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(Emblica ofcinalis) exhibited antioxidant properties in changes in the rat brain brought on by chronic stress [80]. A well-known ayurvedic supplement called Triphala, which contains the herbs, Emblica ofcinalis, Terminalia belerica, and Terminalia chebula, guards against the effects of noise stress on rats’ antioxidant and cell-mediated immune systems [106]. Holi basil, or Ocimum sanctum, is also called “Tulsi” in India. It is used in Ayurveda for its healing and life-giving properties and is regarded as one of India’s holiest plants. There are other Tulsi cultivars that are sometimes referred to as “Holy,” but the Ocimum sanctum is the genuine kind [107]. Tulsi is an upright, hairy annual herb found all over India and as high as 1800m in the Himalayas. A range of disorders can be treated using tulsi. For its impact on the central nervous system, an ethanolic extract from Ocimum sanctum leaves reduced [107]. Pentobarbital-induced reex loss in mice was delayed, and the duration and intensity of convulsions brought on by electroshock and pentylenetetrazole were reduced. By analysing the levels of plasma corticosterone in rats exposed to 30min of noise stress (100dB), the ethanolic extract of leaves from Ocimum sanctum was tested for its anti-stressor effects against acute and chronic noise stress in albino rats [107]. Ethanolic extracts of Tulsi plants (Ocimum sanctum) were used to treat animals which were exposed to acute and long-term noise stress. The results showed that the plant’s anti-stress qualities prevented the increase in plasma levels of corticosterone in these animals [107].

8 Plants Modulating Serotonergic

Systems

To support physical and mental health, Ashwagandha (Withania somnifera) having adaptogenic, antidepressant, and anxiolytic properties mediated through the serotonergic system is widely used [88]. Aloysia polystachya, sometimes referred to as griseb, is a member of the Verbenaceae family. In female rats participating in the forced swim test, the hydroalcoholic extract of its (A. polystachya) leaves at varying concentrations (50, 25, and 12.5mg/kg, i.p.) (12.5, 25, and 50 mg/kg, i.p.) demonstrated anti-depressant effects. Carvone and thujone are two bioactive compounds in A. polystachya with anti-depressant characteristics and properties that can treat serotonergic abnormalities [108]. Aniba riparia (Nees) (family, Lauraceae) contains phytoactive compounds called riparin III, showing antidepressant- like action in mice when evaluated using the Tail Suspension test (TST)

and FST (25 and 50 mg/kg, intraperitoneal) [109]. Additionally, several investigations utilizing mice and rats in the behavioral study have shown that the saponins bacopasides VI-VIII, bacopaside I, bacopaside II, and bacopa saponin C. present in B. monnieri (Brahmi) has anti-depressant properties, regulating the serotonin concentration at doses of 20 and 40mg/kg [88]. A member of the Theaceae family is the tea plant Camellia sinensis (L.) Kuntze. When tested in FST on male mice, the aqueous extract of its plants’ leaves had potent serotonin-regulating activity (antidepressant-like effect) at the dose of 100 mg/kg [88]. A member of the Zingiberaceae family is Curcuma longa, often referred to as turmeric, haldi, or Haridra in India [88]. It includes curcumin, an active phytochemical with several pharmacological benets and anti-inammatory, antioxidant, and neuroprotective effects [88]. Recent research has also shown that in TST and FST, it is a more potent anti- depressant than uoxetine [110]. The Berberidaceae family includes Berberis aristata, often known as Daruharidra or Daruhaldi. It has historically been used to treat inammation, wound healing, and skin conditions. It has other pharmacological uses, including hepatoprotective, anti-diabetic, anti-inammatory, and antioxidant. It contains berberine. This isoquinoline alkaloid is an effective anti-depressant in mice when tested using FST [88]. Root components of the Alliaceae family plant Agapanthus cam- panulatus are used to initiate conventional treatments. A type of mental disorder known as “the spirit” is reported to be treated with various parts of the plant while its extracts showed SSRI action [47]. Decoctions of the plant Boophone disticha’s bulb scales are used to calm aggressive, schizophrenic patients. Bulb infusions are consumed by traditional healers and patients in South Africa as a medication to cure mental diseases and cause hallucinations for divinatory purposes [111]. Buphanidrine and buphanamine, isolated from the Amaryllidaceae plant Boophone disticha, had an afnity for the serotonin transporter (SERT) protein [147]. Powdered leaves from the Gomphocarpus physocarpus of the asclepiadaceae family are used as sedatives and to “strengthen the physique”. Xysmalobium undulatum (L.) leaves extract showed SSRI action. In the Asphodelaceae family, plants like Gasteria croucheri were used in hysteria treatment in South Africa. Leaves of Dioscorea species (Dioscoreaceae family), Millettia grandis, Schotia brachypetala, Leonotis leonurus (Lamiaceae), Mentha aquatica L., Cinnamomum camphora (L.), and Buddleja (L.) species (Loganiaceae) have effective activity against serotonergic disorders like epilepsy, hysteria, convulsions, dispel worries and inducing sleep disorders [47].

