by increased mobility duration, reduced weight gain, and sucrose preference. All these behavior changes are aborted by salvianolic acids or fluoxetine or a combination of them and are associated with a decrease of cerebral TLR4/MyD88 mRNA levels in prefrontal cortex and hippocampal regions[109]. In an experimental rat model of menopausal depression (induced by bilateral ovariectomies followed by chronic mild stress for 21 days), Danshen treatment improves behavioral changes, which are associated with higher circulating levels of norepinephrine, serotonin, and dopamine[110]. In mice, tanshinone IIA improves the duration of immobility that is induced by the forced swim test, associated with increased hippocampal levels of brain-derived growth factor, phosphorylated extracellular signal-regulated kinase, and phosphorylated cyclic adenosine monophosphate response element-binding protein[111]. Other authors thought that the antidepressant effect of Danshen is due to the suppression of neuroinflammation in the hippocampus region through inhibiting the activity of the NLR family pyrin domain-containing 3 inflammasome[112]. Depression-like behaviors can be induced by lipopolysaccharide for two weeks as a result of causing neuroinflammation by increasing the activity of the NLR family pyrin domain-containing 3 inflammasome; these effects are suppressed or attenuated by salvianolic acid B[113].

Neuroprotection: Danshen is being investigated against neurodegeneration induced by acrylamide in an adult Zebrafish model, and it has been observed to have antioxidative properties, reducing the cellular damage, restoring the acetylcholinesterase activity, and reducing the proinflammatory markers[114]. Danshen exerts neuroprotection via suppressing neuroinflammation via different signaling pathways. An extract of Danshen (sodium tanshinone IIA sulfonate) suppressed the neuroinflammation in sepsis-induced encephalopathy by activating the sirtuin 1/peroxisome proliferator-activated receptor gamma coactivator 1-alpha/nuclear respiratory factor 1/transcription factor A mitochondial pathway, resulting in reducing the mortality, preserving the hippocampal neurons, and ameliorating the cognitive and emotional dysfunction[115]. Activation of the c-Jun-N-terminal kinase pathway by salviobalic acid C protects animals from brain damage due to neonatal hypoxic-ischemic injury by its antioxidant and anti-inflammatory effects, as it reduced the levels of TNF-α, IL-6, and IL-1β[116].

Epilepsy: Luteolin, which is a bioactive compound of Salvia miltiorrhiza, has an anticonvulsant effect. In kainic acid-induced convulsions in mice, Danshen reduces the frequency and duration of the seizure and preserves the integrity of the neurons as it suppresses the inflammation and apoptotic processes in the hippocampus[117]. This antiepileptic effect is partly due to the upregulated effect of luteolin on the GADD458 protein because the antiseizure effect of luteolin declines in GADD458 knockdown mice[114]. Neuronal density assessed by immunofluorescence studies demonstrates neuronal apoptosis and suppression of protein kinase B/cyclic adenosine monophosphate response element-binding protein/brain-derived neurotrophic factor signaling pathway proteins in a pentylenetetrazole-induced seizure model[118], which is attenuated and reversed to the normal pictures after using salvianolic acid B, a bioactive compound of Danshen. In another experiment using magnesium-free-induced spontaneous epileptiform wave discharge from hippocampal neurons, tanshinone IIA protects the neurons against epileptiform discharge via upregulation of the brain-derived neurotrophic factor, synaptophysin, postsynaptic density 95, and p-Akt/Akt[119]. This effect is extended to improve the cognitive function and the frequency of seizures in an animal model of epilepsy induced by lithium chloride-pilocarpine via upregulation of synaptophysin and postsynaptic density 95, i.e., it improves the neuronal plasticity[120]. Oral dosage (85 mg/kg) of the compound Danshen dripping pill combined with carbamazepine (100 mg/kg) for 90 days attenuates the severity of seizures and the cognitive function impairment that is induced by intrahippocampal injection of kainic acid. These findings are associated with downregulation of Bcl-2/Bac and upregulation of glial cell line-derived neurotrophic factor in the hippocampus[121].

