1. Introduction {#sec1-jcm-09-01176}
===============

Globally, an estimated 450 million people are suffering from mental disorders and about 425 million are known diabetics \[[@B1-jcm-09-01176],[@B2-jcm-09-01176]\]. In 2016, 650 million adults were obese and about 23.6 million people were estimated to die of cardiovascular diseases (CVDs) by the year 2030 \[[@B3-jcm-09-01176]\]. Metabolic disorders are characterized by hypertension, hyperglycemia, abdominal obesity, and hyperlipidemia, which may worsen the neurological disease risk. Improper diet (high calorie intake), lifestyle (e.g., smoking, chronic alcohol consumption, sedentary habits), and/or low level of nitrosamines (through processed food, tobacco smoke, and nitrate-containing fertilizers) affect the liver and can further lead to fatty liver disease \[[@B4-jcm-09-01176],[@B5-jcm-09-01176]\]. In this condition, fatty changes may be due to increased production or decreased use of fatty acids, which may lead to inflammatory injury of hepatocytes, where inflammatory mediators, such as cytokines and interleukins, are released, which, along with lower adipokines, may eventually develop hepatic insulin resistance \[[@B6-jcm-09-01176]\]. The same pathology also mediates diabetes, obesity, and peripheral insulin resistance. Insulin resistance also promotes the release of ceramides and other toxic lipids which enter the circulation and cross the blood--brain barrier leading to brain insulin resistance, inflammatory changes, and further progression to neurodegeneration and neurological disorders ([Figure 1](#jcm-09-01176-f001){ref-type="fig"}) \[[@B7-jcm-09-01176]\].

*Acorus calamus* Linn. (Acoraceae), also known as Vacha in Sanskrit, is a mid-term, perennial, fragrant herb which is practiced in the Ayurvedic (Indian traditional) and the Chinese system of medicine. The plant's rhizomes are brown in color, twisted, cylindrical, curved, and shortly nodded. The leaves are radiant green, with a sword-like structure, which is thicker in the middle and has curvy margins ([Figure 2](#jcm-09-01176-f002){ref-type="fig"}) \[[@B8-jcm-09-01176]\]. Several reports ascertained a wide range of biological activities involving its myriad of active phytoconstituents. In this sense, the intent of this review is to assemble and summarize the geographical distribution, ethnopharmacology, phytochemistry, mechanism of action of *A. calamus* along with preclinical and clinical claims that are relevant to manage neurological and metabolic disorders. To the best of our knowledge, so far, none of the published reviews has described all the characteristics of this medicinal plant \[[@B9-jcm-09-01176],[@B10-jcm-09-01176],[@B11-jcm-09-01176]\]. The present report is expected to produce a better understanding of the characteristics, bioactivities, and mechanistic aspects of this plant and to provide new leads for future research.

2. Methodology {#sec2-jcm-09-01176}
==============

The literature available in the Ayurvedic classical texts, technical reports, online scientific records such as SciFinder, Google Scholar, MEDLINE, EMBASE, Scopus directory were explored for ethnomedicinal uses, geographical distribution, phytochemistry, pharmacology, and biomedicine by applying the following keywords: "*Acorus calamus*", "Vacha", "Medhya", "neuroprotective", "phytochemistry", "obesity", "oxidative stress", "anticonvulsant", "antidepressant", "antihypertensive", "anti-inflammatory", "immunomodulator", "antioxidant", "diabetes", "mechanism of action" with their corresponding medical subject headings (MeSH) terms using conjunctions OR/AND. The search was focused on identifying Ayurvedic claims in the available ethnomedicinal, phytochemical, preclinical, clinical, and toxicity reports to understand the role of *A. calamus* in neurological and metabolic disorders. This search was undertaken between January 2018 and January 2020. Searches were restricted to the English language. The search methodology as per the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) is stipulated in the flowchart in [Figure 3](#jcm-09-01176-f003){ref-type="fig"}.

3. Geographical Distribution {#sec3-jcm-09-01176}
============================

*A. calamus* grows in high (1800 m) and low (900 m) altitudes and it is found to be geographically available in 42 countries \[[@B8-jcm-09-01176]\]. Furthermore, as per the Global Biodiversity Information Facility records \[[@B12-jcm-09-01176]\], the distribution of this plant in several parts of the world, as well as in India, is highlighted in [Figure 4](#jcm-09-01176-f004){ref-type="fig"}.

4. Ethnomedicinal Use {#sec4-jcm-09-01176}
=====================

This plant is being practiced traditionally in the Indian Ayurvedic tradition, as well as in the Chinese system of medicine for analgesic, antipyretic, tonic, anti-obesity, and healing purposes; it is highly effective for skin diseases, along with neurological, gastrointestinal, respiratory, and several other health disorders. Rhizomes and leaves are found to be profusely practiced in the form of infusion, powder, paste, or decoction \[[@B13-jcm-09-01176],[@B14-jcm-09-01176],[@B15-jcm-09-01176],[@B16-jcm-09-01176],[@B17-jcm-09-01176],[@B18-jcm-09-01176],[@B19-jcm-09-01176],[@B20-jcm-09-01176],[@B21-jcm-09-01176],[@B22-jcm-09-01176],[@B23-jcm-09-01176],[@B24-jcm-09-01176],[@B25-jcm-09-01176],[@B26-jcm-09-01176],[@B27-jcm-09-01176],[@B28-jcm-09-01176],[@B29-jcm-09-01176],[@B30-jcm-09-01176],[@B31-jcm-09-01176],[@B32-jcm-09-01176],[@B33-jcm-09-01176],[@B34-jcm-09-01176],[@B35-jcm-09-01176],[@B36-jcm-09-01176],[@B37-jcm-09-01176],[@B38-jcm-09-01176],[@B39-jcm-09-01176],[@B40-jcm-09-01176],[@B41-jcm-09-01176],[@B42-jcm-09-01176],[@B43-jcm-09-01176],[@B44-jcm-09-01176],[@B45-jcm-09-01176],[@B46-jcm-09-01176],[@B47-jcm-09-01176],[@B48-jcm-09-01176],[@B49-jcm-09-01176],[@B50-jcm-09-01176],[@B51-jcm-09-01176],[@B52-jcm-09-01176],[@B53-jcm-09-01176],[@B54-jcm-09-01176],[@B55-jcm-09-01176],[@B56-jcm-09-01176],[@B57-jcm-09-01176],[@B58-jcm-09-01176],[@B59-jcm-09-01176],[@B60-jcm-09-01176],[@B61-jcm-09-01176],[@B62-jcm-09-01176],[@B63-jcm-09-01176],[@B64-jcm-09-01176],[@B65-jcm-09-01176],[@B66-jcm-09-01176],[@B67-jcm-09-01176],[@B68-jcm-09-01176],[@B69-jcm-09-01176],[@B70-jcm-09-01176],[@B71-jcm-09-01176],[@B72-jcm-09-01176]\]. The ethnomedicinal uses of the *A. calamus* are detailed in [Table 1](#jcm-09-01176-t001){ref-type="table"}.

*A. calamus* rhizomes and leaves are also used as an active pharmaceutical ingredient in various Ayurvedic formulations ([Table 2](#jcm-09-01176-t002){ref-type="table"}).

5. Phytochemistry {#sec5-jcm-09-01176}
=================

The phytochemical investigation of this plant has been ongoing since the year 1957 \[[@B73-jcm-09-01176],[@B74-jcm-09-01176]\]. To date, about 145 compounds were isolated from *A. calamus* rhizomes and leaves, viz. phenylpropanoids, sterols, triterpene glycosides, triterpenoid saponins, sesquiterpenoids, monoterpenes, and alkaloids ([Table 3](#jcm-09-01176-t003){ref-type="table"}). Amongst those, phenylpropanoids (chiefly, asarone and eugenol) and sesquiterpenoids have been considered the principal effective compounds of *A. calamus*. Chemical structures of isolated compounds from *A. calamus* are illustrated in [Figure 5](#jcm-09-01176-f005){ref-type="fig"}.

5.1. Phenylpropanoids {#sec5dot1-jcm-09-01176}
---------------------

Phenylpropanoids have an aromatic ring with a structurally diverse group of phenylalanine-derived secondary plant metabolites (C~6~--C~3~), like *α*-asarone, *β*-asarone, eugenol, isoeugenol, etc. \[[@B75-jcm-09-01176]\]. A number of phenylpropanoids have been identified from *A. calamus* rhizome and leaves **(1-45)**. *α* and *β*-asarone isolated from the rhizome are the predominant compounds present in this plant. A series of aromatic oils from the rhizome with diverse structures are also reported \[[@B74-jcm-09-01176],[@B75-jcm-09-01176],[@B76-jcm-09-01176],[@B77-jcm-09-01176],[@B78-jcm-09-01176],[@B79-jcm-09-01176],[@B80-jcm-09-01176],[@B81-jcm-09-01176],[@B82-jcm-09-01176],[@B83-jcm-09-01176],[@B84-jcm-09-01176],[@B85-jcm-09-01176],[@B86-jcm-09-01176],[@B87-jcm-09-01176],[@B88-jcm-09-01176],[@B89-jcm-09-01176],[@B90-jcm-09-01176],[@B91-jcm-09-01176],[@B92-jcm-09-01176],[@B93-jcm-09-01176],[@B94-jcm-09-01176],[@B95-jcm-09-01176],[@B96-jcm-09-01176],[@B97-jcm-09-01176],[@B98-jcm-09-01176]\].

5.2. Sesquiterpenoids {#sec5dot2-jcm-09-01176}
---------------------

About 44 sesquiterpenes, including lactones, were characterized and identified in *A. calamus* rhizomes. Sesquiterpene lactones are produced of 3 isoprene units and composed of lactone rings. *α*--*β* unsaturated *γ*-lactonic ring in sesquiterpene lactones is believed to be responsible for pharmacological activity (46-99) \[[@B74-jcm-09-01176],[@B78-jcm-09-01176],[@B89-jcm-09-01176],[@B91-jcm-09-01176],[@B93-jcm-09-01176],[@B98-jcm-09-01176],[@B99-jcm-09-01176],[@B100-jcm-09-01176],[@B101-jcm-09-01176],[@B102-jcm-09-01176],[@B103-jcm-09-01176],[@B104-jcm-09-01176]\].

5.3. Monoterpenes {#sec5dot3-jcm-09-01176}
-----------------

Monoterpenes (C-10) are the simplest class of the terpene series that belongs to two isoprene units (tricyclic, bicyclic, monocyclic, etc.). Monoterpenes can have different functional groups, like aldehydes, ketones, esters, ethers, phenols, and alcohols \[[@B80-jcm-09-01176]\]. These organic compounds emit the characteristic flavor and fragrance of *A. calamus* leaves and rhizomes (100-122) \[[@B74-jcm-09-01176],[@B78-jcm-09-01176],[@B89-jcm-09-01176],[@B91-jcm-09-01176],[@B93-jcm-09-01176],[@B97-jcm-09-01176],[@B98-jcm-09-01176]\].

5.4. Triterpenoid Saponins {#sec5dot4-jcm-09-01176}
--------------------------

Triterpenoid saponins are made up of a pentacyclic C-30 terpene skeleton as a pillar. Limited reports studying triterpenoid saponins in *A. calamus* are available, and only two triterpenoid saponins (124, 125) have been isolated from *A. calamus* rhizomes ([Table 3](#jcm-09-01176-t003){ref-type="table"}) \[[@B85-jcm-09-01176]\].

5.5. Other Compounds {#sec5dot5-jcm-09-01176}
--------------------

To date, one xanthone glycoside (123) \[[@B82-jcm-09-01176],[@B83-jcm-09-01176]\], two alkaloids (126-127) \[[@B84-jcm-09-01176]\], one triterpene glycoside (128), one steroid (129) \[[@B85-jcm-09-01176]\], 12 amino acids (130-141) \[[@B86-jcm-09-01176],[@B87-jcm-09-01176]\], and 4 fatty acids (142-145) \[[@B88-jcm-09-01176]\] have been identified in *A. calamus* rhizomes \[[@B83-jcm-09-01176],[@B84-jcm-09-01176],[@B85-jcm-09-01176],[@B86-jcm-09-01176],[@B87-jcm-09-01176],[@B88-jcm-09-01176]\].

6. Pharmacological Properties {#sec6-jcm-09-01176}
=============================

Diverse bioactivities of *A. calamus* extracts are evident from preclinical (in vitro and in vivo) and clinical reports, such as antidiabetic, anti-obesity, antihypertensive, antioxidant, anti-inflammatory, immunomodulatory, anticonvulsant, and neuroprotective \[[@B105-jcm-09-01176],[@B106-jcm-09-01176],[@B107-jcm-09-01176],[@B108-jcm-09-01176],[@B109-jcm-09-01176],[@B110-jcm-09-01176],[@B111-jcm-09-01176],[@B112-jcm-09-01176],[@B113-jcm-09-01176],[@B114-jcm-09-01176],[@B115-jcm-09-01176],[@B116-jcm-09-01176],[@B117-jcm-09-01176],[@B118-jcm-09-01176],[@B119-jcm-09-01176],[@B120-jcm-09-01176],[@B121-jcm-09-01176],[@B122-jcm-09-01176],[@B123-jcm-09-01176],[@B124-jcm-09-01176],[@B125-jcm-09-01176],[@B126-jcm-09-01176],[@B127-jcm-09-01176],[@B128-jcm-09-01176],[@B129-jcm-09-01176],[@B130-jcm-09-01176],[@B131-jcm-09-01176],[@B132-jcm-09-01176],[@B133-jcm-09-01176],[@B134-jcm-09-01176],[@B135-jcm-09-01176],[@B136-jcm-09-01176],[@B137-jcm-09-01176],[@B138-jcm-09-01176],[@B139-jcm-09-01176],[@B140-jcm-09-01176],[@B141-jcm-09-01176],[@B142-jcm-09-01176],[@B143-jcm-09-01176],[@B144-jcm-09-01176],[@B145-jcm-09-01176],[@B146-jcm-09-01176],[@B147-jcm-09-01176],[@B148-jcm-09-01176],[@B149-jcm-09-01176],[@B150-jcm-09-01176],[@B151-jcm-09-01176],[@B152-jcm-09-01176],[@B153-jcm-09-01176],[@B154-jcm-09-01176],[@B155-jcm-09-01176],[@B156-jcm-09-01176],[@B157-jcm-09-01176],[@B158-jcm-09-01176],[@B159-jcm-09-01176],[@B160-jcm-09-01176],[@B161-jcm-09-01176],[@B162-jcm-09-01176],[@B163-jcm-09-01176],[@B164-jcm-09-01176],[@B165-jcm-09-01176],[@B166-jcm-09-01176],[@B167-jcm-09-01176],[@B168-jcm-09-01176],[@B169-jcm-09-01176],[@B170-jcm-09-01176],[@B171-jcm-09-01176],[@B172-jcm-09-01176],[@B173-jcm-09-01176]\]. The summarized information on *A. calamus* botanical parts, extract type, and their bioactivities in neurological and metabolic disorders is stipulated in [Table 4](#jcm-09-01176-t004){ref-type="table"}.