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9 Serotonin Contents inHerbal Plants

extracts

In the years after its discovery, serotonin has been found in more than 37 plant families and 90 species, inuenced by species, family, and the development of the maturational stage [46]. Serotonin was rst discovered in plants in the legume Mucuna pruriens [113]. Moreover, plant serotonin has signicant variations concerning environmental factors, including wavelength, light intensity, abiotic and biotic conditions, stress, and physiological conditions [46,

113, 114]. The aerial tissues of plants appear to have good

serotonin levels in vegetative tissues [115–117]. Reproductive plant parts like owers, fruits, and nuts [118–120] are generally found to have an elevated amount

of serotonin than vegetative tissues, which have classes that vary from one tissue to another and with time, maturity stage, and even within the same tissue [121–123]. The edible tissues with high serotonin concentrations include black walnut (Juglans nigra L.) (4 46 g/g), butternut (Juglans cinerea L.) (398 90 g/g), Carya ovata (Mill.) K.Koch (shagbark) (143 23g/g), and Tomato (Solanum lycopersicum L.) 156.1–221.9g/g. In edible tissues, somewhat high amounts of serotonin is found in corn (Zea mays L.) (108.2 g/g) [124], cranberry (Vaccinium spp.) (105– 122 g/g), banana (96.9 4.3 g/g) [119], ginger (Zingiber ofcinale Ros) and coffee bean (Coffea canephora) (63.3μg/g) [115], spinach, Chinese cabbage, and cherry tomatoes also contain about 100g/g of dry weight serotonin [120] (Table1).

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[37, 126]

[37, 150]

[37, 153]

[37, 157]

[158, 159]

[160, 161]

[37, 162]

[37, 163]

[37, 165]

[37, 163]

[37, 165]

[37, 167]

[37, 169]

[37, 170]

[37, 171]

process of the brain, and controls the gut microbiota

neurotoxicity, lipid peroxidation, and neuroinammation.

Neuroprotection against toxicity, inammation, oxidative stress,

apoptosis, and depression

well as 5-HT, dopamine, and MAO levels

and neurotoxicity

and depression

degeneration, inammation, oxidative stress, and depression

damage, apoptosis, and inammation

properties.

brain against toxicity, inammation, and depression

properties

brain against toxicity, inammation, and depression

stress, depression, and inammation

Improves gut microbiota balance, cognitive health, and

neuroprotection against oxidative stress, inammation, and

neuronal death

Neuroprotection against oxidative stress, toxicity, inammation,

and anxiety

brain from toxicity and oxidative damage

indicators, and 5-HT

oxidative markers

Compound Class Pharmacological Target Pharmacological Action References

Anthocyanins Flavonoid 5-HT, gut, BDNF Anti-depressant, anti-neuroinammatory, slows the ageing

Asiaticoside Terpenoid BDNF, inammatory markers, Improves colitis, GI motility, and homeostasis while preventing

Table 1 The mechanisms of the effect of medicinal herbs on serotonergic transmission

Bacoside A Terpenoid BDNF, 5-HT receptors, and synaptic proteins Anti-depressant and anti-anxiolytic [151, 152]

Astragaloside IV Polyphenol Oxidative, apoptotic, and inammatory factors, as

Anonaine Alkaloid 5-HT Anti-depressants, sedatives, and anxiolytics [154, 155]

Catechins Flavonoid BDNF, microbes, and MAO Protection of the nervous system from oxidative stress, anxiety,

Curcumin Phenol 5-HT BDNF Protection of the nervous system from oxidative stress, apoptosis,

Carvacrol Phenol 5-HT and BDNF Gastro protective and provides neuroprotection against memory

