Allelopathic Properties of Lamiaceae Species: Prospects and Challenges to Use in Agriculture

Herbicide resistance due to the increasing reliance on herbicides is a near-term challenge for the world’s agriculture. This has led to a desire to develop new herbicides with a novel mode of action, to address resistance in weed species. Lamiaceae, a large dicotyledonous plant family, is very well known for the multitudinous pharmacological and toxicological properties of its member species. Moreover, many species of this family are significant for their allelopathic activity in natural and laboratory settings. Thus, plants in Lamiaceae have the potential to be sources of alternative herbicides. However, gaps in our knowledge need to be addressed prior to adopting these allelopathic activities in agriculture. Therefore, we review the existing state of knowledge about the Lamiaceae family, the reported allelopathic properties of plant extracts, and their isolated allelochemicals under laboratory, greenhouse, and field conditions. In addition, we offer a perspective on existing challenges and future opportunities for adopting the allelopathic properties of Lamiaceae plant species for green agriculture.


Introduction
The direct or indirect detrimental or advantageous effects of a plant to its neighboring plants, or the plant itself, through the release of chemical substances are known as allelopathy, and the released substances are called allelochemicals [1]. Allelochemicals are present in nearly all plant tissues, including leaves, stems, rhizomes, roots, flowers, pollen, fruits, and seeds [2]. These allelochemicals are released into the environment through leaf or stem leaching (through precipitation), volatility (predominantly in semi-arid and arid conditions), root secretion, and tissue degradation by microorganisms [3]. Some allelochemicals can be released together and may exert toxicities in an additive or synergistic manner [4]. Upon release, allelochemicals may either inhibit or stimulate the growth of surrounding plants [2].
The present agricultural production system is impossible to imagine without the application of synthetic chemical pesticides. The high efficacy, cost-effectiveness, rapid return, flexibility, and easy accessibility of pesticides are the main reasons for such dependence [5]. The labor shortage due to outmigration from agriculture to other sectors also fuels the flames [6]. However, inappropriate dosages, application times and techniques, and/or storage practices [7] can cause various adverse effects for off-target organisms and farmers' health [8,9]. Continued use of the same pesticides has also increased the rate at which pests develop resistance to the available chemical active ingredients. For example, to date, a total of 512 unique cases of herbicide-resistant weeds have been reported in 96 crops from 71 countries [10]. Going ahead, developing new pesticides will be restricted by harsh environmental, toxicological, and regulatory requirements [11]. This backdrop opens the door to producing natural product-based pesticides. In this context, the allelopathic properties of plants or their isolated allelochemicals may play a vital role. Although the inhibitory properties of the allelochemicals against test species are the main focus for most of the allelopathic studies [12], the biostimulatory activity of these chemicals to the target species at lower doses has also attracted the attention of many researchers [13].
Therefore, it is worth exploring the use of allelopathy in agriculture and studying the determinants preventing it from being implemented as a chemical tool. Lamiaceae is a large plant family and has been intensively studied and used in many applications [14,15]. Moreover, many species in Lamiaceae exhibit strong allelopathy. Hence, this review provides an overview of the present state of knowledge about the allelopathic properties of Lamiaceae plant species and their bioactive substances. This review also addresses the challenges and prospects of using Lamiaceae plants or their bioactive compounds in agriculture and the gaps for further research.

Lamiaceae in Brief
Lamiaceae (also known as Labiatae or the mint family) is a dicotyledonous aromatic plant family of the Angiosperm order Tubiflorae [16], comprising more than 250 genera and 7000 species [17]. The family is commonly distributed in temperate regions. It is one of the most commercially important plant families, and known for its pharmacological, pharmaceutical, and toxicological properties ( Table 1). Most of the species are shrubby or herbaceous in nature, but a limited number of Hyptis and Leucospectrum are small trees; while Gomphostemma is a rain forest tree genus and a few species of Scutellaria are climbers [16]. Mainly they are xerophytes, but a few are hygrophytes, e.g., Stachys palustris [18,19]. The most distinct feature of Lamiaceae is being aromatic, because of the presence of significant quantities of volatile oils e.g., terpenes and their oxygenated derivatives, which are commercially important. Alkaloids are hardly present in this family. Some other substances such as glycosides, saponins, and resins are occasionally present [20]. The presence of these chemicals may confer economic value, and the toxic potential or allelopathic properties make this family one of the most interesting plant families to researchers [21]. A significant number of plant species of this family have medicinal value [20][21][22][23][24][25]. Plants belonging to the Teucrium, Salvia, Dracocephalus, Thymus, Coleus, and Lavandula genera are considered important ornamental species. Besides these, around 175 species of 45 genera of this family are considered weeds in different parts of the world [26].