6.1. Antidiabetic Effect {#sec6dot1-jcm-09-01176}
------------------------

The antidiabetic effect of *A. calamus* ethyl acetate fraction was evaluated in streptozotocin (STZ)-induced and diabetic (db/db) mice. Glucagon-like peptide-1 (GLP-1) levels, plasma insulin, "and related gene expression were evaluated. The fraction (100 mg/kg, intragastric (i.g.)) indicated a significant reduction in blood glucose levels. For in vitro, at the concentration of 12.5 μg/mL, a significant increment in GLP-1 levels was found in the insulin-secreting L-cell culture medium \[[@B108-jcm-09-01176]\]. The ethyl acetate radix fraction exhibited a significant effect on the HIT-T15 cell line and *α*-glucosidase enzyme. The ethyl acetate fraction also enhanced insulin secretion in HIT-T15 cells and blocked the *α*-glucosidase in vitro activity with 0.41 μg/mL of inhibitory concentration (IC~50~) \[[@B109-jcm-09-01176]\]."

6.2. Anti-Obesity Effect {#sec6dot2-jcm-09-01176}
------------------------

The *β*-asarone compound isolated from the rhizome was investigated against high-fat diet (HFD)-induced obesity in animals. *β*-Asarone-treated adipose rats showed weight loss, but also inhibited metabolic transformations, as well as glucose intolerance, elevated cholesterol, and adipokine variance \[[@B143-jcm-09-01176]\]. The in vitro investigation on the *A. calamus* aqueous extract showed lipid-lowering activity through inhibition of the pancreatic lipase percentage (28.73%) \[[@B144-jcm-09-01176]\].

6.3. Antihypertensive Effect {#sec6dot3-jcm-09-01176}
----------------------------

The antihypertensive effects of *A. calamus* were studied on their own, in isolation, and in combination with *Gymnema sylvestre* in the HFD-induced hypertension in rats. The HFD was given for 4 weeks, which significantly increased the average systolic blood pressure (SBP). At a 200 mg/kg dose, *A. calamus* in combination with *G. sylvestre* reduced the SBP and heart rate significantly. *A. calamus* with *G. sylvestre* exhibited synergistic effect as compared with individual herbs \[[@B145-jcm-09-01176]\].

6.4. Anti-Inflammatory and Immunomodulatory Effect {#sec6dot4-jcm-09-01176}
--------------------------------------------------

The methanolic *A. calamus* rhizome extract (12.5 µg/mL) prevented the VCAP-1 and intercellular expression on the surface of mouse myeloid leukemia cells and murine endothelial cells, respectively \[[@B146-jcm-09-01176]\]. In an in vitro anti-inflammatory study (Red blood cell membrane stabilization method), the *A. calamus* aqueous rhizome extract at the highest concentration of 10 mg/mL showed insignificant activity against hemolysis inhibition and the RBC membrane stabilization percentage \[[@B144-jcm-09-01176]\]. Aqueous *A. calamus* leave extract was studied on HaCaT cells and restricted the characteristics of interleukin (IL)-8, IL-6 RNA protein levels alongside interferon regulatory factor 3 (IRF3) and nuclear factor kB (NF-κB) activation \[[@B147-jcm-09-01176]\]. N-hexane, butanolic, and aqueous fractions of *A. calamus* were evaluated against cyclooxygenase (COX) and lipoxygenase (LOX)-mediated eicosanoid production by arachidonic acid. The butanolic fraction inhibited the COX-mediated production of thromboxane B2 (TXB2) and lipoxygenase product 1 (LP1). Investigation of the underlying signaling pathways revealed that the butanolic fraction inhibited phospholipase C (PLC) pathway in platelets, presumably acting on protein kinase C (PKC) \[[@B148-jcm-09-01176]\]. The essential oil isolated from *A. calamus* was evaluated by protein denaturation assay, where at the concentration level of 300 μg/mL, 69.56% of the inhibition level was observed \[[@B149-jcm-09-01176]\].

6.5. Antioxidant Effect {#sec6dot5-jcm-09-01176}
-----------------------

The in vitro antioxidant activity of acetone, acetonitrile, alcoholic, and aqueous extracts of *A. calamus* rhizomes exhibited free radical scavenging activity on the \[2,2′-azinobis (3-ethylbenzothiazoline-6-sulphonic acid)\] free radical scavenging activity assay (ABTS), the (1, 1-diphenyl-2-picrylhydrazyl) free radical scavenging activity assay (DPPH), and the ferric ion reducing antioxidant power assay (FRAP). Strong antioxidant effect was noticed in the acetone extract, followed by acetonitrile and methanol, while in the aqueous extract, poor antioxidant activity was found \[[@B150-jcm-09-01176]\]. The aqueous extract exhibited superior antioxidant effects in metal ion chelation, lipid peroxidation (LPO), and DPPH assays \[[@B144-jcm-09-01176],[@B151-jcm-09-01176]\]. The in vitro antioxidant activity of ethanol, hydro-ethanol, and aqueous whole plant extracts of *A. calamus* was investigated using FRAP, DPPH, nitric oxide, hydroxyl radical, reductive ability, and superoxide radical scavenging activity. The existence of phenolics and flavonoids in *A. calamus* are believed to contribute to the promising antioxidant effect. IC~50~ values of the ethanol extract were found to be 54.82, 109.85, 38.3, 118.802 µg/mL for the scavenging activities of DPPH, hydroxyl radical, superoxide radical, and nitric oxide, respectively. The irreversible potential of the above results and the FRAP values of the extracts were found to augment in a concentration-dependent manner \[[@B152-jcm-09-01176]\]. "Ethanol and hydro-alcoholic extracts of *A. calamus* roots and rhizomes were studied for antioxidant potential against DPPH compared with butylated hydroxyanisole (BHA) and silymarin. Ethanol and hydro-alcoholic extracts showed free radical scavenging activity of 59.13 ± 18.95 and 56.71 ± 19.54, respectively \[[@B153-jcm-09-01176],[@B154-jcm-09-01176],[@B155-jcm-09-01176]\]. The essential oil isolated from *A. calamus* showed strong antioxidant efficacy against the *β*-carotene/linoleic acid bleaching test and DPPH free radicals \[[@B156-jcm-09-01176]\]. The methanol extract of the *A. calamus* rhizome was evaluated against the free radical scavenging activity, and the reported IC~50~ value was 704 µg/mL \[[@B157-jcm-09-01176]\]. The IC~50~ of the essential oil was 1.68 μg/mL, which showed virtuous free radical scavenging activity in the DPPH test \[[@B149-jcm-09-01176]\]."

6.6. Anticonvulsant Effect {#sec6dot6-jcm-09-01176}
--------------------------

The methanol extract shows anticonvulsant effects feasibly through potentiating the action of gamma-aminobutyric acid (GABA) pathway in the central nervous system \[[@B124-jcm-09-01176]\]. When it comes to the purification of *A. calamus* rhizome in cow urine, it is advocated in the Ayurvedic pharmacopoeia of India (API) before its therapeutic use. The purified rhizome was investigated in a maximal electroshock (MES) seizure model, and phenytoin was used as the standard drug. The raw and processed rhizome (11 mg/kg, p.o.) exhibited notable anticonvulsant activity by minimizing the span of the tonic extensor period in rats, whereas the processed rhizome showed better therapeutic activity than when it was raw \[[@B158-jcm-09-01176]\]. The calamus oil isolated from the *A. calamus* rhizome was evaluated at varying dose levels of 30, 100, and 300 mg/kg, p.o., body weight (b.w.), against MES, pentylenetetrazol (PTZ), and minimal clonic seizure (MCS) models. The calamus oil was found to be neurotoxic at 300 mg/kg, though it was effective in the MCS test at 6 Hz. The protective index value of calamus oil was found to be 4.65 \[[@B125-jcm-09-01176]\].

6.7. Antidepressant Effect {#sec6dot7-jcm-09-01176}
--------------------------

Interaction of the methanolic *A. calamus* rhizome extract with the adrenergic, dopaminergic, serotonergic, and GABAergic system was found responsible for the expression of antidepressant activity \[[@B128-jcm-09-01176]\]. In another study, the methanolic *A. calamus* leave extract showed significant activity through a reduction in the immobility period in the TST and FST \[[@B129-jcm-09-01176]\]. Through interaction with the adrenergic and dopaminergic system, the hydro-alcoholic extract was normalized to the over-activity of the hypothalamic pituitary adrenal (HPA) axis \[[@B131-jcm-09-01176]\]. Sobers capsules (a herbo-mineral formulation containing *A. calamus*) were evaluated by tail suspension and forced swimming tests in mice. At the oral dose of 50 mg/kg for 14 days, capsules exhibited insignificant impact on locomotor activity, and caused antidepressant effects in experimental animals \[[@B159-jcm-09-01176]\]. Tensarin (the traditional medicine of Nepal containing *A. calamus*) was evaluated for the anxiolytic effect in mice using the open field test (OFT), activity monitoring along with the passive avoidance test. At all three dose levels (50, 100, 200 mg/kg), Tensarin produced an anxiolytic effect in a dose-dependent way by an improvement in rearing, number of passages, and duration of the period employed by mice \[[@B160-jcm-09-01176]\].

6.8. Neuroprotective Effect {#sec6dot8-jcm-09-01176}
---------------------------

The ethanolic extract was studied (25, 50, and 100 mg/kg doses, oral and intraperitoneal routes) for learning and memory-enhancing activity. The subjects used consisted of male rates, through Y maze and shuttle box tests models. The findings showed an increase in acquisition--recalling and spatial recognition data \[[@B161-jcm-09-01176]\]. The ethanolic *A. calamus* rhizome extract (0.5 mL/kg, i.p.) potentiated pentobarbitone-created sleep periods, which caused significant inhibition of conditioned avoidance response in rats and marked (40--60%) protection against PTZ-induced convulsions, although it did not show any spontaneous motor activity and impact the aggressive or fighting behavior response in male rat pairs \[[@B162-jcm-09-01176]\].

6.9. Cardioprotective Effect {#sec6dot9-jcm-09-01176}
----------------------------

The alcoholic *A. calamus* rhizome extract (100 and 200 mg/kg) considerably attenuated isoproterenol-led cardiomyopathy in rats and showed a significant reduction in the heart/body weight ratio, level of serum calcineurin, serum nitric oxide, serum lactate dehydrogenase (LDH), and thiobarbituric acid reactive substances (TBARS) level. However, the level of the antioxidant enzyme was found increased at the 100 mg/kg extract dose level \[[@B163-jcm-09-01176]\]. The crude extract and its fractions (0.01--10 mg/mL) were investigated in an isolated rabbit heart, which showed mild reduction in the force of forced vital capacity (FVC), hazard ratio (HR), and cystic fibrosis (CF), while the ethyl acetate extract exhibited complete suppression, and the n-hexane fraction showed the same effect on FVC and HR, but enhanced CF. The extract and its fractions exhibited controlled coronary vasodilator effect, interceded maybe by an endothelial-derived hyperpolarizing factor \[[@B164-jcm-09-01176]\]. The cardioprotective potential of the whole plant's ethanolic extract (100 and 200 mg/kg) reduced serum enzyme levels and shielded the myocardium from the lethal effect of DOX \[[@B141-jcm-09-01176]\].

6.10. Cytochrome Inhibitory Activities {#sec6dot10-jcm-09-01176}
--------------------------------------

Cytochromes P450 (CYPs) are the prime enzymes that catalyze the oxidative metabolism of a wide variety of xenobiotics. It is known that 2,4,5-trimethoxycinnamic acid is the main metabolite of α- or β- asarone \[[@B165-jcm-09-01176]\]. The metabolism rate of α- and β-asarone was shown to be directly proportional to the CYPs concentration in rat hepatocytes and liver microsomes \[[@B166-jcm-09-01176],[@B167-jcm-09-01176]\]. CYP3A4 (CYP isoforms) has been reported for bioactivation of α-asarone \[[@B168-jcm-09-01176]\]. The hydro-alcoholic *A. calamus* extract and α-asarone were evaluated by the CYPs-carbon monoxide complex method. The extract exhibited moderate potential interaction in CYP3A4 (IC~50~ = 46.84 μg/mL) and CYP2D6 (IC~50~ = 36.81 μg/mL), while α-asarone showed higher interaction in CYP3A4 (IC~50~ = 65.16 μg/mL) and CYP2D6 (IC~50~ = 55.17 μg/mL) \[[@B169-jcm-09-01176]\]. These outcomes indicated that both extracts and α-asarone interacted quite well in drug metabolism and also had an inhibitory effect on CYP3A4 and CYP2D6. The drug-drug interaction effect of the *A. calamus* extract and its main chemical constituent (α and β-asarone) needs to be studied in more CYPs isomers, like CYP2C9 and CYP2E1.