Parkinson’s disease: The reasons behind the role of Danshen in treating Parkinson’s disease are the ability of the bioactive compounds, including tanshinone I, tanshinone IIA, and cryptotanshinone, to inhibit the human monooxidase B at an inhibitory concentration of < 25 μM, and proteochemometric modeling found that tanshinone I selectively antagonizes the muscarinic acetylcholine receptor at M4[35].

Substance abuse: Salvia miltiorrhiza is one of the traditional Chinese medicines that has been found to be effective in reducing alcohol intake in patients with alcohol addiction[122].

Salvia nemorosa (woodland sage, Balkan clary)

The active compounds extracted from Salvia nemorosa, including rosmarinic acid, sagerinic acid, and caffeoylquinic acid, explained the antioxidant and anti-inflammatory effects of sage[123]. According to its active ingredients, it is possibly effective in anxiety-depression-like behavior.

Salvia plebeian

The wide pharmacological properties of Salvia plebeian are broad and extend to the central nervous system, which has anticonvulsant and sedative effects[124]. Eupafolin is one of the active compounds of sage that is reported to have an antiepileptic effect similar to carbamazepine in the kainic acid-induced epilepsy model[125]. It has been reported that eupafolin inhibits the release of glutamate in the synaptosomes via inhibiting CaMKII/synapsin I pathway as a result of blocking the P/Q-type calcium channels[126]. The antiaging effect of the sage is related to the constituent rosmarinic acid[127]. In addition, the bioactive compounds of Salvia plebeian inhibit the neurodegeneration effect of hydrogen peroxide on the PC12 cells associated with anti-inflammatory effects as they decrease the level of IL-6, IL-1β, and inducible nitric oxide synthase, suggesting that they could be useful in the management of neurodegenerative disease, e.g., Alzheimer’s disease[128].

Salvia pratensis (clary)

It contains large amounts of hydroxycinnamic acids (e.g., caffeic, p-coumaric, and ferulic acids), and the total phenolic compounds are approximately 79.22 mg/g dry extract[129]. It modulates the GABAergic neurons; therefore, it is used as a traditional medicine to produce a calming effect. The extract of Salvia pratensis is one among four medicinal plants that inhibits the amyloid aggregation of α-synuclein in vitro and downregulates the overexpression of protein in neuroblastoma cells[130], suggesting that it could be applicable as a therapeutic agent in neurodegenerative diseases, e.g., Alzheimer’s dementia, Parkinson’s disease, etc. In addition, the large amount of ferulic acid in the sage could explain the neuroprotective effect of the sage, as ferulic acid was investigated in the preclinical and clinical studies of Alzheimer’s dementia, and it was found to be a useful nutraceutical[131].

Salvia rosmarinus Spenn. (Rosmarinus officinalis L.)