Salvia (Sage)
Salvia is a well-known genus of Lamiaceae that consists of nearly 1000 species. The "salvia phenomenon" is one of the best-known examples of allelopathy (Tables 2 and 3). Current allelopathic research gained momentum after 1964, when a picture of Salvia leucophylla inhibition zones appeared on the cover page of the journal Science [119]. Muller et al. [120] reported the volatile growth inhibitors of Salvia leucophylla and S. apiana. Two years later, Muller [121] isolated the allelopathic substances of S. leucophylla that are responsible for its growth-suppressive properties. After Muller, many researchers investigated the allelopathic activity and allelopathic substances of the genus Salvia [122,123]. The crude extract, essential oils (EOs), and isolated allelochemicals of Salvia spp. showed growth inhibitory/stimulatory activity for the target plant species. A summary of the allelopathic activity of Salvia spp. reported elsewhere is presented in Tables 2 and 3. Although terpenoids are identified as the major allelopathic substances of Salvia spp., phenolic compounds and fatty acids (two common groups of allelochemicals) are also reported in Salvia macrochylamis extracts [124] (Table 3). Bisio et al. [125] identified 13 clerodane diterpenoids from Salvia miniata Fernald, whereas Martino et al. [126] identified 88 compounds from the essential oils of Salvia africana L., Salvia greggii A. Gray, Salvia elegans Vahl, Salvia munzii Epling, and Salvia mellifera Green. The amount of monoterpenoids and sesquiterpenoids are very similar in S. africana; while, in other species, the percentage of monoterpenoid is higher than the sesquiterpenoids. On the other hand, Nishida et al. [127] identified five volatile monoterpenoids: camphor, α-pinene, β-pinene, 1,8-cineole, and camphene from Salvia leucophylla, among them the volatile monoterpenoids camphor, 1,8-cineole are considered to be responsible for the "Salvia phenomenon" in natural settings [128].   No inhibition on the seed germination of the legumes, except for C. arietinum [143] Leaf extract Amaranthus spinosus L.

Microcystis aeruginosa
Inhibited the growth and decreased the photosynthetic pigments (chlorophyll-a and carotenoids) [179] Rosmarinus officinalis L. Dry plant powder EOs
Inhibited seed germination and growth [184] Satureja montana L. Aerial parts Aqueous extracts Capsicum annuum L. and Solanum nigrum L.
Not phytotoxic, induced lipid peroxidation in S. nigrum roots, and increased the pyrogallol and guaiacol peroxidase in S. nigrum leaves [185] Satureja thymbra L. Aerial parts Aqueous extracts Pinus halepensis Mill. and Ceratonia siliqua L.
Inhibited the germination of C. siliqua, and the root length and number of leaves of P. halepensis and C. siliqua [186] Satureja montana L. Aerial parts Aqueous extracts Datura stramonium L.
Inhibited the seed germination and seedling growth [195] Leaves and flowers Aqueous extracts L. sativa No inhibitory potential on the percentage and average germination time [196] Leaves Leachates Vigna unguiculata, Momordica charantia and Solanum melongena L.
Completely inhibited seed germination, and root and shoot growth [243] Rosmarinus officinalis L. Aerial parts L. rigidum L. and P. brachystachys L.

Methanolic extract and EOs
Arabidopsis thaliana (L.) Heynh Farnesene and trans-caryophyllene had a strong inhibitory effect on root growth, and pulegone at the highest concentrations reduced lateral root formation. The addition, at low concentration, of farnesene to pulegonecamphor-trans-caryophyllene mixture further increased the inhibitory effect on root elongation [201] Calamintha ashei Saturated aqueous solutions of menthofuran, (+)-evodone, (-)-calaminthone, (+)desacetylcalaminthone, 4α,5β−diacetoxymenthofuran, and a mixture of (+)-evodone and (+)desacetylcalaminthone Fresh aerial parts Schizachyrium scoparium and Leptochloa dubia and L. sativa Inhibited germination and root growth [246] Salvia extracts have insecticidal, antimicrobial, and antifungal activities. For example, a crude acetone extract of the aerial parts of Salvia moorcraftiana Wall. had moderate antifungal activity against animal and plant pathogens [129]. Salvia sclarea aqueous extract had a toxic effect on Trialeurodes vaporariorum (whitefly) with 57% mortality [130]. Zhang et al. [206] isolated and identified neo-przewaquinone A (a potent algicidal compound) from Salvia miltiorrhiza extract and reported this compound caused morphologic damage or lysis to cells, increased malondialdehyde content, and decreased the soluble protein content, total antioxidant, and superoxide dismutase activity; and significantly inhibited three photosynthesis-related genes (psaB, psbD, and rbcL) of Microcystis aeruginosa. On the other hand, Fraga et al. [207] identified demethylsalvicanol, 14-deoxycoleon U, demethylcryptojaponol, and a few other compounds from the roots of Salvia broussonetii. Among them, demethylsalvicanol and 14-deoxycoleon U were moderate and strong antifeedants to Leptinotarsa decemlineata, respectively, while demethylcryptojaponol was toxic to this insect.