6.11. Toxicity and Safety Concerns {#sec6dot11-jcm-09-01176}
----------------------------------

In acute and sub-acute toxicity of the hydro-alcoholic extract of *A. calamus* in rats, at the highest dose level of 10 gm/kg, no severe changes were observed, and the lethal dose (LD~50~) was found to be 5 g/kg \[[@B170-jcm-09-01176]\]. The petroleum ether extracts (obtained by cold rolling, water distillation, and Soxhlet extraction methods) of the *A. calamus* rhizome showed mild toxicity in two-day-old oriental fruit flies \[[@B171-jcm-09-01176]\]. The ethanolic extract of the *A. calamus* rhizome at oral dosage of 175, 550, 1750, and 5000 mg/kg b.w. was given for 14 days within an acute toxicity study, while at the dose level of 0, 200, 400, and 600 mg/kg, p.o., the extract was given for 90 days within a chronic toxicity study. At the doses of 1750 and 5000 mg/kg, piloerection, tremors, and abdominal breathing were found for 30 min \[[@B172-jcm-09-01176]\]. In that study, *A. calamus* was purified for 3 h in cow urine, decoction of *Sphaeranthus indicus*, and decoction of leaves of *Mangifera indica*, *Eugenia jambolana*, *Feronia limonia*, *Citrus medica*, and *Aegle marmelos*, followed by fomentation with Gandhodaka (decoction of six aromatic herbs) for 1 h. The acute oral toxicity test of raw and purified *A. calamus* was performed in albino rats at 2000 mg/kg for 2 weeks. At the 2000 mg/kg dose, *A. calamus* did not produce any toxic symptoms within 14 days \[[@B173-jcm-09-01176]\].

The *β*-asarone compound isolated from *A. calamus* was found to be carcinogenic and toxic \[[@B174-jcm-09-01176]\]. The LD~50~ value of *β*-asarone by oral and intraperitoneal route was found to be 1010 and 184 mg/kg, respectively, in mice and rats \[[@B175-jcm-09-01176]\]. The LD~50~ of calamus oil was found to be 8.88 gm/kg b.w. \[[@B176-jcm-09-01176]\], while in the calamus oil obtained from Jammu, India, the LD~50~ was 777 mg/kg b.w. \[[@B177-jcm-09-01176]\]. Overall, several investigations have been carried out on *A. calamus* regarding its toxicity; however, no noticeable data on toxicity have been found so far.

7. Clinical Reports {#sec7-jcm-09-01176}
===================

*A. calamus* has also been clinically investigated as a monotherapy as well as in combination with other medicinal herbs in healthy subjects and sufferers of various metabolic and neurological ailments. Most clinical research has looked at the *A. calamus* effect on obesity, depression, neuroprotection, and cardiovascular disease \[[@B178-jcm-09-01176],[@B179-jcm-09-01176],[@B180-jcm-09-01176],[@B181-jcm-09-01176],[@B182-jcm-09-01176],[@B183-jcm-09-01176],[@B184-jcm-09-01176],[@B185-jcm-09-01176],[@B186-jcm-09-01176],[@B187-jcm-09-01176],[@B188-jcm-09-01176],[@B189-jcm-09-01176],[@B190-jcm-09-01176],[@B191-jcm-09-01176]\]. The data obtained so far can be found in [Table 5](#jcm-09-01176-t005){ref-type="table"}. Furthermore, a systematic review reveals that *A. calamus* (alone or in combination therapy) exhibits anti-obesity, antidepressant, and cardioprotective effects, as well as helps physical and mental performance.

8. Mechanistic Role {#sec8-jcm-09-01176}
===================

The proposed mechanism of action of *A. calamus* in neurological and metabolic disorders includes a synergic integration of antioxidant defense, GABAergic transmission, brain stress hormones modulation, pro-inflammatory cytokines, leptin and resistin levels, adipocytes inhibition, calcium channel blocker effect, protein synthesis, oxidative stress, acetylcholinesterase (AChE) inhibition, and anti-dopaminergic properties. A compendium of mechanisms of action of *A. calamus* in neurological and metabolic protection is illustrated in [Figure 6](#jcm-09-01176-f006){ref-type="fig"} and [Table 6](#jcm-09-01176-t006){ref-type="table"}. *A. calamus* significantly affects fasting blood sugar, insulin resistance, HbA1c, and the adipogenic transcription expression factor through various mechanisms, viz. antioxidant, anti-inflammatory, β-cells regeneration, improving insulin sensitivity, gluconeogenesis, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, and glucose transporter type 4 (GLUT-4)-mediated transport inhibition.

The antihypertensive effect of *A. calamus* may be explained by Ca^2+^ antagonists that affect the nitric oxide pathway. The chemical constituents of *A. calamus* upregulate the antioxidant effect, suppress pro-inflammatory cytokines, and act as detoxifying enzymes through the NF-κB and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathways. The Nrf2 pathway may be activated by phenylpropanoids, sesquiterpenoids, and monoterpenes by interaction of active phytoconstituents with nitric oxide derivatives react with thiol groups between KEAP1 and Nrf2, along with Nrf2 phosphorylation. "When Nrf2 is released from the Kelch-like erythroid-derived CNC (cap'n'collar) homology protein (ECH)-associated protein 1 (KEAP1), it transfers into the nucleus, where it induces the genes encoding protein expression impenetrable in glutathione (GSH) synthesis, antioxidant, and detoxifying phase 2 enzymes. Oxidative stress and ligands for tumor necrosis factor receptors (TNFRs) and toll-like receptors (TLRs) activate upstream Ik-B kinases (IKKs), ensuing phosphorylation of IkB that is generally bound to the inactive NF-kB dimer in the cytoplasm. After that, IkB is targeted for proteasomal degradation and NF-kB, then it moves into the nucleus where it induces inflammatory cytokine expression in addition to the genes encoding proteins like superoxide dismutase (SOD) 2 and B cell chronic lymphocytic leukemia (CLL)/lymphoma 2 (Bcl2) involved in adaptive stress response ([Figure 7](#jcm-09-01176-f007){ref-type="fig"}). The bioactive molecules of *A. calamus* can inhibit NF-kB in inflammatory immune cells, while other phytoconstituents may activate NF-kB in neuronal cells to improve stress resistance." *A. calamus* phytoconstituents regulate NF-kB, LOX, and COX-2 activity. These compounds dose-dependently suppress the production of inflammatory factors like NO, TNF-α, IL-6, IL-1β, and JNK signaling, acting as anti-inflammatory agents. In addition, it was also noted that the inflammation induced by various chemicals was inhibited by bioactive constituents through suppression of IkB/NF-kB and JNK/AP-1 signaling pathways. Thus, over several studies, it has been reported that asarone compounds have a potential against neurodegenerative diseases.

PPAR gene and C/EBP are involved in the differentiation process. PPAR-δ and PPAR-γ promote adipogenesis. In the same way, amino acids and glucose react with C/EBP- δ and C/EBP-β. If low levels of glucose induce gadd153, the inactive dimer is formed, with C/EBP-β inhibiting the progress of adipocyte development. C/EBP delta activates C/EBP-α. This is mainly involved in the formation of mature adipocytes and lipid accumulation in adipose tissue. In 3T3-L1 preadipocytes, *α*-asarone and *β*-asarone inhibited adipocyte differentiation and reduced the intracellular lipid accumulation, and also decreased the expression levels of adipogenic transcription factors (PPARγ and C/EBPα). These phytochemicals significantly promoted adenosine monophosphate-activated protein kinase (AMPK), which is known to suppress adipogenesis. It was also found that pretreatment with *α*-asarone and *β*-asarone, a typical inhibitor of AMPK, attenuated the inhibitory effect of asarone on AMPK phosphorylation. The asarone-induced AMPK activation leads to a decrease in adipogenic transcription factor expression, and suppresses adipogenesis.

9. Perspectives and Future Directions {#sec9-jcm-09-01176}
=====================================

The present review provides a plethora of information apropos ethnomedicinal uses, marketed formulations, geographical distribution, chemical constituents, pharmacological activities of crude, n-hexane, ethyl acetate, methanolic, ethanolic, hydro-alcoholic, aqueous extracts along with pure compounds, and clinical trials related to *A. calamus*.

Investigations on extracts and compounds of *A. calamus* suggested antidiabetic, anti-obesity, antihypertensive, anti-inflammatory, antioxidant, anticonvulsant, antidepressant, neuroprotective, and cardioprotective potentials with distinct underlying signaling pathways. The biological potential and mechanisms of action of some of the chemical constituents (*α*-asarone, *β*-asarone, eugenol) are known. However, other compounds need to be scientifically explored for their bioactivities and molecular modes of action, which could provide a lead for further development into therapeutics. More systematic, well-designed, and multi-center clinical studies are warranted to evaluate standardized extracts of *A. calamus* therapeutically and to identify the pharmacokinetic-dynamic roles of pharmacologically active biomolecules. There is scarce data from experimental and clinical reports on hypertension, diabetes, and atherosclerosis, and less supporting evidence is available on the use of *A. calamus* to treat hypertension and diabetes. Based on the available data, it is suggested that this plant could be used as an adjuvant to the established targeted drugs for neurological and metabolic disorders.

In 1974, United States food & drug administration (USFDA) banned *A. calamus* due to its carcinogenic effects following animal studies. They reported *β*-asarone as a carcinogenic agent, but the study was conducted on the calamus oil which consists of *β*-asarone in about 80%, while its different genotype in Europe and India contains *β*-asarone in lower concentrations. *A. calamus* cultivated in various geographical regions may have different chemical compositions along with therapeutic properties challenging quality control, toxicity, and safety concerns of *A. calamus*. In addition, the heavy metal, mycotoxin, and pesticide concentrations are required to be addressed in all toxicity studies.

10. Conclusions {#sec10-jcm-09-01176}
===============

Compelling in vitro, in vivo and clinical evidence suggests that the potential role of *A. calamus* rhizomes for modulating metabolic and neurological disorders could be due to their richness in several classes of active phytoconstituents. The predominant compounds present in rhizomes and leaves responsible for expression of potent bioactivities include *α*-asarone, *β*-asarone, eugenol, and calamine. The present report is expected to fill the gaps in the existing knowledge and could provide a lead for researchers working in the areas of phytomedicine, ethnopharmacology, and clinical research.

The authors express their sincere gratitude to Bharat Ratna Mahamana Pandit Madan Mohan Malviya, the founder of the Banaras Hindu University, Varanasi, for his services to humanity, great vision, and blessings. This work was also supported by University of Hradec Kralove (Faculty of Science, VT2019-2021) \[KK, EN\].

R.S. and V.S. conceived the idea and wrote the manuscript. D.S.G., K.K., E.N., and N.M. edited and proofread the document. The entire team approved the submission of the final manuscript. All authors have read and agreed to the published version of the manuscript.

This paper was supported by the UHK Excellence project.

The authors declare no conflict of interest.

![Pathophysiology of insulin resistance, metabolic malfunction, and progression to a neurological disorder. TNF, tumor necrosis factor; IL, interleukin.](jcm-09-01176-g001){#jcm-09-01176-f001}

![Photographs of *Acorus calamus*: (**A**) Natural habitat; (**B**) Fresh rhizome; (**C**) Dried rhizome.](jcm-09-01176-g002){#jcm-09-01176-f002}

![Flowchart of the selection process.](jcm-09-01176-g003){#jcm-09-01176-f003}

![Distribution of *A. calamus* worldwide and in India.](jcm-09-01176-g004){#jcm-09-01176-f004}

###### 

Chemical structures of isolated compounds from *A. calamus*.

![](jcm-09-01176-g005a)

![](jcm-09-01176-g005b)

![](jcm-09-01176-g005c)

![Illustration of role of *A. calamus* mechanisms in the treatment of neurological and metabolic disorders. AChE, acetylcholinesterase; APP, amyloid precursor protein; Bcl-2, B-cell lymphoma 2; CHOP, C/EBP homologous protein; CCAAT (cytosine-cytosine-adenosine-adenosine-thymidine)-enhancer-binding protein homologous protein; C/EBP, CCAAT enhancer-binding protein; GABAA, γ-Aminobutyric acid type A; GRP78, 78-kDa glucose-regulated protein; HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A; iNOS, inducible nitric oxide synthase; JNK, c-Jun NH2-terminal kinase; LC3b, microtubule-associated proteins 1A/1B light chain 3B; MCP, modified citrus pectin; MDA, malondialdehyde; MIP, macrophage inflammatory protein; p-PERK, phospho-protein kinase RNA-like ER kinase; PPARγ, peroxisome proliferator-activated receptor gamma; ERK1/2, extracellular signal-regulated protein kinase.](jcm-09-01176-g006){#jcm-09-01176-f006}

![The role of the Nrf-2, NF-κB, PI3K/AKT, Ras/MAPK, and PPARγ signaling pathways as affected by phytoconstituents of *Acorus calamus* to upregulate antioxidant, neuroprotective, detoxifying enzymes and suppress inflammation. Ub, ubiquitin; NEMO, NF-kB essential modulator; ARE, antioxidant response element; Maf, musculoaponeurotic fibrosarcoma oncogene homolog; NLS, nuclear localization signal; CAT, catalase; GPX, glutathione peroxidase; Trk, tyrosine kinase receptor; LPS, lipopolysaccharide; TLRs, toll-like receptors; PI3K, phosphatidylinsoitol-3-kinase; MAPK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; ERK, extracellular signal-regulated kinases; Nrf2, nuclear factor e2-related factor 2; Keap-1, kelch-like ECH-associated protein-1; MEK, mitogen-activated protein kinase; JNK, c-Jun N-terminal kinase;NADPH, nicotinamide adenine dinucleotide phosphate; NF-κB, nuclear factor-kappa B; IkB, inhibitor of kB; IKK, inhibitor of kB kinases.](jcm-09-01176-g007){#jcm-09-01176-f007}

jcm-09-01176-t001_Table 1

###### 

Ethnomedicinal use of *A. calamus* in various countries.

