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

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.