Nepeta
The plant species of the genus Nepeta are generally known as "Catnip" or "Catmint". The genus comprises more than 250 species. Although the species of this genus are usually distributed in North America, Europe, Asia, and Africa, the greatest species diversity is found in Asia (111 species) [53]. The extracts and essential oils of various Nepeta species have a wide spectrum of biological activities (Table 1). Mutlu et al. [209] published an image of the inhibition zone of Nepeta meyeri that did not allow the germination of other wild plant species in natural settings. Several researchers around the globe also reported the allelopathic activity of Nepeta spp. and identified the allelopathic substances responsible for their phytotoxic activity (Tables 2 and 3).
The EOs from the aerial parts of Nepeta cataria L. showed phytotoxic activity to three noxious weeds (Hordeum spontaneum Koch, Avena fatua L., and Taraxacum officinale) and tree crops (Lipidium sativum, Ocimum basilicum, and Nepeta cataria) species, at different inhibition levels [247]. For example, with a concentration of 1200 µL L −1 , 100% inhibition of seed germinations (complete inhibition) of all test species except in H. spontaneum were observed. At this concentration, 26% seed germination of H. spontaneum was observed. In addition, the germination percentages of A. fatua and T. officinale at 600 µL L −1 and L. sativum and O. basilicum at 1200 µL L −1 were completely inhibited (100%) [247]. Eom et al. [208] reported that the volatiles of N. × faassenii fresh foliage and its aqueous and methanol extracts significantly inhibited the seedling growth of curly cress (Lepidium sativum). They observed that N. × faassenii volatiles inhibited shoot and root growth by 48% and 44%, respectively, at 10 g of foliage, whereas the root and shoot growth of L. sativum was completely inhibited with the 20 g foliage treatment. On the other hand, aqueous extracts of N. × faassenii showed higher inhibition compared to methanolic extracts when similar dosages of extracts were applied. Complete (100%) inhibition on the germination of L. sativum was observed when exposed to concentrations of 0.5 mg mL −1 or more aqueous extracts and 1.0 mg mL −1 methanolic extracts, respectively. Furthermore, the aqueous foliage extracts exhibited greater activity in seedling growth reduction on a per-weight basis than methanolic extracts. Three phytotoxic compounds responsible for N. × faassenii phytotoxic activity: 2-(2-ethoxyethoxy)ethanol, alloaromadendrene, and x-cadinene, were isolated from the volatile mixture, methanolic extract, and the aqueous foliar extract [208].
Mutlu and Atici [135] observed that the roots and leaves extracts of Nepeta meyeri Benth. showed an allelopathic effect on the germination and seedling growth of barley and sunflower. On the other hand, both extracts significantly increased the seedling growth of canola, wheat, and safflower, especially at the lower concentrations (up to 0.5% of the extract). Interestingly, a neutral effect was found at higher concentrations only in wheat and being phytotoxic to other species. Their findings reported that the allelopathic activity of N. meyeri depends on the source of the plant extract (leaf or root), and the highest inhibitory activity was observed with leaf extracts. Mutlu et al. [209] identified a strong oxygenated monoterpene; 4aα,7α,7aβ-nepetalactone from the EOs of Nepeta meyeri Benth. aerial parts, as a major compound responsible for their phytotoxicity. This monoterpene showed concentration-dependent inhibitory activity on the germination and growth of weed species, including Amaranthus retroflexus L., Bromus intermedius Guss., Bromus danthoniae Trin., Cynodon dactylon L., Chenopodium album L., and Lactuca serriola L. Kordali et al. [35], on the other hand, evaluated the phytotoxic activities of the essential oil, n-hexane, chloroform, acetone, and methanol extracts of the aerial parts and roots of N. meyeri Benth. against the germination and growth of four weed species: A. retroflexus, C. album, Cirsium arvense L., and Sinapsis arvensis L. The essential oil of N. meyeri completely inhibited the germination of all weed seeds, although the extracts showed a wide variation in their inhibition of the seedling growth of the weed species. The extracts and EOs also showed phytotoxicity against these weeds. The acetone extract was the most effective compared to the other extracts. The mortality percentage ranged from 22-66% (48 h after application). Finally, Kordali et al. [35] isolated the main compound from the EOs and n-hexane extract, and reported 4aα,7α,7aβ-nepetalactone (>80%) as the main allelopathic compound responsible for the phytotoxic activity of N. meyeri. The genotoxical activity of 4aα,7α,7aβ-nepetalactone isolated from the EOs of the aerial parts of N. meyeri was also reported against the weeds, Bromus danthoniae and Lactuca serriola; and crops, Brassica napus and Zea mays [212].