Its native region is the Mediterranean, and it is cultivated all over the world. It is considered a “psychoaromatherapeutic agent” for the following reasons[132,133]: (1) Inhibition of acetylcholinesterase: The neuroprotective effect of sage is due to its inhibitory effect against acetyl- and butyrylcholinesterase with an IC₅₀ of 41.86 μg/mL due to its antioxidant effect[134,135]. In addition, Salvia rosmarinus spenn is rich with carnosic acid, which is a potential natural neuroprotective agent that inhibits the acetylcholinesterase activity, which plays a role in the development of Parkinson’s disease and Alzheimer’s dementia[136]. Ethyl acetate rosemary extract inhibits the acetylcholinesterase by 75% compared with 88% induced by galanthamine, with an IC₅₀ of 272 μg/mL, which is lower than that produced by the aqueous extract (534 μg/mL)[137]; (2) Modulation of dopaminergic and oxytocinergic systems: The psychostimulant effect of cocaine results from the downregulation of the potassium voltage-gated channels subfamily Q (member 3 and/or 5). This effect is attenuated by using carnosic acid, which acts on the reward center in the brain, leading to impairing the cocaine reward and volitional intake of cocaine in mice[138]. This preclinical finding suggested using Salvia rosmarinus for treatment of withdrawal symptoms. Another active compound is α-pinene, which is found to enhance the production and secretion of dopamine following the stressful conditions via the hypothalamus-pituitary-adrenal axis[139]. In an animal model of anxiety and depression, Rosmarinus officinalis extract significantly improves the central oxytocin levels as a result of upregulation of oxytocin expression and is associated with increased levels of circulated corticosteroids[140]; (3) Attenuating neuropathic pain via inhibiting oxidative and inflammatory proteins; (4) Antidepressant and anxiolytic: A double-blinded randomized controlled clinical trial included 68 participants who consumed 500 mg of rosemary and a placebo twice daily for one month; the scores of the Hospital Anxiety and Depression Scale and the quality of sleep were improved[141]; and (5) Improving amnesia in scopolamine-, lipopolysaccharide-, AlCl₃-, and H₂O₂-induced amnesia. In a rat model of scopolamine-induced amnesia-like Alzheimer’s dementia, essential oils of rosemary showed significant improvement of the working and spatial memory process associated with increased levels of brain-derived neurotrophic factor in the hippocampus[142]. In comparison, between rosemary and methylphenidate in AlCl₃-induced impairment of memory, both compounds significantly improved memory impairment; rosemary reduced depression and anxiety and showed an antidepressant effect, but it induced anxiety-like behavior[143]. Neither rosemary nor methylphenidate produced a significant reduction in amyloid protein[143].

Rosemary: Docking analysis and network pharmacology

The results of the docking analysis of rosemary active substances targeting the proteins that are involved in the progression of Alzheimer’s dementia, notably angiotensin converting enzyme, β-secretase 1, glycogen synthase kinase-3, and tumor necrosis factor-α-converting enzyme, showed that α-amyrin is highly bound to angiotensin converting enzyme, and β-secretase 1 (-10 kcal/mol, -9.1 kcal/mol, and -9.9 kcal/mol, respectively), and the target of benzenesulfonamide, 4-methyl-N-(5-nitro-2-pyridinyl), is tumor necrosis factor-α-converting enzyme (-9.1 kcal/mol), indicating that rosemary is a potential nutraceutical therapy for Alzheimer’s dementia[144]. The results of one network pharmacology study showed that the anti-inflammatory property of rosemary essential oils is the mechanism of the anti-dementia effect, and it is mediated by downregulation of the IL-17 and advanced glycation endproducts-receptor for advanced glycation endproducts signaling pathways[145]. The effect of rosemary bioactive compounds on insomnia is related to their actions on the 5-hydroxtryptamine 1A receptor, leading to serotonin release and upregulation of GABA-A[146]. This docking analysis result is proved by an experimental animal study with variable effects[146]. Network pharmacology showed that the targets of rosemary differ from its bioactive compound, carnosic acid, in cerebral ischemia-reperfusion injury, indicating that each active compound could have a definite therapeutic effect[147].

Salvia sagittata

The Andes Mountains (South America) are the native home of this sage. The antioxidative effect of Salvia sagittata extract or its active constituents was demonstrated in the culture of vascular endothelial cells by reducing the interleukin 6[148].

Salvia sclarea (clary)