  Country                                                                                                                                                                                                                                                                                                                                         Ailment/Use                                                                                                                       Part Used/Dosage Form                                                                                                                                    Route of Administration                                           References
  ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- --------------------------------------------------------------------------------------------------------------------------------- -------------------------------------------------------------------------------------------------------------------------------------------------------- ----------------------------------------------------------------- -------------------------
  India                                                                                                                                                                                                                                                                                                                                           Eczema                                                                                                                            The paste of *A. calamus* rhizomes are given with the paste of *Curcuma aromatica* rhizomes and *Azadirachta indica* leaves                              Oral                                                              \[[@B13-jcm-09-01176]\]
  Skin diseases                                                                                                                                                                                                                                                                                                                                   Rhizomes paste *A. calamus* and *C. aromatica* are applied with the seed paste of *Argemone Mexicana*                                                                                                                                                                                                                                                        
  Cough, stuttering, ulcer, fever, dermatitis, scab, sores                                                                                                                                                                                                                                                                                        Rhizomes                                                                                                                          \[[@B14-jcm-09-01176]\]                                                                                                                                                                                                    
  Cold, cough, and fever                                                                                                                                                                                                                                                                                                                          Rhizomes paste of *A. calamus* is given to children with mother's milk, *Myristica fragrance*, and *Calunarejan spinosa* fruits   \[[@B15-jcm-09-01176]\]                                                                                                                                                                                                    
  Two teaspoonfuls of herbal powder containing *A. calamus* rhizomes, *Boerhaavia diffusa* roots, *Calonyction muricutum* flower pedicles, *Ipomoea muricate* seeds, *Senna* leaves, *Cassia fistula* fruits pulp, *Curcuma longa* rhizomes, *Helicteres isora* fruits, and *Mentha arvensis* leaves, black pepper is taken with lukewarm water   \[[@B16-jcm-09-01176]\]                                                                                                                                                                                                                                                                                                                                      
  Gastric disorders                                                                                                                                                                                                                                                                                                                               *A. calamus* rhizomes paste is given with cow milk                                                                                \[[@B17-jcm-09-01176]\]                                                                                                                                                                                                    
  Carminative, flavoring, tonic, and head lice infestation                                                                                                                                                                                                                                                                                        Infusion of a dried rhizomes (collected and stored in the autumn season)                                                          \[[@B17-jcm-09-01176],[@B18-jcm-09-01176],[@B19-jcm-09-01176]\]                                                                                                                                                            
  Epilepsy, dysentery, mental illnesses, diarrhea, kidney and liver disorders                                                                                                                                                                                                                                                                     *A. calamus* rhizomes paste is given with honey                                                                                   \[[@B20-jcm-09-01176]\]                                                                                                                                                                                                    
  Wounds, fever, body pain                                                                                                                                                                                                                                                                                                                        Rhizomes                                                                                                                          \[[@B21-jcm-09-01176],[@B22-jcm-09-01176]\]                                                                                                                                                                                
  Dysentery                                                                                                                                                                                                                                                                                                                                       Fresh ground rhizomes is mixed with hot water and given for 3 days                                                                \[[@B23-jcm-09-01176]\]                                                                                                                                                                                                    
  Stimulant                                                                                                                                                                                                                                                                                                                                       Dry powder of *A. calamus* is given with honey                                                                                    \[[@B24-jcm-09-01176]\]                                                                                                                                                                                                    
  Injuries                                                                                                                                                                                                                                                                                                                                        External application of the *A. calamus* rhizomes paste                                                                           Dermal                                                                                                                                                   \[[@B25-jcm-09-01176]\]                                           
  Stomachache                                                                                                                                                                                                                                                                                                                                     Ash of the *A. calamus* rhizomes paste                                                                                            \[[@B26-jcm-09-01176]\]                                                                                                                                                                                                    
  Otitis externa                                                                                                                                                                                                                                                                                                                                  *A. calamus* roots paste is given with coconut husk juice                                                                         \[[@B27-jcm-09-01176]\]                                                                                                                                                                                                    
  Lotion                                                                                                                                                                                                                                                                                                                                          Fresh leaves of *A. calamus*                                                                                                      \[[@B28-jcm-09-01176]\]                                                                                                                                                                                                    
  Cough, cancer, and fever                                                                                                                                                                                                                                                                                                                        *A. calamus* roots juice is given with honey and *MyristicaDactyloides*                                                           Oral                                                                                                                                                     \[[@B29-jcm-09-01176]\]                                           
                                                                                                                                                                                                                                                                                                                                                  Analgesic                                                                                                                         *A. calamus* rhizomes are given with cinchona bark                                                                                                       \[[@B30-jcm-09-01176]\]                                           
  Gastrointestinal, respiratory, emmenagogue, antihelmintic                                                                                                                                                                                                                                                                                       Rhizomes                                                                                                                                                                                                                                                                                                                                                     
  Prolonged labor                                                                                                                                                                                                                                                                                                                                 Rhizomes is applied with saffron and horse milk                                                                                                                                                                                                                                                                                                              
  Paralysis, arthritis                                                                                                                                                                                                                                                                                                                            Rhizomes ash is applied with castor oil                                                                                                                                                                                                                                                                                                                      
  Neurological disorder, gastrointestinal, respiratory, increases menstrual flow, analgesic, contraceptive                                                                                                                                                                                                                                        Rhizomes                                                                                                                          Oral                                                                                                                                                     \[[@B31-jcm-09-01176],[@B32-jcm-09-01176],[@B33-jcm-09-01176]\]   
  Herpangina, analgesic, neurological disorder, gastrointestinal, respiratory                                                                                                                                                                                                                                                                     \[[@B34-jcm-09-01176]\]                                                                                                                                                                                                                                                                                                                                      
  Pakistan                                                                                                                                                                                                                                                                                                                                        Colic and diarrhea                                                                                                                Whole plant                                                                                                                                              \[[@B35-jcm-09-01176]\]                                           
  Nepal                                                                                                                                                                                                                                                                                                                                           Blood pressure                                                                                                                    Roots infusion of *A. calamus*                                                                                                                           \[[@B36-jcm-09-01176]\]                                           
  Cough, headache, snake bite, sore throat, and pain                                                                                                                                                                                                                                                                                              Rhizomes                                                                                                                          \[[@B37-jcm-09-01176]\]                                                                                                                                                                                                    
  Dysentery                                                                                                                                                                                                                                                                                                                                       Rhizomes juice is given with hot water                                                                                                                                                                                                                                                                                                                       
  Neurological, respiratory                                                                                                                                                                                                                                                                                                                       Rhizomes                                                                                                                          \[[@B38-jcm-09-01176]\]                                                                                                                                                                                                    
  Malaysia                                                                                                                                                                                                                                                                                                                                        Rheumatism, diarrhea, dyspepsia, and hair loss                                                                                    Whole plant                                                                                                                                              \[[@B39-jcm-09-01176]\]                                           
  Tibet                                                                                                                                                                                                                                                                                                                                           Fever, gastrointestinal                                                                                                           Dried rhizomes is given with *Saussurea lappa*, *Ferula foetida*, *Terminalia chebula*, *Cuminum cyminum*, *Inula racemosa*, and *Zingiber officinale*   \[[@B40-jcm-09-01176]\]                                           
  Cancer                                                                                                                                                                                                                                                                                                                                          Rhizomes                                                                                                                          \[[@B41-jcm-09-01176]\]                                                                                                                                                                                                    
  China                                                                                                                                                                                                                                                                                                                                           Gastrointestinal, respiratory, neuroprotective, analgesic, contraceptive, cancer                                                  Rhizomes                                                                                                                                                 \[[@B42-jcm-09-01176],[@B43-jcm-09-01176],[@B44-jcm-09-01176]\]   
  Antipyretic and ear-related disease                                                                                                                                                                                                                                                                                                             Rhizomes given with squeezed *Coccinia cordifolia* stems along with water                                                         \[[@B45-jcm-09-01176]\]                                                                                                                                                                                                    
  Detoxification                                                                                                                                                                                                                                                                                                                                  Rhizomes with vinegar, *Alpinia galanga*, *Zingiber purpureum*                                                                                                                                                                                                                                                                                               
  Analgesic                                                                                                                                                                                                                                                                                                                                       Herbal baths of the rhizome                                                                                                       External                                                                                                                                                                                                                   
  Hemorrhage                                                                                                                                                                                                                                                                                                                                      Rhizomes paste                                                                                                                    \[[@B46-jcm-09-01176]\]                                                                                                                                                                                                    
  Aphrodisiac                                                                                                                                                                                                                                                                                                                                     Rhizomes                                                                                                                          Oral                                                                                                                                                     \[[@B47-jcm-09-01176]\]                                           
  Hallucination                                                                                                                                                                                                                                                                                                                                   Rhizomesare mixed with Indian hemp and *Podophyllum pleianthum*                                                                   \[[@B48-jcm-09-01176]\]                                                                                                                                                                                                    
  Fair skin                                                                                                                                                                                                                                                                                                                                       Leaves of *A. calamus* are given with *Artemisia vulgaris*                                                                        Dermal                                                                                                                                                   \[[@B49-jcm-09-01176]\]                                           
  Indonesia                                                                                                                                                                                                                                                                                                                                       Gastrointestinal                                                                                                                  Rhizomes                                                                                                                                                 Oral                                                              \[[@B50-jcm-09-01176]\]
  England                                                                                                                                                                                                                                                                                                                                         Rhizomes blended with chalk and magnesium oxide                                                                                   \[[@B51-jcm-09-01176]\]                                                                                                                                                                                                    
  Gastrointestinal, antibacterial, analgesic                                                                                                                                                                                                                                                                                                      Rhizomes                                                                                                                          \[[@B52-jcm-09-01176]\]                                                                                                                                                                                                    
  Neurological, dysentery, and chronic catarrh                                                                                                                                                                                                                                                                                                    Rhizomesare given with *Gentiana campestris* L.                                                                                                                                                                                                                                                                                                              
  Malaria                                                                                                                                                                                                                                                                                                                                         Rhizomes                                                                                                                          \[[@B53-jcm-09-01176]\]                                                                                                                                                                                                    
  Europe                                                                                                                                                                                                                                                                                                                                          Obesity, influenza, gastrointestinal, respiratory                                                                                 \[[@B54-jcm-09-01176],[@B55-jcm-09-01176]\]                                                                                                                                                                                
  Republic of South Africa                                                                                                                                                                                                                                                                                                                        Tooth powder, gastrointestinal, tonic, aphrodisiac                                                                                \[[@B56-jcm-09-01176]\]                                                                                                                                                                                                    
  Sweden                                                                                                                                                                                                                                                                                                                                          Liquor                                                                                                                            \[[@B57-jcm-09-01176]\]                                                                                                                                                                                                    
  Germany                                                                                                                                                                                                                                                                                                                                         Increases menstrual flow, gastrointestinal                                                                                        \[[@B58-jcm-09-01176],[@B59-jcm-09-01176]\]                                                                                                                                                                                
  Java                                                                                                                                                                                                                                                                                                                                            Lactation                                                                                                                         \[[@B60-jcm-09-01176]\]                                                                                                                                                                                                    
  Lithuania                                                                                                                                                                                                                                                                                                                                       Chest pain, diarrhea                                                                                                              Rhizomes and leaves are taken with sugar                                                                                                                 \[[@B52-jcm-09-01176]\]                                           
  Relieves pain, gout, rheumatism                                                                                                                                                                                                                                                                                                                 Leaves decoction                                                                                                                  External                                                                                                                                                 \[[@B61-jcm-09-01176]\]                                           
  New Guinea                                                                                                                                                                                                                                                                                                                                      Miscarriage                                                                                                                       Rhizomes                                                                                                                                                 Oral                                                              \[[@B62-jcm-09-01176]\]
  Philippines                                                                                                                                                                                                                                                                                                                                     Gastrointestinal, rheumatism                                                                                                      \[[@B56-jcm-09-01176]\]                                                                                                                                                                                                    
  Russia                                                                                                                                                                                                                                                                                                                                          Typhoid, syphilis, baldness, fever, cholera                                                                                       \[[@B63-jcm-09-01176]\]                                                                                                                                                                                                    
  Thailand                                                                                                                                                                                                                                                                                                                                        Blood purifier, fever                                                                                                             \[[@B64-jcm-09-01176]\]                                                                                                                                                                                                    
  Turkey                                                                                                                                                                                                                                                                                                                                          Wound healing, cough, tuberculosis                                                                                                External and oral                                                                                                                                        \[[@B61-jcm-09-01176]\]                                           
  Gastrointestinal                                                                                                                                                                                                                                                                                                                                Oral                                                                                                                              \[[@B65-jcm-09-01176],[@B66-jcm-09-01176]\]                                                                                                                                                                                
  Arab countries                                                                                                                                                                                                                                                                                                                                  Gastrointestinal, tuberculosis                                                                                                    \[[@B67-jcm-09-01176],[@B68-jcm-09-01176]\]                                                                                                                                                                                
  Brazil                                                                                                                                                                                                                                                                                                                                          Destroys parasitic worms                                                                                                          \[[@B68-jcm-09-01176]\]                                                                                                                                                                                                    
  Argentina                                                                                                                                                                                                                                                                                                                                       Dysmenorrhea                                                                                                                      \[[@B69-jcm-09-01176]\]                                                                                                                                                                                                    
  United States                                                                                                                                                                                                                                                                                                                                   Gastrointestinal, abortifacient, stimulant, tonic, respiratory disorder                                                           Rhizomes                                                                                                                                                 \[[@B70-jcm-09-01176]\]                                           
  Korea                                                                                                                                                                                                                                                                                                                                           Improves memory and life span                                                                                                     \[[@B71-jcm-09-01176]\]                                                                                                                                                                                                    
  Sri Lanka                                                                                                                                                                                                                                                                                                                                       Cough, worm infestation                                                                                                           Rhizomes paste are given with milk                                                                                                                       \[[@B72-jcm-09-01176]\]                                           

jcm-09-01176-t002_Table 2

###### 

Pharmaceutical products of *A. calamus* available in the market.