Ocimum
The genus Ocimum, commonly known as basil, comprises around 60 species. They are widely distributed throughout tropical and subtropical Asia [137,141,250]. Due to its numerous pharmacological properties (Table 1), the plant is designated as "Holy Basil" in India. It is grown in the front of houses and temples by the Hindus, besides being cultivated for EO production. The EOs of Ocimum spp. have either phenolic constituents, eugenol, thymol, or sesquiterpene alcohols as single major oil constituents, or terpene compounds as minor constituents [55,56].
Culpeper [251] reported that Ocimum and Ruta graveolens never grow together, nor near one another; this was probably the first report about the allelopathic activity of any plant species of the Lamiaceae family. Since that, several reports have been found in the literature about the allelopathic activity of Ocimum species (Tables 2 and 3). Samunder and Megh [252] reported the autotoxic activity of Ocimum leachate (collected from soil). Likewise, soil incorporation of Ocimum root/shoot biomass in a 1:12 ratio (Ocimum: soil) had no inhibitory effect on the emergence of Desmodium tortuosum, Sorghum halepense, Morrenia odorata, Amaranthus retroflexus, Senna obtusifolia, Bidens pilosa, and Cyperus esculentus. However, Ocimum suppressed the growth of all those weed species, except Cyperus esculentus. The aqueous extract of Ocimum basilicum L. aerial parts showed a dose-dependent inhibition on the germination of Sorghum bicolor L. Moench, Pennisetum glaucum L. R. Br., Zea mays L., and Triticum vulgare L. [138]. A similar type of inhibition was also observed on the plant height, root length, seedling fresh, and dry weight of those crop seedlings when powder of its aerial parts was used.
Mota et al. [253] evaluated the insecticidal properties of EO of Ocimum micranthum Willd against Aleurodicus cocois (whitefly). They observed that the EO at 1% concentration was highly toxic to A. cocois, with faster mortality (6.82 h). They also identified eugenol, elemicin, and beta-caryophyllene as the major allelochemicals that were responsible for the insecticidal properties of O. micranthum essential oil.

Lavandula (Lavender)
The genus Lavandula comprises 40 species and around 80 wild infra-specific taxa and hybrids [254,255]. The Lavandula spp. is one of the important aromatic plants cultivated near the Mediterranean basin. Lavandula angustifolia Mill., Lavandula stoechas L., Lavandula latifolia Medik., and Lavandula × intermedia are the four major species of lavender. The EOs of Lavandula species are very well known for their myriad of pharmacological, toxicological, and pharmaceutical properties [146,147,217,218,256,257] (Table 1).
Lavender extracts and their EOs have allelopathic properties, as reported by many researchers worldwide (Tables 2-4). The aqueous extracts of L. officinalis shoot were allelopathic to weed species, including Amaranthus retroflexus and Chenopodium murale germination and growth [258]. Likewise, aqueous extracts of L. stoechas were phytotoxic to the germination and growth of both crop (Triticum aestivum) and weed (Phalaris minor) species [259]. The EOs of L. stoechas and L. angustifolia were also reported as phytotoxic to the seedling growth of A. retroflexus and Portulaca oleracea, two common weeds of Lycopersicon esculentum and Gossypium spp. [260]. Uremis et al. [261] reported that the volatile compounds of L. angustifolia negatively affect the germination of the most common weed species: Xanthium strumarium L., Avena sterilis L., and Phalaris brachystachys L.  Inhibited the shoot and root growth [202] Haig et al. [146] examined the allelopathic activity of Lavandula spp. against Lolium rigidum. They reported that the extract at the concentration of 10% completely inhibited the root growth of the test species and that coumarin was the main allelochemical responsible for its phytotoxicity. The EOs (linalool and linalyl acetate) of Lavandula × hybrida Rev. were evaluated against the germination and seedling growth of two crops (Triticum aestivum L. and, Hordeum vulgare L.) and two weeds (Lolium rigidum L. and Phalaris brachystachys L.), where the EOs showed no effect on crop species but inhibited the germination and seedling growth of both weeds [218]. Similarly, Lavandula angustifolia Mill. EOs, terpinen-4-ol, lavandulol and linalyl acetate, and lavandulyl acetate completely inhibited the germination and root length of Setaria verticillata (L.) P. Beauv. at concentrations of 80, 160, and 320 nL mL −1 , respectively [217]. Recently, two new tricyclic sesquiterpenoids, stoechanones A and B have been isolated from the organic extract of Lavandula stoechas, which exhibited strong phytotoxicity against the germination and seedling growth of Amaranthus retroflexus [219].