The essential oils of Salvia sclarea are used in the cosmeceutical and perfume industries, and their antibacterial effect is comparable to meropenem; in addition, they showed insecticidal and antioxidant effects[149]. The spasmolytic (analgesic) effect of this sage active compound (sclareol) was demonstrated in the ex vivo and in vivo study using uterine smooth muscle of the rat, as it inhibits the effect of prostaglandin F2-alpha, acetylcholine, and oxytocin through different mechanisms that regulate the calcium, e.g., myosin light chain kinase, cyclooxygenase-2, and expression of phospho-myosin light chain 20[150]. This spasmolytic effect was also reported on the spontaneous contraction of ileal smooth muscle with the use of 80% methanol extract, and the results of docking analysis demonstrated that the voltage-gated calcium channel is the target of its active compounds, apigenin-7-O-glucoside and luteolin-7-O-glucoside[151]. In Parkinson’s animal model, sclareol exerts a neuroprotective effect via inhibiting the calcium voltage-gated 1.2 L-type channels, an effect similar to that produced by cinnarizine[152]. Sclareol at a higher dose significantly prolonged the latency of sleep induced by sodium thiopental, as proved by docking analysis that shows it binds the GABA-A receptors[153]. The neuroprotective effect of sclareol in an experimental model of Alzheimer’s dementia is due to the downregulation of the NF-κB signaling pathway, leading to the suppression of neuroinflammation in the microglia as a result of targeting the cyclin-dependent kinase 9[154]. Another effect of sclareol on the central neurotransmitters is an antiemetic effect, probably via its modulatory central effect on serotonin and dopamine, as network pharmacology analysis revealed that 5HT₃, D₂, M₃/AChM, H₁, or NK₁ receptors are involved in emesis[155]. In an observational clinical study carried out on 72 patients with diabetic feet and presenting with depression of variable degrees, Salvia sclarea oil reduces the stress scale and the visual analog scales of anxiety and depression[156]. It has been suggested that the antidepressant effect of clary is related to its active compound “linalyl acetate”[157]. In addition. Linalyl acetate in an in vivo experimental animal study significantly has antidepressant-like behavioral effects associated with improvement of the circulating and cerebral cortex and hippocampus tissues of the brain-derived neurotrophic factors and decrease of circulating corticosteroid and proinflammatory markers[158].

Salvia uliginosa (bog sage)

In the Caenorhabditis elegans Alzheimer’s dementia model, the extract of the Brazilian medicinal plant Salvia uliginosa increased the life span of the nematode associated with decreasing neurotoxicity due to β-amyloid (Aβ)-induced paralysis and deposition in the susceptible neurons, suggesting it has a therapeutic effect in neurodegenerative diseases[159]. It has been proven that sage species generally are effective natural remedies with sedative effects, and they potentially inhibit acetylcholine esterase, leading to improved cognitive function, and this explains why researchers are extensively working on the effect of sage on cognitive function (Figure 4).

Figure 4 Salvia species demonstrated positive effects on the cognitive function in the preclinical and clinical studies.

PRECLINICAL AND CLINICAL EVIDENCE OF ANTIPSYCHIATRIC VALUE OF SAGE

This narrative review explores the central effects of sage related to psychiatric signs and symptoms, as supported by experimental studies ranging from behavioral observations (e.g., depression, anxiety, or cognitive function) to biochemical measurements, histopathological findings, and the identification of signaling pathways and protein-to-protein interactions through docking and network pharmacology. Table 1 shows that there are many experimental models introduced to assess the effectiveness of the sage or their active ingredients in behavior-related psychiatric illnesses. These models do not precisely represent human psychiatric illnesses. Therefore, the results obtained from these studies are supportive and cannot be approved for psychiatric signs and symptoms. In addition, the ideal extracts or the active ingredients are not identified in terms of solvents, extraction methods, and the effective dose or concentrations. The acute toxicity study to identify the effective dose of 50% and lethal or toxic dose (50%) is done in a few studies, so the generalization of the effectiveness of the sage in psychiatric practice is limited. There is no doubt that Salvia species are used as folk medicines for calming and sedation purposes. The clinical studies that were carried out on psychiatric patients are a few (Table 2) and of variable directions, which means the clinical-based evidence needs further studies[51,100,160-162]. There is no doubt that the active ingredients of the Salvia species have definite psychiatric-related effects, but they are not comparable to the synthetic medicines that are approved for the treatment of generalized anxiety disorder, depression, memory impairment, and Alzheimer’s diseases. Salvia divinorum, as a crude plant, is a safe hallucinogen, and evidence of producing analgesic effect is reported.

Table 1 Preclinical studies (experimental and on healthy humans) demonstrated the value of Salvia species or their active ingredients on the behavior-like psychiatric illness.