  Medicine/Formulations                                       Indications/Use                                          Manufacturers
  ----------------------------------------------------------- -------------------------------------------------------- --------------------------------------------
  Pilochek tablets                                            Hemorrhoids                                              Dabur India Limited
  Brahm Rasayan                                               Nervine tonic                                            
  Mahasudarsan Churna                                         Malaria                                                  
  Janma Ghunti Honey                                          Babies growth, Constipation, Diarrhea                    
  Brahmi Pearls capsules                                      Brain Nourisher                                          Kerala Ayurveda
  GT capsules                                                 Osteoarthritis, osteoporosis, hyperlipidemia             
  Histantin tablets                                           Anti-allergic                                            
  Santhwanam oil                                              Antioxidant, rejuvenate                                  
  Mahathikthaka Ghrita capsules                               Skin disease, malabsorption syndrome                     
  Calamus root tincture                                       Stimulates the digestive system                          Florida Herbal Pharmacy
  Vacha capsules                                              Food supplements                                         DR Wakde's Natural Health Care, London
  Mentat tablets and syrup                                    Nervine tonic                                            Himalaya Herbal Healthcare
  Abana                                                       Cardiovascular disorders, hyperlipidemia, dyslipidemia   
  Mentat tablets and Syrup                                    Anxiety, depression, insomnia                            
  Muscle & Joint Rub                                          Backaches, muscular sprains, pain                        
  Anxocare                                                    Anxiety                                                  
  Erina-EP                                                    Ectoparasites                                            
  Himpyrin, Himpyrin Vet                                      Analgesic and anti-inflammatory                          
  Scavon Vet                                                  Anti-bacterial, anti-fungal                              
  Vacha powder                                                Brain tonic, improves digestion, and prevents nausea     Bixa Botanical
  Amalth                                                      Herbal supplements                                       Mcnow Biocare Private Limited
  Sunarin capsules                                            Anal fissures, piles, rectal inflammation, congestion    SG Phyto Pharma
  Dr Willmar Schwabe India *Acorus calamus* mother tincture   Intestinal worms and stomach disorders, fever, nausea    Dr Willmar Schwabe India Pvt Ltd.
  Himalayan calamus root essential oil                        Pain relief and calm mind                                Naturalis Essence of Nature
  Calamus oil                                                 Body, skin care, hair growth                             Kazima Perfumers
  Calamus root powder                                         Mental health problems                                   Heilen Biopharm
  Winton tablets and syrup                                    Reduce tension, stress, and anxiety                      Scortis Healthcare
  Chesol syrup                                                Muscular aches and pains, chest colds, and bronchitis    J & J Dechane Laboratories Private Limited
  Enzo Fast                                                   Acidity, gastritis, flatulence, indigestion              Naturava
  Dark Forest Vekhand powder                                  Abdomen pain, worms (infants)                            Simandhar Herbal Pvt. Ltd.
  Nervocare                                                   Insomnia                                                 Deep Ayurveda
  Antress tablets                                             Anxiety and stress disorders                             Ayursun Pharma
  Grapzone syrup                                              Mental wellness                                          Alna Biotech Pvt Ltd.
  Memoctive syrup                                             Improves memory power                                    Aayursh Herbal India
  Smrutihills capsules                                        Stress, anxiety, adaptogenic                             Ayush Arogyam
  Gastrin capsules                                            Gastritis, dyspepsia                                     Sarvana Marundhagam
  Pigmento tablets                                            Leukoderma or vitiligo                                   Charak Pharma
  Paedritone drops                                            Digestive functions                                      
  Vacha Churna                                                Brain tonic, digestion, nausea                           Sadvaidyasala
  Alert capsules                                              Immunomodulator, anxiety                                 Vasu Healthcare
  Brento tablets                                              Increasing cognitive functions                           Zandu Realty Limited
  Livotrit Forte                                              Hepatitis, jaundice                                      
  Zanduzyme                                                   Indigestion and dyspepsia                                
  Vedic Slim                                                  Anti-obesity                                             Vedic Bio-Labs Pvt. Ltd.
  Hinguvachaadi Gulika                                        Anorexia, indigestion, appetite loss                     Nagarajuna Pvt. Ltd.
  Nilsin capsules                                             Sinusitis and allergic rhinitis                          Phytomarketing
  Norbeepee tablet                                            Hypertension                                             AVN Formulations
  Sooktyn tablet                                              Antacid, antispasmodic                                   Alarsin Pharma Pvt. Ltd.
  Deonac oil                                                  Pain reliving oil                                        Doux Healthcare Pvt. Ltd.
  Smrutisagar Rasa                                            Memory enhancer                                          Shree Dhootpapeshwar Limited
  Yogaraj Guggul                                              Vitiligo, anorexia, indigestion, loss of appetite        
  Kankayan Bati                                               Gastritis, flatulence, dyspepsia                         Baidyanath Pvt. Ltd.
  Brahmi Ghrita                                               Insanity and memory issues                               
  Fat Go                                                      Controls high cholesterol level                          Jolly Healthcare
  Divya Medha Vati                                            Improves memory power                                    Patanjali Ayurveda
  Divya Mukta Vati                                            High blood pressure                                      

jcm-09-01176-t003_Table 3

###### 

Chemical compounds isolated from different botanical parts of *A. calamus*.

  -------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
  Classification          Compound No.                                                                                      Chemical Ingredient                                                                                                   Methods of Characterization                                                           Parts/Extract                                                     References
  ----------------------- ------------------------------------------------------------------------------------------------- --------------------------------------------------------------------------------------------------------------------- ------------------------------------------------------------------------------------- ----------------------------------------------------------------- -----------------------------------------------------------------------------------------------------------------------------
  Phenylpropanoids        **1 **                                                                                            *α*-Asarone                                                                                                           GC-FID, GC-MS                                                                         Rhizomes/n-hexane, aqueous, methanol, ethanol                     \[[@B74-jcm-09-01176],[@B78-jcm-09-01176],[@B84-jcm-09-01176],[@B89-jcm-09-01176],[@B90-jcm-09-01176],[@B91-jcm-09-01176]\]

  **2 **                  *β*-Asarone                                                                                                                                                                                                                                                                                                                                                                     

  **3 **                  *γ*-Asarone                                                                                                                                                                                                                                                                                                                                                                     

  **4 **                  Eugenyl acetate                                                                                   GC-MS                                                                                                                 Rhizomes/aqueous extract                                                              \[[@B74-jcm-09-01176],[@B78-jcm-09-01176],[@B91-jcm-09-01176]\]   

  **5 **                  Eugenol                                                                                                                                                                                                                                                                                                                                                                         

  **6 **                  Isoeugenol                                                                                                                                                                                                                                                                                                                                                                      

  **7 **                  Methyl eugenol                                                                                    Rhizomes/n-hexane,\                                                                                                   \[[@B92-jcm-09-01176]\]                                                                                                                                 
                                                                                                                            ethyl acetate                                                                                                                                                                                                                                                                 

  **8 **                  Methyl isoeugenol                                                                                 Rhizomes/hexane                                                                                                       \[[@B74-jcm-09-01176],[@B78-jcm-09-01176],[@B91-jcm-09-01176],[@B94-jcm-09-01176]\]                                                                     

  **9 **                  Calamol                                                                                           Rhizomes/aqueous extract                                                                                              \[[@B74-jcm-09-01176],[@B78-jcm-09-01176],[@B91-jcm-09-01176]\]                                                                                         

  **10 **                 Azulene                                                                                                                                                                                                                                                                                                                                                                         

  **11 **                 Eugenol methyl ether                                                                                                                                                                                                                                                                                                                                                            

  **12 **                 Dipentene                                                                                                                                                                                                                                                                                                                                                                       

  **13 **                 Asaronaldehyde                                                                                                                                                                                                                                                                                                                                                                  

  **14 **                 Terpinolene                                                                                                                                                                                                                                                                                                                                                                     

  **15 **                 1,8-cineole                                                                                                                                                                                                                                                                                                                                                                     

  **16 **                 (*E*)-isoeugenol acetate                                                                          GC-FID, GC-MS                                                                                                         \[[@B89-jcm-09-01176]\]                                                                                                                                 

  **17 **                 (*E*)-methyl isoeugenol                                                                                                                                                                                                                                                                                                                                                         

  **18 **                 Cis-methyl isoeugenol                                                                             Rhizomes/n-hexane, ethyl acetate                                                                                      \[[@B92-jcm-09-01176]\]                                                                                                                                 

  **19 **                 Euasarone                                                                                                                                                                                                                                                                                                                                                                       

  **20 **                 Cinnamaldehyde                                                                                                                                                                                                                                                                                                                                                                  

  **21 **                 Cyclohexanone                                                                                     GC-MS                                                                                                                 Rhizomes/hexane                                                                       \[[@B94-jcm-09-01176]\]                                           

  **22 **                 Acorin                                                                                            NMR                                                                                                                   Rhizomes/chloroform                                                                   \[[@B95-jcm-09-01176]\]                                           

  **23 **                 Isoasarone                                                                                                                                                                                                                                                                                                                                                                      

  **24 **                 Safrole                                                                                                                                                                                                                                                                                                                                                                         

  **25 **                 Z-3-(2,4,5-trimethoxyphenyl)-2-propenal                                                           FTIR, NMR                                                                                                             Rhizomes/ethanol                                                                      \[[@B96-jcm-09-01176]\]                                           

  **26 **                 2,3-dihydro-4,5,7-trimethoxy-1-ethyl-2-methyl-3 (2,4,5-trimethoxyphenyl) indene                                                                                                                                                                                                                                                                                                 

  **27 **                 (Z)-asarone                                                                                       GC-MS                                                                                                                 Leaves/n-hexane                                                                       \[[@B97-jcm-09-01176]\]                                           

  **28 **                 (E)-caryophyllene                                                                                                                                                                                                                                                                                                                                                               

  **29 **                 Estragole                                                                                         Rhizomes/aqueous                                                                                                      \[[@B98-jcm-09-01176]\]                                                                                                                                 

  **30 **                 Carvacrol                                                                                                                                                                                                                                                                                                                                                                       

  **31 **                 2-cyclohexane-1-one                                                                                                                                                                                                                                                                                                                                                             

  **32 **                 Naphthalene                                                                                                                                                                                                                                                                                                                                                                     

  **33 **                 *γ*-Cadinene                                                                                                                                                                                                                                                                                                                                                                    

  **34 **                 Aristolene                                                                                                                                                                                                                                                                                                                                                                      

  **35 **                 1(5),3-aromadenedradiene                                                                                                                                                                                                                                                                                                                                                        

  **36 **                 5-n-butyltetraline                                                                                                                                                                                                                                                                                                                                                              

  **37 **                 4,5-dehydro-isolongifolene                                                                                                                                                                                                                                                                                                                                                      

  **38 **                 Calarene                                                                                                                                                                                                                                                                                                                                                                        

  **39 **                 Isohomogenol                                                                                                                                                                                                                                                                                                                                                                    

  **40 **                 Zingiberene                                                                                                                                                                                                                                                                                                                                                                     

  **41 **                 *α*-Calacorene                                                                                                                                                                                                                                                                                                                                                                  

  **42 **                 5,8-dimethyl isoquinoline                                                                                                                                                                                                                                                                                                                                                       

  **43 **                 Cyclohexane methanol                                                                                                                                                                                                                                                                                                                                                            

  **44 **                 Longifolene                                                                                                                                                                                                                                                                                                                                                                     

  **45 **                 Isoelemicin                                                                                                                                                                                                                                                                                                                                                                     

  Sesquiterpenoids        **46 **                                                                                           Calamene                                                                                                              \[[@B74-jcm-09-01176],[@B78-jcm-09-01176],[@B91-jcm-09-01176]\]                                                                                         

  **47 **                 Calamenenol                                                                                                                                                                                                                                                                                                                                                                     

  **48 **                 Calameone                                                                                                                                                                                                                                                                                                                                                                       

  **49 **                 Preisocalamendiol                                                                                                                                                                                                                                                                                                                                                               

  **50 **                 1,4-(trans)1,7(trans)-acorenone                                                                   \[[@B93-jcm-09-01176]\]                                                                                                                                                                                                                                                       

  **51 **                 1,4-(cis)-1,7-(trans)-acorenone                                                                                                                                                                                                                                                                                                                                                 

  **52 **                 2,6 diepishyobunone                                                                                                                                                                                                                                                                                                                                                             

  **53 **                 *α*-Gurjunene                                                                                                                                                                                                                                                                                                                                                                   

  **54 **                 *β*-Gurjunene                                                                                                                                                                                                                                                                                                                                                                   

  **55 **                 *α*-Cedrene                                                                                       \[[@B98-jcm-09-01176]\]                                                                                                                                                                                                                                                       

  **56 **                 *β*-Elemene                                                                                                                                                                                                                                                                                                                                                                     

  **57 **                 *β*-Cedrene                                                                                       \[[@B93-jcm-09-01176]\]                                                                                                                                                                                                                                                       

  **58 **                 *β*-Caryophyllene                                                                                                                                                                                                                                                                                                                                                               

  **59 **                 Valencene                                                                                                                                                                                                                                                                                                                                                                       

  **60 **                 Viridiflorene                                                                                                                                                                                                                                                                                                                                                                   

  **61 **                 *α*-Selinene                                                                                      GC-FID, GC-MS                                                                                                         \[[@B89-jcm-09-01176],[@B93-jcm-09-01176]\]                                                                                                             

  **62 **                 δ-Cadinene                                                                                        GC-MS                                                                                                                 \[[@B93-jcm-09-01176]\]                                                                                                                                 

  **63 **                 α-Curcumene                                                                                                                                                                                                                                                                                                                                                                     

  **64 **                 Shyobunone                                                                                        \[[@B84-jcm-09-01176],[@B93-jcm-09-01176],[@B99-jcm-09-01176],[@B100-jcm-09-01176]\]                                                                                                                                                                                          

  **65 **                 Isoshyobunone                                                                                     \[[@B93-jcm-09-01176],[@B99-jcm-09-01176],[@B101-jcm-09-01176]\]                                                                                                                                                                                                              

  **66 **                 Caryophyllene oxide                                                                               \[[@B93-jcm-09-01176]\]                                                                                                                                                                                                                                                       

  **67 **                 Humulene oxide II                                                                                 GC-FID, GC-MS                                                                                                         \[[@B89-jcm-09-01176],[@B93-jcm-09-01176]\]                                                                                                             

  **68 **                 Elemol                                                                                            GC-MS                                                                                                                 \[[@B93-jcm-09-01176]\]                                                                                                                                 