Mentha
The genus Mentha (commonly known as mint) has 61 species and hundreds of subspecies, varieties, and cultivars, which are widely distributed throughout the world, except South America and Antarctica [220,271,272]. The species of this genus are also well known for their relatively high content of EOs and a significant number of medicinal and pharmaceutical properties [271][272][273][274] (Table 1). The allelopathic properties of Mentha spp. from their different parts (leaves, stem, flowers, seeds, and roots) and fractions (essential oils, volatiles, below ground soils, dry biomass) under several experimental settings (laboratory, greenhouse, pot or field conditions) have been well documented, as shown in Tables 2-4.
The major allelochemicals isolated from the EOs of Mentha spp. known to date are piperitone oxide and piperitenone oxide from M. longifolia (L.) Huds.; carvone, piperetenone oxide from M. spicata L.; (-)-menthol, menthone from M. × piperita L.; menthol, mentone, menthofuran from M. × piperita L. cv. Mitcham; pulegone, menthone from M. pulegium L. and M. × piperita and menthone/isomenthone from M. spicata, M. crispa, and M. longifolia (Table 2). In addition, trans-ferulic acid, hesperidin, ellagic acid, and sinapic acid have been isolated from the aqueous extract of M. × piperita L. cv. Mitcham [148,225]. All these compounds either inhibited (at high concentration) or stimulated (at low concentration) the germination, growth, and other morpho-physiological processes of different test species ( Table 2). Maffei et al. [275] reported that an increase of Mentha piperita L. EOs concentration from 5 to 50 ppm decreased the membrane potential hyperpolarization of 10 -3 mV, while concentrations from 100 to 900 ppm decreased the depolarization of membrane potential (from 5 to 110 mV). In another study, Skrzypek et al. [264] reported that increasing concentrations of aqueous extracts of M. × piperita L. decreased the chlorophyll a, while increasing the chlorophyll b content of Helianthus annuus L. Sarheed et al. [224] found that menthone disrupted the microtubules and induced mortality, linked with rapid permeabilization of the plasma membrane of both tobacco BY-2 cells and Arabidopsis thaliana seedlings.
In a pot experiment, direct incorporation of M. spicata L. plant residue into the soil could boost tomato tolerance against soil-borne fungi and soil fertility, and accordingly increased the yield and quality of the tomato [264]. Similarly, mixed cultivation of two M. × piperita varieties in glasshouse stimulated the leaf development of Brassica oleracea [265], and application of dry leaves of M. spp. in pots also stimulated the seedling emergence of Brassica napus [267]. By contrast, the introduction of M. spicata L. and M. piperita L. in crop rotation inhibited the plant height, biomass, photosynthetic rate, stomatal conductance, and relative chlorophyll content of maize [266].

Thyme
The genus Thymus comprises around 400 species, with several subspecies, varieties, sub-varieties, and forms. Thymus species are extensively used as a culinary herb in both fresh and dried forms [155,276]. The plants of this genus are widely used in different industries, due to their numerous pharmacological, pharmaceutical, cosmetic, perfume, and toxicological properties [276][277][278][279][280][281] (Table 1). Thymus species are also used for flavoring and preservation of different foods [279]. A significant number of articles are available in the literature explaining the allelopathic properties of Thymus.