Salvia spp., or active ingredients	Experimental model	Psychiatric pathological conditions	Results	Ref.
Asiatic acid (a triterpene)	Quinolinic acid toxicity-induced induced spatial memory defect in rats	Memory	Improved	[14]
Hugan Tiaoshen formula	PPI network identified core targets by topological analysis	Schizophrenia	Strong binding between, β-sitosterol, and the targets	[20]
	Machine learning	Sleep disorder
Tanshinone IIA	Conditioned fear and single-prolonged stress tests in mouse	Posttraumatic stress disorder	Decreased freezing time in contextual fear test	[33]
			Relieved anxiety-like behavior in open field and elevated plus maze tests
			Upregulated synaptic plasticity-related proteins
Tanshinone IIA	Depression-like behavior	Depression-like behavior	Upregulated expression of GABA transporter 1	[34]
	Cognitive impairment model (in rat)	Cognitive impairment	Reduced expression of synaptic proteins centrally
Tashinone I and II	Targeting recombinant human monoamine oxidase isoenzymes	Depression	Inhibition of monoamine oxidase A	[35]
		Parkinson
Mesyl Sal B (analogue of Salvinorin A)	Cocaine-induced hyperactivity and behavioral sensitization in rats	Drug dependence	Attenuate with limited antinociceptive effect	[52]
Essential oil of Salvia fruticose	H2O2-induced astrocyte cell death, in vitro study	Neurodegenerative disease	Protects the cell from death	[59]
α-humulene	In vivo behavioral responses of adult zebrafish	Behavior responses	Anxiolytic-like effect	[61]
Salvia guaranitica extracts	In vivo sedative and hypnotic effects in mice	Sedative and hypnosis	Cirsiliol produced a dose-dependent hypnotic action	[62]
Active ingredients
Salvia hispanica L. seeds	In vivo writhing test in rats	Analgesia	Antinoceptive	[71]
Salvia officinalis aqueous extract Salvia lavandulaefolia-encapsulated essential oil	In vivo long-term administration in rats	Neuronal plasticity (neurogenesis, neuronal activity, neurotrophins)	Improved	[72]
	Y-maze markers
	Morris water maze markers
Essential oil extract of Salvia lavandulaefolia	Controlled-placebo study on healthy human subjects	Cognitive function	Improved immediate word recall	[73]
	Cognitive Drug Research Computerized test Batter
Salvia lavandulaefolia essential oil	Double-blind controlled-placebo study on healthy human subjects	Cognitive function	Improved performance of secondary memory	[74]
	Cognitive Demand Battery		Improved attention tasks
	Computerized memory and attention tasks		Reduced mental fatigue
Salvia lavandulaefolia eessential oil	In vivo, experimental rats	Choline esterase activity in the brain	A significant decrease of choline esterase in striatum and hippocampus	[75]
Salvia lavandulaefolia Vahl. essential oil	In vitro, human red cell	Choline esterase activity in red cell	Significant decrease	[78]
A combination of Salvia officinalis and Salvia lavandulaefolia	Cross-over, randomized, double-bind placebo-controlled trial; healthy subjects. A Stroop task	Cognitive function	Improved the cognitive functions (perceived exertion, working memory, and reaction time)	[78]
	A simple reaction time task
	A backward digit span memory task
Salvia leucantha Cav. essential oil	In vitro	Choline esterase activity	Significant inhibition	[81]
Salvia limbata C.A. Mey extract	Sedative-hypnotic-anxiolytic (pentobarbital-model inducing loss of righting reflex test and open field test)	Anxiety	Anxiolytic and hypnotics (modulates GABA-A receptors)	[85]
		Insomnia
Rosmarinic acid	In vitro, GABA receptors, glutamate release in cerebrocortical synaptosomes	CNS-neurotransmitters and receptors	Activates GABA-A receptors	[86]
			Inhibits glutamate release
			Decreases Ca2+ influx
S. limbate and and S. hypolecuca extracts	In vivo, morphine-dependence model in mice	Antinociceptive activity	Significant inhibition of pain and development of morphine dependence	[87]
Salvia cinnabarina, Salvia lavanduloides, Salvia longispicata methanolic extracts	In vivo evaluation of the antinociceptive effect and acute oral toxicity	Antinociceptive	A significant antinociceptive effect at a dose of 300 mg/kg administered orally LD50 > 2000 mg/kg	[88]
Salvia officinalis, Salvia microphylla extracts	Scopolamine-induced memory impairment in rats. Histopathology	Cognitive function	Reduced β-amyloid deposition	[90]