  **69 **                 Cedrol                                                                                                                                                                                                                                                                                                                                                                          

  **70 **                 Spathulenol                                                                                                                                                                                                                                                                                                                                                                     

  **71 **                 Acorenone                                                                                                                                                                                                                                                                                                                                                                       

  **72 **                 *α*-Cadinol                                                                                                                                                                                                                                                                                                                                                                     

  **73 **                 Humulene epoxide II                                                                               GC-FID, GC-MS                                                                                                         \[[@B89-jcm-09-01176]\]                                                                                                                                 

  **74 **                 *α*-Bisabolol                                                                                                                                                                                                                                                                                                                                                                   

  **75 **                 Asaronaldehyde                                                                                    NMR                                                                                                                   Rhizomes/chloroform                                                                   \[[@B95-jcm-09-01176]\]                                           

  **76 **                 Calamusenone                                                                                      GLC, IR, NMR                                                                                                          Rhizomes/petroleum ether                                                              \[[@B99-jcm-09-01176]\]                                           

  **77 **                 Isocalamendiol                                                                                                                                                                                                                                                                                                                                                                  

  **78 **                 Dehydroxyiso-calamendiol                                                                                                                                                                                                                                                                                                                                                        

  **79 **                 Epishyobunone                                                                                                                                                                                                                                                                                                                                                                   

  **80 **                 Acorone                                                                                           NMR                                                                                                                   Rhizomes/hydro alcoholic                                                              \[[@B100-jcm-09-01176]\]                                          

  **81 **                 Neo-acorane A                                                                                     Rhizomes/ethanol                                                                                                      \[[@B102-jcm-09-01176]\]                                                                                                                                

  **82 **                 Acoric acid                                                                                                                                                                                                                                                                                                                                                                     

  **83 **                 Calamusin D                                                                                                                                                                                                                                                                                                                                                                     

  **84 **                 1*β*,5*α*-Guaiane-4*β*,10*α*-diol-6-one                                                           \[[@B103-jcm-09-01176]\]                                                                                                                                                                                                                                                      

  **85 **                 Dioxosarcoguaiacol                                                                                HPLC                                                                                                                  Rhizomes/petroleum ether                                                              \[[@B101-jcm-09-01176]\]                                          

  **86 **                 7-tetracycloundecanol,4,4,11,11-tetramethyl                                                       GC-MS                                                                                                                 Rhizomes/ethanol                                                                      \[[@B84-jcm-09-01176]\]                                           

  **87 **                 4*α*,7-Methano-4α-naphth\[1,8a-b\] oxirene,                                                                                                                                                                                                                                                                                                                                     

  **88 **                 Spathulenol                                                                                       Rhizomes/aqueous                                                                                                      \[[@B98-jcm-09-01176]\]                                                                                                                                 

  **89 **                 Vulgarol B                                                                                                                                                                                                                                                                                                                                                                      

                          **90 **                                                                                           Tatanan A                                                                                                             HPLC, NMR                                                                             Rhizomes/95% ethanol                                              \[[@B104-jcm-09-01176]\]

  **91 **                 Acoramone                                                                                                                                                                                                                                                                                                                                                                       

  **92 **                 2-hydroxyacorenone                                                                                                                                                                                                                                                                                                                                                              

  **93 **                 4-(2-formyl-5-methoxymethyl\                                                                                                                                                                                                                                                                                                                                                    
                          pyrrol-1-yl) butyric acid methyl ester                                                                                                                                                                                                                                                                                                                                          

  **94 **                 2-acetoxyacorenone                                                                                                                                                                                                                                                                                                                                                              

  **95 **                 Acoramol                                                                                                                                                                                                                                                                                                                                                                        

  **96 **                 N-transferuloyl\                                                                                                                                                                                                                                                                                                                                                                
                          tyramine                                                                                                                                                                                                                                                                                                                                                                        

  **97 **                 Tatarinoid A                                                                                                                                                                                                                                                                                                                                                                    

  **98 **                 Tatarinoid B                                                                                                                                                                                                                                                                                                                                                                    

  **99 **                 Acortatarin A                                                                                                                                                                                                                                                                                                                                                                   

  Monoterpenes            **100 **                                                                                          *α*-Pinene                                                                                                            GC-MS                                                                                 Rhizomes, roots/aqueous                                           \[[@B74-jcm-09-01176],[@B78-jcm-09-01176],[@B91-jcm-09-01176],[@B93-jcm-09-01176]\]

  **101 **                *β*-Pinene                                                                                                                                                                                                                                                                                                                                                                      

  **102 **                Camphene                                                                                          \[[@B74-jcm-09-01176],[@B78-jcm-09-01176],[@B91-jcm-09-01176],[@B93-jcm-09-01176],[@B98-jcm-09-01176]\]                                                                                                                                                                       

  **103 **                o-Cymol                                                                                           \[[@B98-jcm-09-01176]\]                                                                                                                                                                                                                                                       

  **104 **                p-Cymene                                                                                          GC-FID, GC-MS                                                                                                         \[[@B89-jcm-09-01176],[@B93-jcm-09-01176],[@B98-jcm-09-01176]\]                                                                                         

  **105 **                *γ*-Terpinene                                                                                     GC-MS                                                                                                                 \[[@B98-jcm-09-01176]\]                                                                                                                                 

  **106 **                *α*-Terpinolene                                                                                                                                                                                                                                                                                                                                                                 

  **107 **                Anethole                                                                                                                                                                                                                                                                                                                                                                        

  **108 **                Thymol                                                                                                                                                                                                                                                                                                                                                                          

  **109 **                Isoaromadendrene epoxide                                                                                                                                                                                                                                                                                                                                                        

  **110 **                Camphor                                                                                           Rhizome, leaves, roots/aqueous, hexane                                                                                \[[@B93-jcm-09-01176],[@B97-jcm-09-01176]\]                                                                                                             

  **111 **                Sabinene                                                                                          Roots/aqueous                                                                                                         \[[@B93-jcm-09-01176]\]                                                                                                                                 

  **112 **                2-hexenal                                                                                                                                                                                                                                                                                                                                                                       

  **113 **                Limonene                                                                                          \[[@B93-jcm-09-01176],[@B98-jcm-09-01176]\]                                                                                                                                                                                                                                   

  **114 **                Cis-linaloloxide                                                                                  \[[@B93-jcm-09-01176]\]                                                                                                                                                                                                                                                       

  **115 **                Cis-sabinene hydrate                                                                                                                                                                                                                                                                                                                                                            

  **116 **                Trans-linalol oxide                                                                                                                                                                                                                                                                                                                                                             

  **117 **                Linalool                                                                                          \[[@B93-jcm-09-01176],[@B97-jcm-09-01176]\]                                                                                                                                                                                                                                   

  **118 **                Terpinen-4-ol                                                                                     \[[@B93-jcm-09-01176]\]                                                                                                                                                                                                                                                       

  **119 **                *α*-Acoradiene                                                                                                                                                                                                                                                                                                                                                                  

  **120 **                *β*-Acoradiene                                                                                                                                                                                                                                                                                                                                                                  

  **121 **                *α*-Terpineol                                                                                                                                                                                                                                                                                                                                                                   

  **122 **                Isoborneol                                                                                        Leaves/hexane                                                                                                         \[[@B97-jcm-09-01176]\]                                                                                                                                 

  Xanthone glycosides     **123 **                                                                                          4,5,8-trimethoxy-xanthone-2-*O*-*β*-D-glucopyranosyl (1-2)-*O*-*β*-D-galactopyranoside                                NMR                                                                                   Rhizome/ethanol                                                   \[[@B83-jcm-09-01176]\]

  Triterpenoid saponins   **124 **                                                                                          1*β*,2*α*,3*β*, 19*α*-Tetrahydroxyurs-12-en-28-oic acid-28-O- {(*β*-D-glucopyranosyl (1-2)}-*β*-D galactopyranoside   \[[@B82-jcm-09-01176]\]                                                                                                                                 

  **125 **                3-*β*, 22-*α*-24,29-Tetrahydroxyolean-12-en-3-O-(*β*-Darabinosyl (1,3)}-*β*-D-arabinopyranoside                                                                                                                                                                                                                                                                                 

  Alkaloids               **126 **                                                                                          Trimethoxyamphetamine,2,3,5                                                                                           GC-MS                                                                                 \[[@B84-jcm-09-01176]\]                                           

  **127 **                Pyrimidin-2-one,4-\[N-methylureido\]-1-\[4methyl amino carbonloxy methy\]                                                                                                                                                                                                                                                                                                       

  Triterpene glycoside    **128 **                                                                                          22-\[(6-deoxy-*α*-L-rhamnopyranosyl) oxy\]-3,23-dihydroxy-, methyl ester, (3*β*,4*β*,20*α*,22*β*)                     NMR                                                                                   Root, Rhizomes/ethyl acetate                                      \[[@B85-jcm-09-01176]\]

  Steroids/Sterols        **129 **                                                                                          *β*-daucosterol                                                                                                                                                                                                                                                               

  Amino acids             **130 **                                                                                          Arginine                                                                                                              HPLC                                                                                  Roots/ethanol                                                     \[[@B86-jcm-09-01176],[@B87-jcm-09-01176]\]

  **131 **                Lysine                                                                                                                                                                                                                                                                                                                                                                          

  **132 **                Phenylalanine                                                                                                                                                                                                                                                                                                                                                                   

  **133 **                Threonine                                                                                                                                                                                                                                                                                                                                                                       

  **134 **                Tryptophan                                                                                                                                                                                                                                                                                                                                                                      

  **135 **                *α*-alanine                                                                                                                                                                                                                                                                                                                                                                     

  **136 **                Asparagine                                                                                                                                                                                                                                                                                                                                                                      

  **137 **                Aspartic acid                                                                                                                                                                                                                                                                                                                                                                   

  **138 **                Norvaline                                                                                                                                                                                                                                                                                                                                                                       

  **139 **                Proline                                                                                                                                                                                                                                                                                                                                                                         

  **140 **                Tyrosine                                                                                                                                                                                                                                                                                                                                                                        

  **141 **                Glutamic acid                                                                                                                                                                                                                                                                                                                                                                   

  Fatty acids             **142 **                                                                                          Palmitic acid                                                                                                         GLC                                                                                   Rhizome/petroleum ether                                           \[[@B88-jcm-09-01176]\]

  **143 **                Myristic acid                                                                                                                                                                                                                                                                                                                                                                   

  **144 **                Palmitoleic acid                                                                                                                                                                                                                                                                                                                                                                

  **145 **                Stearic acid                                                                                                                                                                                                                                                                                                                                                                    
  -------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

GC-FID, gas chromatography -- flame ionization detector; GC-MS, gas chromatography -- mass spectrometry; NMR, nuclear magnetic resonance; FTIR, Fourier-transform infrared spectroscopy; GLC, gas liquid chromatography; IR, infrared spectroscopy; HPLC, high-performance liquid chromatography.

jcm-09-01176-t004_Table 4

###### 

Preclinical claims of *A. calamus* in neurological and metabolic disorders.