Chrysin Flavonoid 5-HT and MAO Protection of the gut and the nervous system from oxidative

Ferulic acid Phenol 5-HT, MAOA, and BDNF Increases 5-HT levels and has antidepressant and neuroprotective

Ginkgolides B Terpenoid BDNF and serotonin Increases cognitive functions and decreases stress and anxiety [37, 164]

Hesperidin Flavonoid BDNF Controls gastrointestinal motility and prevents damage for the

Hyperforin Terpenoid MAOA, kynurenine/Trp ratio, and 5-HT Antidepressant [37, 166]

Ferulic acid Phenol 5-HT, MAO-A, and BDNF Increases 5-HT levels and has antidepressant and neuroprotective

Ginkgolides B Terpenoid BDNF and serotonin Increases cognitive functions and decreases stress and anxiety [37, 164]

Hesperidin Flavonoid BDNF Controls gastrointestinal motility and prevents damage for the

Hyperforin Terpenoid MAOA, kynurenine/Trp ratio, and 5-HT Antidepressant [37, 166]

Limonene Terpene Gut microbiome, BDNF, and melatonin Neuroprotection against inammation and oxidative stress (IBD) [37, 165]

Ellagic acid Phenol 5-HT and BDNF Memory improvement and neuroprotection against oxidative

Ginsenoside Rg5 Terpenoid BDNF and serotonin Antidepressant [37, 168]

Linalool Terpenoid Mucosal immunity, gut microbiota, inammatory

Lycopene Carotenoid BDNF, serotonin, dopamine, inammatory, and

Resveratrol Polyphenol Serotonin, SERT, and BDNF Increases 5-HT levels, prevents 5-HT reuptake, and protects the

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10 Geographical Distribution ofPlants

Aecting Serotonergic System

In countries like India, Japan, China, Pakistan, Thailand, and Sri Lanka, traditional medicine is widely used. Medicinal plants are found in various habitats throughout India, but tropical forests in the Eastern and Western Ghats and the Himalayas are home to about 70% of the country’s medicinal plants [125]. A large number of plants, derivatives or metabolites of plants, or extracts of traditional plants helpful for serotonergic transmission, are distributed worldwide according to their suitable climatic conditions (Table2).

11 Medicinal Plants andTheir

Mechanism ofAction onSerotonergic Transmission

Inhibition of Serotonin transporter (SERT) is the main focus because SERT transports serotonin back into the presynaptic serotonergic neuron after 5-HT release into synaptic space and reduces the serotonin level in the synaptic cleft. Various plants or their extract act as SERT inhibitors to control serotonin levels [127] (Figs.3 and 4).

Jäger, A.K etal., 2013 has shown that many plants, like Danish folk, had more MAO-A inhibiting activity than inhibiting serotonin reuptake activity [127]. The Borago ofcinalis extract examined in a functional experiment for serotonin reuptake transporter inhibition, where the extract showed promising activity. The MAO inhibition is observed in ethanolic extracts of Trigonella foenum-graecum seeds (IC50 4mg/mL), Apium graveolens leaves (IC50 5mg/mL), and water extracts of aerial parts of Calluna vulgaris (IC50 8mg/ mL). Quercetin extracted from Calluna vulgaris has also shown MAO-A inhibition [127, 128]. Plant compounds such as phenols (like jatrorrhizine) [129, 130] and alkaloids [129–

132] contain MAO-A activity. It has been demonstrated that

the phenolic substance derived from the plants Paeonia mou- tan and Primula auricular is an MAO-A inhibitor, useful in increasing serotonin levels [129]. Monoamine oxidase A inhibitory action is present in the Paeonia seeds from Primula veris and Primula elatior, thus modulating serotonergic trans- mission [127]. A piperidine derivative called piperine (1-[5-(1,3-benzodioxol-5-yl)-1-oxo-2,4-pentadienyl]piperidine) preferentially inhibited MAO-A over MAO-B [129]. Eugenol inhibits human MAO-A more than MAO-B [130]. The MAO-A inhibiting activity of eugenol may be the mechanism behind its antidepressant-like effects. Acori graminei rhizoma is historically been used to treat depression [130]. Colossal plant kingdoms facilitate serotonergic transmission and regulate serotonin levels helping in the treatment of dis-