	Virtual docking to the active sites of the human acetylcholinesterase		Decreased acetylcholine esterase activity
Salvia miltiorrhizae radix extract	Estimation of glycogen synthase kinase 3β, AutoDockTools	Cognitive function	Decrease the glycogen synthase kinase 3β	[91]
Rosmarinic acid	Chronic cortisone injection induced depression-like behavior in mice	Behavior like-depression	Modulating the hippocampal glucocorticoid signaling and hippocampal neurogenesis	[93]
Rosmarinic acid	1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine MPTP-induced mouse model of Parkinson’s disease	Motor activity	Decreased the mRNA levels of α-synuclein	[94]
Salvia miltiorrhiza Bunge ethanolic extract	Anxiolytic model using plus-maze test and the hole-board test	A decrease in spontaneous locomotor activity	Anxiolytic effect via activation of the benzodiazepine and serotonin (5HT1A) receptors	[97]
Salvia miltiorrhiza: Tanshinone IIA	Double stress exposure in mice	PTSD-like symptoms	Increased the spine density and upregulated synaptic plasticity-related proteins	[99]
Salvianolic Acid B: Salvia miltiorrhiza	Pain-depression comorbidity models	Alzheimer’s disease models	Suppresses amyloid-beta formation and neuroinflammation	[101]
	Histopathological
	Signaling pathways
Salvianolic acid A	Integrative network pharmacology, molecular docking, and pathway enrichment analysis	Cognitive function	Ameliorates cognitive decline Decreases tau protein hyperphosphorylation	[105]
			Reduced amyloid-β accumulation
Compound Danshen	Alzheimer’s disease rat model: Aβ25-35 peptide intracerebroventricularly injection	Memory	Improvement	[106]
	Spatial learning and memory impairments
	Memory impairment in both Morris water maze and passive avoidance task
Salvianolic acids	Chronic mild stress-induced depressive-like behaviors in rats. Sucrose preference	Behavior-like depression	Weight gains	[109]
			Alleviated depressive-like behaviors
	Immobility duration in forced swimming		Reduced cerebral TLR4/MyD88 mRNA levels in brain
Danshen-Honghua	In vivo, chronic mild stress in rats	Menopausal depression	Improved open-field locomotor scores	[110]
			Improved sucrose intake
			Improved serum monoamines level
Tanshinone IIA of Salvia miltiorrhiza	Brain-derived neurotrophic factor expression in the hippocampus of depressive mice: In ex-vivo and in vitro	Cognitive function	Improved p-ERK and p-CREB, BDNF proteins expression in mice	[111]
Salvianolic acid B of Salvia militiorrhiza Bunge	Chronic mild stress for 6 weeks, in rats	Behavior-like depression	Improved sucrose consumption	[112]
			Reverse the hyperactivity of hypothalamic-pituitary-adrenal
			Decreased inflammatory cytokines
Tanshinone IIA	Acrylamide-induced depression and cognitive impairment in adult zebrafish model; in vivo, and ex vivo	Cognitive function	Restored the morphological brain damage	[114]
		Motor activity
Saebias A-G (1-7) from Salvia plebeia R.Br.	In vitro neuroprotection using; lipopolysaccharide induced changes in BV-2 cells, and H2O2 in PC12 cells	Neuroinflammation	Neuroprotection	[128]
Salvia rosmarinus essential oil	In vitro assay of AChE and BuChE	Neuroprotection	Inhibition	[134]
Rosmarinus officinalis	Docking analysis of ursolic acid, rosmarinic acid and carnosic acid, targeting Alzheimer’s disease-associated proteins	Alzheimer’s diseases	Strong binding affinity with acetylcholine esterase, butylcholine esterase-1 and synapsin I, II and III	[135]
Rosmarinus officinalis extract	Stress markers	Anxiety, depression	Ameliorates stress markers	[140]
	In vivo stress model using tail suspension test and elevated plus maze test in mice		Reversed the behavioral changes
			Improved oxytocin expression
Rosemary oils	Scopolamine-induced amnesia-like Alzheimer’s dementia	Cognitive function	Improved performance of working and spatial memory	[142]
Rosmarinus officinalis	AlCl3-induced mouse model of AD, formation of amyloid beta plaques in hippocampus	Cognitive function	Improved the memory	[143]
Rosemary oils	Docking analysis targeting ACE, BACE1, GSK3, and TACE proteins (AD progression)	Alzheimer’s dementia	Highest binding affinity against each protein	[144]
Rosmarinus officinalis L.	Network pharmacology	Insomnia	Upregulation of GABA-A expression	[146]
	Open-field experiments
	ELISA kits (5-HT, GABA, and DA), western-blotting, Rt-PCR and immunohistochemical assay experiments