  Action                                                    Parts of Plant                                    Extract/Compound                                                          Animal Model                                                                           Dosage                                                                                                                                                                                            Results                                                                                          References
  --------------------------------------------------------- ------------------------------------------------- ------------------------------------------------------------------------- -------------------------------------------------------------------------------------- ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ------------------------------------------------------------------------------------------------ --------------------------
  Antidiabetic effects                                      Rhizomes                                          Methanol                                                                  STZ-induced                                                                            50, 100, and 200 mg/kg, p.o. to rats                                                                                                                                                              ↓ Lipid profile and blood glucose, while ↑ levels of plasma insulin, tissue glycogen, and G6PD   \[[@B105-jcm-09-01176]\]
  Alloxan-induced                                           150 and 200 mg/kg, p.o. to rat                    ↓ Blood glucose level                                                     \[[@B106-jcm-09-01176]\]                                                                                                                                                                                                                                                                                                                                                                  
  Ethyl acetate                                             Genetically obese diabetic C57BL/Ks db/db mice    100 mg/kg, p.o.                                                           ↓ Levels of triglycerides and serum glucose                                            \[[@B107-jcm-09-01176]\]                                                                                                                                                                                                                                                                           
  GLP-1 expression and secretion with STZ-induced           100 mg/kg, i.g.                                   ↑ Secretion of GLP-1 and ↓ blood glucose levels                           \[[@B108-jcm-09-01176]\]                                                                                                                                                                                                                                                                                                                                                                  
  In vitro HIT-T15 cell line and alpha-glucosidase enzyme   6.25, 12.5, and 25 µg/mL                          ↑ Insulin secretion in HIT-T15 cells                                      \[[@B109-jcm-09-01176]\]                                                                                                                                                                                                                                                                                                                                                                  
  Glucose tolerance                                         400 and 800 mg/kg, p.o. to mice                   ↓ Serum glucose, and abolished the ↑ level of blood glucose                                                                                                                                                                                                                                                                                                                                                                                                         
  Anti-obesity effects                                      Ethanol and aqueous                               HFD-induced                                                               100 and 200 mg/kg to rats                                                              ↓ Levels of serum cholesterol and triglycerides, ↑ lipoprotein fraction                                                                                                                           \[[@B110-jcm-09-01176]\]                                                                         
  Diethyl ether                                             HFD-induced                                       20 and 40 mg/kg, p.o. to rats                                             ↓ Total cholesterol and low-density lipoprotein levels, ↑ plasma fibrinogen levels     \[[@B111-jcm-09-01176]\]                                                                                                                                                                                                                                                                           
  Methanol                                                  Triton-X-100-induced hyperlipidemic               250 and 500 mg/kg to rats                                                 Dose-dependent anti-hyperlipidemic effect                                              \[[@B112-jcm-09-01176]\]                                                                                                                                                                                                                                                                           
  HFD-induced                                               250 and 500 mg/kg, p.o. to rats                   ↓ Level of total cholesterol, triglycerides, and LDL, ↑ HDL cholesterol   \[[@B113-jcm-09-01176]\]                                                                                                                                                                                                                                                                                                                                                                  
                                                            Aqueous                                           HFD-induced                                                               100, 200, and 300 mg/kg, p.o. to rats                                                  ↓ Levels of serum glucose, leptin, and insulin along with ↓ triglyceride, low-density lipoprotein, very LDL cholesterol, total cholesterol, phospholipids, and free fatty acid increased levels   \[[@B114-jcm-09-01176]\]                                                                         
  Antihypertensive effects                                  Ethyl acetate                                     Clamping the left kidney artery for 4 h                                   250 mg/kg, p.o. to rats                                                                ↓SBP and DBP, blood urea nitrogen, creatinine and LPO, ↑ level of nitric oxide, SOD, CAT, GPX                                                                                                     \[[@B115-jcm-09-01176]\]                                                                         
  Crude extract, ethyl acetate and n-hexane                 Blood pressure lowering effect in normotensive    10, 30, and 50 mg/kg to anesthetized rats                                 Relaxant effects mediated through Ca^+2^ antagonism and NO pathways                    \[[@B116-jcm-09-01176]\]                                                                                                                                                                                                                                                                           
  Ethanol and α-asarone                                     Dimethyl sulfoxide-induced noise stress to rats   100 and 9 mg/kg, p.o. to rats                                             ↓ Destructive effect of stress enlightening the morphological changes of hippocampus   \[[@B117-jcm-09-01176]\]                                                                                                                                                                                                                                                                           
  Anti-inflammatory effects                                 Leaves                                            Ethanol                                                                   Carrageenan-induced paw edema                                                          100 and 200 mg/kg to rats                                                                                                                                                                         ↓ Histamine, 5-HT, and kinins                                                                    \[[@B118-jcm-09-01176]\]
  Antioxidant effects                                       Rhizomes                                          *α*-asarone                                                               Noise stress induced to rats                                                           3, 6, and 9 mg/kg, i.p. to rats                                                                                                                                                                   ↑ SOD and LPO, decreased ↓ CAT, GPX, GSH, vitamins C and E, and protein thiol levels             \[[@B119-jcm-09-01176]\]
  Leaves and rhizomes                                       Ethyl acetate and methanol                        DPPH radical scavenging chelating ferrous ions, FRAP                      200, 100, 80, 60, 40, 20, 10, and 5 μg/mL                                              Prominent DPPH scavenging activity, chelating ferrous ions, and reducingpower                                                                                                                     \[[@B120-jcm-09-01176],[@B121-jcm-09-01176]\]                                                    
  Rhizomes                                                  Ethanol                                           Acetaminophen-induced                                                     250, 500 mg/kg, p.o. to rats                                                           ↓ MDA and ↑ SOD, CAT, GPX, GSH levels                                                                                                                                                             \[[@B122-jcm-09-01176]\]                                                                         
  Anticonvulsant effects                                    Roots                                             Ethanol and *β*-asarone                                                   Kainic acid-induced convulsion                                                         35 and 20 mg/kg                                                                                                                                                                                   ↓ Epileptic seizure, neuroprotective, and regenerative ability                                   \[[@B123-jcm-09-01176]\]
  Methanol                                                  PTZ-induced convulsion                            100 and 200 mg/kg, p.o. to mice                                           ↑ Latency period and ↓ PTZ-induced seizure time                                        \[[@B124-jcm-09-01176]\]                                                                                                                                                                                                                                                                           
  Rhizomes                                                  Calamus oil                                       MES, PTZ, and MCS model                                                   30, 100, and 300 mg/kg, p.o. to mice                                                   Calamus oil is found stable                                                                                                                                                                       \[[@B125-jcm-09-01176]\]                                                                         
  Ethanol                                                   MES and PTZ-induced convulsion                    250, 500 mg/kg, p.o. to mice                                              ↓ Hind limb extension and tonic flexion of forelimbs                                   \[[@B126-jcm-09-01176]\]                                                                                                                                                                                                                                                                           
  Methanol                                                  MES and PTZ-induced                               250 and 150 mg/kg, p.o. to rats                                           ↓ Immobility time at 250 mg/kg; however, ineffective at 150 mg/kg                      \[[@B127-jcm-09-01176]\]                                                                                                                                                                                                                                                                           
  Antidepressant effects                                    TST and FST                                       50 and 100 mg/kg, i.p. to mice                                            ↓ Immobility time in a dose-dependent manner                                           \[[@B128-jcm-09-01176]\]                                                                                                                                                                                                                                                                           
  Leaves                                                    TST and FST                                       50 and 100 mg/kg                                                          ↓ Immobility time                                                                      \[[@B129-jcm-09-01176]\]                                                                                                                                                                                                                                                                           
  Roots                                                     Aqueous                                           TST and FST                                                               100, 150, 200 mg/kg, p.o. to mice                                                      ↓ Immobility time                                                                                                                                                                                 \[[@B130-jcm-09-01176]\]                                                                         
  Rhizomes                                                  Hydro-alcoholic extract                           TST and FST                                                               75 and 150 mg/kg, p.o. to mice                                                         ↓ Corticosteroid levels                                                                                                                                                                           \[[@B131-jcm-09-01176]\]                                                                         
  Ethanol                                                   OFB and HPM test                                  72 mg/kg, p.o.                                                            No stimulation of postsynaptic 5-HT1A receptors                                        \[[@B132-jcm-09-01176]\]                                                                                                                                                                                                                                                                           
  Methanol and acetone                                      Behavioral despair test                           5, 20, and 50 mg/kg, p.o.                                                 ↓ Spontaneous locomotor activity                                                       \[[@B133-jcm-09-01176]\]                                                                                                                                                                                                                                                                           
  *β*-asarone                                               EPM and FST                                       25, 50, and 100 mg/kg, p.o.                                               ↓ Immobility time                                                                      \[[@B134-jcm-09-01176]\]                                                                                                                                                                                                                                                                           
  Neuroprotective effects                                   Hydro-alcoholic                                   CCI of sciatic nerve-induced neuropathic pain                             10 mg/kg to rats                                                                       Significantly ameliorated CCI-induced nociceptive pain                                                                                                                                            \[[@B135-jcm-09-01176]\]                                                                         
  CCI of sciatic nerve-induced peripheral neuropathy        100 and 200 mg/kg to rats                         Prevented CCI-induced neuropathy through ↓ oxidation and inflammation     \[[@B136-jcm-09-01176]\]                                                                                                                                                                                                                                                                                                                                                                  
  Leaves                                                    Methanol and acetone                              Apomorphine-induced stereotypy and haloperidol-induced catalepsy          20 and 50 mg/kg to mice                                                                Reversed stereotypy induced by apomorphine and significantly potentiated catalepsy induced by haloperidol                                                                                         \[[@B137-jcm-09-01176]\]                                                                         
  Rhizomes                                                  Ethanol                                           Spontaneous electrical activity and monoamine levels of the brain         200 and 300 mg/ kg to rats                                                             Depressive response by altering electrical activity, including changing brain monoamine levels                                                                                                    \[[@B138-jcm-09-01176]\]                                                                         
  Hydro-alcoholic                                           MCAo-produced brain ischemia                      25 mg/kg to rats                                                          Improvement in neurobehavioral performance, ↓ levels of GSH, SOD, and ↑ LPO level      \[[@B139-jcm-09-01176]\]                                                                                                                                                                                                                                                                           
  Ethanol                                                   Methotrexate-induced stress                       5, 10, 15, 20, 25 ppm concentration to fruit flies                        ↓ Elevated ROS, SOD, CAT, and GPX levels                                               \[[@B140-jcm-09-01176]\]                                                                                                                                                                                                                                                                           
  Cardioprotective effects                                  Whole plant                                       DOX-induced myocardial toxicity                                           100 and 200 mg/kg to rats                                                              ↓ Serum enzyme levels and protected the myocardium from the toxic effect of DOX                                                                                                                   \[[@B141-jcm-09-01176]\]                                                                         
  Rhizomes                                                  Crude, n-hexane, ethyl acetate                    Guinea pig tracheal segments                                              0.01 mg/mL                                                                             ↓ Force and rate of contractions at higher concentrations                                                                                                                                         \[[@B142-jcm-09-01176]\]                                                                         

CAT, catalase; CCI, chronic constriction injury; COX, cyclooxygenase; DBP, diastolic blood pressure; DOX, doxorubicin; DPPH, 2,2-diphenyl-1-picrylhydrazyl radical; EPM, elevated plus maze; FRAP, ferric reducing antioxidant power; FST, forced swim test; GLP-1, glucagon-like peptide-1; GPX, glutathione peroxidase; GR, glutathione reductase; GSH, reduced glutathione; HDL, high-density lipoproteins; HFD, high-fat diet; HPM, high plus maze; i.g., intragastric; i.p., intraperitoneal; LDL, low-density lipoprotein; LPO, lipid peroxides; MCAo, middle cerebral artery occlusion; MCS, minimal clonic seizure; MDA, malondialdehyde; MES, maximal electroshock; NO, nitric oxide; OFB, open field behavior; p.o., per oral; PTZ, pentylenetetrazol; ROS, reactive oxygen species; SBP, systolic blood pressure; SOD, superoxide dismutase; STZ, streptozotocin; TST, tail suspension test.

jcm-09-01176-t005_Table 5

###### 

Clinical claims of *A. calamus* in neurological and metabolic disorders.

  ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
  Formulations/Dosage forms *A. calamus*                                                                                                                                                                       Subjects                                                                                Study Design                                                 Intervention                                                                                                       Primary Endpoint                                                                           Outcome                                                                                                                                                               Evidence Quality   Reference
  ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ --------------------------------------------------------------------------------------- ------------------------------------------------------------ ------------------------------------------------------------------------------------------------------------------ ------------------------------------------------------------------------------------------ --------------------------------------------------------------------------------------------------------------------------------------------------------------------- ------------------ --------------------------
  *A. calamus* rhizome powder                                                                                                                                                                                  24 patients of both sexes with hyperlipidemia                                           Randomized single-blind controlled study                     500 mg twice daily after meal for 1 month                                                                          BMI, body perimeter, skinfold depth                                                        Significant reduction in skinfold depth, fatigue, and excessive hunger                                                                                                III                \[[@B178-jcm-09-01176]\]

  Davaie Loban capsules (*A. calamus*, nut grass, incense, ginger, and black pepper)                                                                                                                           24 patients of both sexes with Alzheimer's disease                                      Double-blind randomized clinical study                       500 mg capsule thrice daily for 3 months                                                                           ADAS-cog and CDR-SOB scores                                                                At 4 weeks and 12 weeks: significant reduction in the ADAS-cog and CDR-SOB scores                                                                                     III                \[[@B179-jcm-09-01176]\]

  70% hydro-alcoholic extract of *A. calamus*                                                                                                                                                                  33 patients of both sexes (20 male and 13 female) with anxiety disorder                 Non-randomized, open-label, single-arm study                 500 mg extract of one capsule twice daily after meal for 2 months                                                  BPRS score                                                                                 Significant reduction of anxiety and stress-related disorder                                                                                                          III                \[[@B180-jcm-09-01176]\]

  Vachadi Churna (*A. calamus*, *Cyperus rotundus*, *Cedrus deodara*, ginger, *Aconitum Heterophyllum*, *T. chebula*)                                                                                          30 obese patients of both sexes aged 14--50 years                                       Non-randomized, open-label, single-arm study                 3 g powder twice daily with lukewarm water before meal for 1 month                                                 BMI, girth measurements of mid-thigh, abdomen, hip, chest                                  Significant improvement in extreme sleep, body heaviness, fatigue, and excessive hunger                                                                               III                \[[@B181-jcm-09-01176]\]

  Guduchyadi Medhya Rasayana, (*A. calamus*, *Tinospora cordifolia*, *Achyranthes aspera*, *Embelia ribes*, *Convolvulus pluricaulis*, *T. chebula*, *S. lappa*, *Asparagus racemosus*, cow ghee, and sugar)   138 patients of both sexes aged 55--75 years with senile memory impairment              Randomized, two-parallel-group study                         3 g granule thrice daily after meal for 3 months                                                                   Mini--Mental State Examination, BPRS score, and estimation of serum acetylcholinesterase   Significant improvement in terms of recall memory, cognitive impairment, amnesia, concentration ability, depression, and stress                                       III                \[[@B182-jcm-09-01176]\]

  Dried aqueous extract of *A. calamus*                                                                                                                                                                        40 healthy volunteers, both sexes aged 18--50 years with a premedicant for anesthesia   Open-label randomized, two- parallel-group study             90 min before anesthesia;\                                                                                         Pulse rate, blood pressure, respiratory rate, body temperature                             The dried aqueous extract exhibited anti-hyperthermic and sedative effect without producing\                                                                          III                \[[@B183-jcm-09-01176]\]
                                                                                                                                                                                                                                                                                                                                                                    In the control group:\                                                                                                                                                                                        any respiratory depression                                                                                                                                                               
                                                                                                                                                                                                                                                                                                                                                                    0.2 mg intramuscular (IM) glycopyrrolate and a 0.2 mg IM 50 mg tablet of promethazine hydrochloride with water;\                                                                                                                                                                                                                                                                                       
                                                                                                                                                                                                                                                                                                                                                                    In the second group: 0.2 mg IM glycopyrrolate and 100 mg *A. calamus* extract                                                                                                                                                                                                                                                                                                                          

  Shankhapushpyadi Ghana Vati (*A. calamus*, *C. pluricaulis*, *Bacopa monnieri*, *T. cordifolia*, *C. fistula*, *A. indica*, *S. lappa*, *Tribulus terrestris*)                                               20 hypertensive patients of both sexes                                                  Randomized single-blind controlled\                          1 g twice daily after meal for 2 months                                                                            SBP and DBP                                                                                Significant relief in raised SBP and DBP                                                                                                                              III                \[[@B184-jcm-09-01176]\]
                                                                                                                                                                                                                                                                                                       study                                                                                                                                                                                                                                                                                                                                                                                                                                                               