eases or symptoms caused by serotonin imbalance. From various invivo studies, it has been shown that avonoids from Hemerocallis citrina affected the serotonergic and dopaminergic systems, which modulate mood [133]. In the cerebral cortex of experimental mice, ethanol extract of Uncaria lanosa Wallich var plants could increase 5-HT and 5-HIAA [134]., Tagetes erecta L. could mimic the effects of anti- depressant medications by modulating with the serotonergic, nitrergic, and sigma receptor pathways [135], Annona cheri- mola elevated the serotonin levels in the mouse brain [136], In Curcuma longa, curcumin exerted anti-depressant effects by increasing serotonin levels [137]. Phenols of Rosmarinus ofcinalis lead to a rise in pyruvate carboxylase and tyrosine hydroxylase [138]. Bupleurum falcatum affected the serotonergic systems and confers anti-depressant effects [139], via inhibiting mouse tryptophan 2, 3-dioxygenase and the expression of its genes. Extract of H. perforatum stimulates serotonin levels and elevates mood in mice [38, 166]. Paeonia glycosides increase the hippocampal production of serotonin (5-HT) and its metabolite, 5-hydroxy indole acetic acid [141]. Monoglycosides of Cynanchum auriculatum Royle inhibited serotonin reuptake in rats [142], Hypericum perforatum stimulate serotonin levels and elevates mood in those animals [38], Sideritis species as a triple monoamine reuptake inhibitor, effectively treated various illnesses, including depression and anxiety [143], Tagetes lucida Cav. show anti-depressant effects via inuencing the serotonergic system and serotonin production [144], Fructus Akebiae extract increases extracellular 5-HT and thus induce euphoria and antidepressant like effects invivo [145], Areca catechu nut increases serotonin levels [146]. Active alkaloids of some plants of the Amaryllidaceae family has both anti- depressant and happiness-boosting properties [147], Apium graveolens increases serotonin through the MAO-A activation [127], Borago of- cinalis increase serotonin levels through altering the serotonin transporter [148], Calluna vulgaris increases serotonin levels through the MAO-A activation [148] and Trigonella foenum-graecum increased serotonin levels through the MAO-A activation [148] Table2 (Figs.3 and 4).

12 Conclusion

Numerous medicinal plants, their extract, or isolated active constituents have been shown to have pharmacological effects against serotonergic disorders like depression, anxiety, insomnia, and cognitive alterations. They have fewer side effects and are available at lower cost compared to their synthetic counterparts, thus providing promising therapeutic applications against serotonin associated psychiatric disorders.

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serotonin contents (μg/g

Fresh Weight) References

K. Mallick and S. Banerjee

[187, 188]

19–28

Methanol 110.9±22.5 [174, 175]

leaves

Amaranthaceae Spinach leaves Methanol 34.4±2.4 [173]

Cruciferae Chinese cabbage

Methanol 251 [181]

fruit

Zygophyllaceae Leaves Methanol 18,200 [176–178]

Juglandaceae The embryo of the

Rosaceae Red Fruit Methanol 10 [189, 190]

Orissa, West Bengal, Bihar, Madhya

Asia and the Near East with Europe

Medicinal plants Geographical distribution Family Plant parts used Extraction Reaction

Spinacia oleracea Tamil Nadu, Pondicherry, Maharashtra,

Brassica rapa Jammu, Kashmir, Europe, Russia, Central

Table 2 Serotonin contents in plants

Peganum harmala Africa, the Middle East, India, Pakistan,

South America, Mexico and several other

countries

Madhya Pradesh, India Solanaceae Tomato Methanol 221.9±3.8 [179, 180]

Lycopersicon

China, China, India, Japan, Siberia

esculentum

Juglans mandshurica Western and Central Asia, especially in

Mimosa tenuiora Africa, South-East Asia, India Fabaceae Leaves Methanol 8.3 [182–184]

Musa sapientum All over the tropical world Musaceae Fruit’s peel Methanol 40–150

distributed

Prunus domestica Europe, Asia, India and Worldwide

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Fig. 3 Biosynthesis and metabolism of Serotonin (5-HT); reuptake of 5-HT and Serotonin syndrome caused by serotonin receptor hyper stimulation and mechanism of action of phytomolecules

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Fig. 4 Mechanism of action of Herbal Medicinal Plant to control serotonin level by inhibiting the serotonin transporter (SERT) and activity of Monoamine oxidase A enzyme which convers serotonin to HIAA

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