GABA-A: Gamma-aminobutyric acid type A; PPI: Protein-protein interaction; LD₅₀: Lethal dose 50%; 5HT_1A: 5-hydroxytryptamin 1A; PTSD: Posttraumatic stress disorder; p-ERK: Phosphorylated extracellular signal-regulated kinase; p-CREB: Phosphorylated cyclic adenosine monophosphate response element-binding protein; BDN: Brain-derived neurotrophic factor; AChE: Acetylcholinesterase enzyme; BuChE: Butyryl cholinesterase enzyme; CNS: Central nervous system; MPTP: Methyl phenyl tetrahydropyridine; ACE: Acetylcholinesterase; BACE1: Β-secretase 1; GSK3: Glycogen synthase kinase 3; TACE: Tumor necrosis factor-α converting enzyme; AD: Alzheimer disease; 5-HT: 5-hydroxytryptamine; GABA: Gamma aminobutyric acid; DA: Dopamine; Rt-PCR: Reverse transcription polymerase chain reaction; ELISA: Enzyme linked immunosorbent assay.

Table 2 Clinical trials conducted on the effect of Salvia species or their active ingredients on patients presented with psychiatric-related illnesses.

Ref.	Study	Sample size	Salvia species active ingredients	Psychiatric illness	Primary outcomes	Results
Wang et al[100], 2023	Randomized double-blind placebo-controlled study	100 patients vs 100 healthy subjects	Guanxin Danshen Dripping Pills (0.4 g thrice daily for 12 weeks)	Anxiety and depression + coronary heart disease	Generalized Anxiety Scale, Patient Health Questionnaire-9	Significant improvement
Wu et al[160], 2024	The ADECODE-Real World Study: Cohort clinical observational study	1428 patients	Guanxin Danshen Dripping Pills (0.4 g thrice daily for 12 weeks)	Anxiety and depression + coronary heart disease	Clinical signs and symptoms	Significant improvement
					Generalized Anxiety Scale
					Patient Health Questionnaire-9
Azizi et al[161], 2022	A randomized, double-blind, placebo-controlled trial	44 patients	Hard gelatin capsule containing rosmarinic acid (21.13 ± 0.56 mg/g crude Salvia rosemarinus) once daily for eight weeks	Major depressive disorder	Hospital Anxiety and Depression Scale and Beck Depression Inventory	Improvement
Akhondzadeh et al[162], 2003	Placebo-controlled clinical trial	42 patients	Fixed dose (60 drops/day) crude Salvia officinalis extract	Cognitive function	Cognitive subscale of Alzheimer's Disease Assessment Scale Clinical Dementia Rating	Improvement
Karam et al[51], 2019	Cross-sectional study	47 patients	Drug users screening between Salvia users and non-salvia users	Illicit drug users	Hallucinogen Rating Scale	No significant difference