  Brahmyadiyoga (*A. calamus*, *Centella asiatica*, *Rauvolfia serpentina*, *Saussurea lappa*, *Nardostachys jatamansi*)                                                                                       10 schizophrenia patients of both sexes aged 18--40 years                               Non-randomized,\                                             4 tablets thrice daily for three months after meal                                                                 Symptoms rating scale                                                                      Significant effect as a brain tonic, tranquillizer, hypnotic, and sedative                                                                                            III                \[[@B185-jcm-09-01176]\]
                                                                                                                                                                                                                                                                                                       open-label, single-\                                                                                                                                                                                                                                                                                                                                                                                                                                                
                                                                                                                                                                                                                                                                                                       arm study                                                                                                                                                                                                                                                                                                                                                                                                                                                           

  Bala compound (*A. calamus*, *Emblica officinalis*, *E. ribes*, *T. cordifolia*, *Piper longum*, *Glycyrrhiza glabra*, *C. rotundus*, *A. heterophyllum*)                                                    24 neonates, both sexes, 2.5--3 kg body weight                                          Randomized single-blind controlled\                          5 oral drops twice daily for 6 months                                                                              Change in serum immunoglobulins (IgG, IgM, and IgA) levels                                 Significant improvement in immunoglobulin levels after 6 months                                                                                                       Ib                 \[[@B186-jcm-09-01176]\]
                                                                                                                                                                                                                                                                                                       study                                                                                                                                                                                                                                                                                                                                                                                                                                                               

  Vachadi Ghrita (*A. calamus*, *T. cordifolia*, *Hedychium spicatum*, *C. pluricaulis*, *E. ribes*, ginger, *A. aspera*, *T. chebula*, and cow ghee)                                                          90 healthy individuals of both sexes aged 40--50 years for assessment of cognition      Non-randomized\                                              10 g twice daily for 1 month with lukewarm water                                                                   Post Graduate Institute Memory Scale (PGIMS) test                                          Significant change in the mental balance score, holding\                                                                                                              III                \[[@B187-jcm-09-01176]\]
                                                                                                                                                                                                                                                                                                       positive-controlled study                                                                                                                                                                                                                                                  of like and different pairs, late-immediate memory, and also improved digestion                                                                                                          

  Bramhi Vati (*A. calamus*, *B. monnieri*, *C. pluricaulis*, *Onosma bracteatum*, copper pyrite, iron pyrite, mercuric sulphide, *Piper nigrum*, *N. jatamansi*)                                              68 essential hypertension patients of both sexes aged 20--70 years                      Randomized, double-blind, parallel-group comparative study   500 mg tablets twice daily for 1 month                                                                             Hamilton anxiety rating scale, SBP and DBP, and MAP                                        Significant improvement in the Hamilton anxiety rating scale, SBP and DBP, and MAP                                                                                    III                \[[@B188-jcm-09-01176]\]

  Tagaradi Yoga (*A. calamus*, *Valeriana wallichii*, *N. jatamansi*)                                                                                                                                          24 insomnia patients of both sexes aged 18--75 years                                    Non-randomized positive-controlled study                     500 mg hydro-alcoholic extract capsule twice daily after meal for 15 days                                          Sleep duration, initiating time of sleep, quality of sleep                                 Significant improvement in sleep duration, in the initiating time of sleep, and in quality of sleep                                                                   III                \[[@B189-jcm-09-01176]\]

  *Acorus calamus* rhizome powder                                                                                                                                                                              20 obese patients of both sexes                                                         Randomized single-blind study                                250 mg rhizome powder twice daily for 1 month                                                                      Body weight, height according to age, waist-hip ratio, and BMI                             Significant improvement in extreme sleep, body heaviness, fatigue, and excessive hunger                                                                               III                \[[@B190-jcm-09-01176]\]

  *Acorus calamus* rhizome powder                                                                                                                                                                              45 ischemic heart disease patients                                                      Non-randomized positive-controlled study                     3 gm rhizome powder twice daily for 3 months                                                                       ECG, serum cholesterol level                                                               Improvement of chest pain, dyspnea on effort, reduction of the body mass index, improved ECG: reduced serum cholesterol, reduced serum LDL, and increased serum HDL   Ib                 \[[@B191-jcm-09-01176]\]
  ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

ADAS-cog, alzheimer's disease assessment scale--cognitive subscale; BMI, body mass index; BPRS, brief psychiatric rating scale; CDR-SOB, clinical dementia rating scale sum of boxes; DBP, diastolic blood pressure; ECG, electrocardiogram; Ib, evidence from at least one randomized study with control; HDL, high-density lipoprotein; Ig, immunoglobulin; III, evidence from well-performed nonexperimental descriptive studies, as well as from comparative studies, correlation studies, and case studies; LDL, low-density lipoprotein; MAP, mean arterial pressure; SBP, systolic blood pressure.

jcm-09-01176-t006_Table 6

###### 

Mechanistic role of phytochemicals of *A. calamus* in the treatment of neurological and metabolic disorders.

  Study                         Compound                                                Model                                                                                                  Increased Level                                                              Decreased Level                                                                   References
  ----------------------------- ------------------------------------------------------- ------------------------------------------------------------------------------------------------------ ---------------------------------------------------------------------------- --------------------------------------------------------------------------------- --------------------------
  Anti-Parkinson                *β*-Asarone                                             6-OHDA parkinsonian                                                                                    Bcl-2 expression                                                             GRP78, p-PERK, CHOP, and Beclin-1 expression                                      \[[@B192-jcm-09-01176]\]
  6-OHDA parkinsonian           \-                                                      mRNA levels of GRP78 and CHOP and p-IRE1and XBP1                                                       \[[@B193-jcm-09-01176]\]                                                                                                                                       
  Dopamine in the striatum      TH plasma concentrations                                Striatal COMT levels                                                                                   \[[@B194-jcm-09-01176]\]                                                                                                                                       
  6-OHDA parkinsonian           L-DOPA, DA, DOPAC, and HVA levels                       P-gp, ZO-1, occludin, actin, and claudin-5                                                             \[[@B195-jcm-09-01176]\]                                                                                                                                       
  Alzheimer's                   A*β*25-35-induced inflammation                          Bcl-2 level                                                                                            TNF-*α*, IL-1*β*, IL-6, Beclin-1, and LC3B level                             \[[@B196-jcm-09-01176]\]                                                          
  NG108 cells                   \-                                                      Upregulated SYP and GluR1 expression                                                                   \[[@B197-jcm-09-01176]\]                                                                                                                                       
  PC12 cells                    \-                                                      A*β*-induced JNK activation, Bcl-w and Bcl-xL levels, cytochrome c release, and caspase-3 activation   \[[@B198-jcm-09-01176]\]                                                                                                                                       
  A*β*-induced cytotoxicity     Cell viability, p-Akt and p-mTOR                        NSE levels, Beclin-1 expression                                                                        \[[@B199-jcm-09-01176]\]                                                                                                                                       
  Neuroprotective               Pb-induced impairments                                  NR2B protein expression along with Arc/Arg3.1 and Wnt7a mRNA levels                                    \-                                                                           \[[@B200-jcm-09-01176]\]                                                          
  *β*-Asarone, eugenol          Scopolamine-induced                                     Improvement of neuron organelles and synaptic structure                                                APP expression                                                               \[[@B201-jcm-09-01176]\]                                                          
  Neotatarine                   MTT reduction assay                                     \-                                                                                                     A*β*25-35--induced PC12 cell death                                           \[[@B202-jcm-09-01176]\]                                                          
  *β*-asarone, paeonol          MCAo model                                              Cholecystokinin and NF-κB signaling                                                                    TNF-*α*, IL-1*β*, IL-6 production                                            \[[@B203-jcm-09-01176]\]                                                          
  *β*-Asarone                   Cultured rat astrocytes                                 NGF, BDNF, and GDNF expression                                                                         \-                                                                           \[[@B204-jcm-09-01176]\]                                                          
  SN4741 cells                  p62, Bcl-2 expression                                   JNK, p-JNK and Beclin-1 expressions                                                                    \[[@B205-jcm-09-01176]\]                                                                                                                                       
  Tatarinolactone               hSERT-HEK293 cell line                                  \-                                                                                                     SERTs activity                                                               \[[@B206-jcm-09-01176]\]                                                          
  *β*-Asarone                   RSC96 Schwann cells                                     GDNF, BDNF, and CNTF expression                                                                        \-                                                                           \[[@B207-jcm-09-01176]\]                                                          
  A*β*-induced                  p-mTOR and p62 expression                               AChE and A*β*~42~ levels, p-Akt, Beclin-1, and LC3B expression, APP mRNA and Beclin-1 mRNA levels      \[[@B208-jcm-09-01176]\]                                                                                                                                       
  A*β*1--42-induced injury      \-                                                      GFAP, AQP~4~, IL-1*β*, and TNF-*α* expression                                                          \[[@B209-jcm-09-01176]\]                                                                                                                                       
  Anti-depression               Chronic unpredictable mild stress                       BDNF expression                                                                                        Blocked ERK1/2-CREB signaling                                                \[[@B210-jcm-09-01176]\]                                                          
  *α*-Asarone                   Noradrenergic and serotonergic neuromodulators in TST   *α*~1~ and *α*~2~ adrenoceptors and 5-HT~1A~ receptors                                                 \-                                                                           \[[@B211-jcm-09-01176]\]                                                          
  Anticonvulsant and sedative   Eudesmin                                                MES and PTZ                                                                                            GABA contents, expressions of GAD65, GABAA, and Bcl-2                        Glu contents and ratio of Glu/GABA, caspase-3                                     \[[@B212-jcm-09-01176]\]
  Anti-anxiety                  *α*-Asarone                                             BLA or CFA-induced                                                                                     Down-regulation of GABA~A~ receptors                                         Up-regulation of GluR1-containing AMPA, NMDA receptors                            \[[@B213-jcm-09-01176]\]
  Anti-epilepsy                 Temporal lobe epilepsy                                  Levels of GABA, GAD67, and GABAAR-mRNA expression                                                      GABA-T                                                                       \[[@B214-jcm-09-01176]\]                                                          
  Mitral cells                  Down-regulation of GABA~A~ receptors                    Na^+^ channel blockade                                                                                 \[[@B215-jcm-09-01176]\]                                                                                                                                       
  *β*-Asarone                   KA-induced                                              GABA                                                                                                   Glu                                                                          \[[@B216-jcm-09-01176]\]                                                          
  Anti-inflammatory             *α*-Asarone                                             Spinal cord injury                                                                                     IL-4, IL-10, and arginase 1 levels                                           TNF-*α*, IL-1*β*, IL-6, MCP-1, MIP-2, iNOS levels                                 \[[@B217-jcm-09-01176]\]
  Cytoprotective                *β*-Asarone                                             tBHP-induced astrocyte injury                                                                          GST, GCLM, GCLC, NQO1, Akt phosphorylation                                   \-                                                                                \[[@B218-jcm-09-01176]\]
  Cardioprotective              Cultured neonate rat cardiac myocytes                   Viability of cardiac myocytes                                                                          Pulse frequency                                                              \[[@B219-jcm-09-01176]\]                                                          
  Arteriosclerosis              ECV304 cell strain                                      Apoptotic rate of ECV304 cells                                                                         Apoptotic rate of MMP, stabilized MMP and VSMC proliferation                 \[[@B220-jcm-09-01176]\]                                                          
  Anti-adipogenic               3T3-L1 preadipocytes                                    \-                                                                                                     C/EBP*β*, C/EBP*α*, and PPAR*γ* expression levels, ERK1/2 phosphorylation    \[[@B89-jcm-09-01176]\]                                                           
  Antioxidant                   Cerebral artery occlusion                               Antioxidant activity                                                                                   Focal cerebral ischemic/reperfusion injury                                   \[[@B221-jcm-09-01176]\]                                                          
  Anti-diabetic                 *α*-Asarone + *β*-asarone + metformin HCl               STZ-induced                                                                                            Insulin level                                                                Glucose, glycosylated hemoglobin level, liver dysfunction, and tumor biomarkers   \[[@B222-jcm-09-01176]\]
  Asarone                       3T3-L1 preadipocytes                                    Hormone-sensitive lipase phosphorylation                                                               Intracellular triglyceride levels, down-regulation of PPAR*γ* and C/EBP*α*   \[[@B223-jcm-09-01176]\]                                                          

6-OHDA, 6-hydroxydopamine; Ox-LDL, oxidized low-density lipoprotein; BDNF, brain-derived neurotrophic factor; NGF, nerve growth factor; GDNF, glial derived neurotrophic factor; SERTs, serotonin transporters; MCAo, middle cerebral artery occlusion; A*β*, *β*-amyloid; NSE, neuron specific enolase; AMPA, *α*-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; NMDA, NR2A-containing N-methyl-D-aspartate; GABA~A~, *γ*-aminobutyric acid A; BLA, basolateral amygdala; CFA, complete Freund's adjuvant; CNTF, ciliary neurotrophic factor; COMT, catechol-O-methyltransferase; TH, tyrosine hydroxylase; DA, dopamine; DOPAC, 3,4-dihydroxyphenylacetic acid; HVA, homovanillic acid; P-gp, P-glycoprotein; ZO-1, zonula occludens-1; SYP, synaptophysin; GluR1, glutamatergic receptor 1; GABA-T, GABA transaminase; TST, tail suspension test; KA, kainic acid; MCP-1, monocyte chemoattractant protein 1; MIP-2, macrophage inflammatory protein 2; iNOS, inducible nitric oxide synthase; GST, glutathione S-transferase; GCLM, glutamate-cysteine ligase modulatory subunit; GCLC, glutamate-cysteine ligase catalytic subunit; NQO1, NAD(P)H quinone oxidoreductase; GFAP, glial fibrillary acidic protein; AQP, aquaporin; VSMC, vascular smooth muscle cells; MMP, mitochondrial membrane potential; C/EBP, CCAAT enhancer-binding protein; PPAR*γ*, peroxisome proliferator-activated receptor gamma; ERK1/2, extracellular signal-regulated protein kinase; XBP1, x-box binding protein; IRE1, inositol-requiring enzyme 1; Aβ1-42, amyloid β peptide; mTOR, mammalian target of rapamycin; MTT, 3-(4,5-dimethythiazol-. 2-yl)-2,5-diphenyl tetrazolium bromide; CREB, cAMP response element-binding protein; GABAAR, gamma-aminobutyric acid type-A receptor, tBHP, t-butyl hydroperoxide.