SAFETY AND TOXICITY OF SAGE

Sage in general is safe, as it is used in traditional medicine, beverages, and additive food. Adverse reactions to the Salvia could occur depending on the consumption of a large quantity, the Salvia species, or its active ingredients. Consumption of a large amount of S. officinalis produces symptoms and signs of cholinergic activation, e.g., vomiting, diarrhea, salivation, flushing, and convulsion[163]. Oral administration of Salvia blancoana subsp. mesatlantica (Maire) Figuerola at doses of 0.5-11 g/kg is safe, while the intraperitoneal administration causes dose-dependent acute toxicity with a lethal dose (50%) of 6.82 g/kg in mice; a decrease of blood glucose was observed with chronic toxicity[164]. A broad spectrum of toxicity (e.g., embryotoxic and genotoxic) induced by the active ingredients of sage, e.g., α-terpinene, camphor, and thujone, particularly in pregnant women[165]. The interaction of herbal medicine (sage) with drugs produces synergism rather than adverse reactions, as the Salvia species have anti-inflammatory, antioxidant, antimicrobial, antidiabetic, etc.

Salvia divinorum is also referred to as “magic mint”, “diviner’s sage", and “mystic sage”. It has a potent hallucinogenic effect that is comparable to lysergic acid diethylamide, a classical hallucinogen, but with a short-lasting effect extended up to 60 minutes[166]. The pharmacokinetics of its active constituent, Salviorin A, are characterized by high lipid solubility, which makes it easily penetrate the blood-brain barrier, and it produces atypical dissociative states in the absence of euphoria or negative impact on the cardiorespiratory systems. It is potentially addictive due to its modulatory effects on the dopaminergic and glutamatergic systems[167,168]. Salvinorin A is safe, as it does not impair the vital signs or cognitive function, and it lacks excitatory effects[39,169]. In rats, a toxic dose of 1600 μg/kg does not produce harmful effects on the body temperature of cardiac conduction[170]. In human inhalation, 12 mg of salvinorin A does not produce adverse reactions[170]. Most acute and chronic studies demonstrated the safety of Salvia divinorum and salvinorin A[171].

LIMITATIONS

There are several limitations to using some Salvia species in the management of anxiety and depression and improving cognitive functions, as well as to avoid using Salvia divinorum because it is a hallucinogenic plant. Therefore, using sage as folk medicine to produce calming and sedative effects cannot be used in the same way as benzodiazepines in producing sedation and hypnosis for the following reasons: (1) It is uncertain whether the extracted active ingredients or the crude extracts are precisely producing central effects; (2) The methods of preparing crude extracts and extraction of the active ingredients need standardization, and the effective dose (50%) that produces calming or antidepressant effects needs to be identified; (3) The majority of these studies are preclinical or clinical at different phases, which indicates extensive research on this topic is necessary; and (4) The preclinical studies are important to show the pharmacodynamic and pharmacokinetic properties of sage, and this explains that using sage is safe and there are no severe adverse reactions reported even with using Salvia divinorum.

CONCLUSION

Great caution in using sage is necessary, as it could have three different psychiatric effects: Beneficial (e.g., Salvia miltiorrhiza, Salvia rosmarinus spenn), dual (e.g., Salvia coccinea), and psychoactive (Salvia divinorum). Their pharmacological actions are mainly reported in preclinical studies, and different mechanistic pathways are involved. Their active ingredients show multiple pharmacological effects, and the precise effective dose and duration of treatment have not yet been established. Current evidence is predominantly preclinical and insufficient to recommend Salvia preparations for psychiatric practice. The available evidence points to the fact that no Salvia preparation is currently established for routine psychiatric treatment. Chemical standardization, toxicological characterization, pharmacokinetic investigation, and adequately powered randomized trials will precisely identify the effectiveness of sage in psychiatric illnesses, mainly in anxiety and affective disorders, as well as in cognitive functions.

ACKNOWLEDGEMENTS

The authors express their gratitude to the Ishtar Medical Institute of Technology for encouraging scientific research and for providing facilities to complete this review.