Hyptis
The genus Hyptis is composed of 400 species that mainly occur in tropical America, but are also found in other regions of the world [283]. The species of this genus is tradi-tionally used to treat various ailments [76,284] (Table 1). A few are considered as invasive weeds in some parts of the world, and possess allelopathic properties. For example, Hyptis suaveolens (L.) Poit is an important invader of tropical and sub-tropical regions, and that restricted the growth and establishment of other plant species near their clumps [77,[285][286][287]. A plausible reason could be their allelopathic properties [78,160,164,288,289]. This statement is supported by the isolation and identification of a putative allelochemical 14αhydroxy-13β-abiet-8-en-18-oic acid (suaveolic acid) from this plant species by Islam et al. [32].

Leonurus
Similar to the other genus of Lamiaceae, Leonurus species also has myriad medicinal properties (Table 1) and are used by herbalists to treat gynecological and obstetrical disorders in China, and anxiety and heart diseases in European countries [299]. To date, 24 species of Leonurus have been identified. Leonurus japonicus (also known as L. heterophyllus) and L. cardiaca are the distinctive species of Eastern Asia and Europe, respectively [299]. Some other dominant species of Leonurus include L. japonicus, L. cardiaca, L. persicus, L. sibiricus, L. macranthus, L. turkestanicus, and L. glaucescens.
Very little is known about the allelopathic and phytotoxic properties of the species from this genus. The few articles related to their allelopathy are mostly with L. sibiricus. In addition, most of the reports of L. sibiricus allelopathy have mainly been based on simple laboratory bioassay experiments (Tables 2 and 3). Mandal [235] reported that caffeic acid, isolated from the root exudates, is responsible for the growth inhibitory activity of L. sibiricus. Almeida et al. [236] isolated three major allelopathic compounds, 3 -OHgenkwanin, rutin, and isoquercitrin, from the methanol extract of L. sibiricus. Other than these, Wu et al. [300] isolated (−)-loliolide from L. japonicus. The phytotoxic properties of loliolide (isolated from the species of other plant families) for different test species has been reported by a few researchers from Japan and China [301][302][303][304]. Moreover, Labdane diterpenoids are the typical compounds of Leonurus [299]. The mixture of the two members of this group is responsible for the allelopathic activity Leucas aspera [30]. A Labdane-type diterpene isolated from Hyptis spicigera inhibited the larval growth of the European corn borer [293], as reported earlier.

Origanum
Origanum, commonly known as oregano, is an important culinary genus of Lamiaceae. It comprises around 900 species and is distributed throughout the world [86,87]. Considering pharmacological, pharmaceutical, and toxicological properties, the species from this genus are not different from other Lamiaceae genus (Table 1). A number of research works have been conducted to explore the allelopathic potential of Origanum plants or their essential oils (Tables 2 and 3).

Rosmarinus (Rosemary)
Rosmarinus, another popular genus of Lamiaceae family, comprises three different species, e.g., R. officinalis, R. eryocalix, and R. tomentosus, mainly found in the western Mediterranean region. Similar to other genus of this family, Rosmarinus also has a number of medicinal properties (Table 1). However, the genus is very popular as a culinary herb and is used as a food flavoring or food preservative [89]. Few allelopathic reports of Rosmarinus officinalis were found in literature ( Table 2). The major allelochemicals of R. officinalis EOs are α-pinene, 1,8-cineole, and piperitone, which significantly inhibited the germination and seedling growth of weed species, e.g., Eleusine indica (L.) Gaertn., Cynodon dactylon (L.) Pers., digitaria sanguinalis (L.) Scop., Amaranthus retroflexus L., and Lolium perenne [39,89]. Najem et al. [180] also reported the anti-cyanobacterial activity of R. officinalis essential oil on Microcystis aeruginosa and Chroococcus minor, where M. aeruginosa was more sensitive than C. minor. However, no reports related to the allelopathic properties of R. officinalis under field conditions were found in literature.

Hyssopus (Hyssop)
Hyssopus is a small aromatic medicinal genus of the Lamiaceae family, comprising only 70 species, of which Hyssopus officinalis L. is the most dominant [305]. Very little work has been conducted to explore the allelopathic activities of this genus so far. Dragoeva et al. [173] reported its allelopathic properties from a preliminary laboratory bioassay of Hyssopus officinalis on Cucumis sativus L., Triticum aestivum L., and Allium cepa L. However, Ortiz de Elguea-Culebras et al. [306] reported that 1,8-cineole (53%) and β-pinene (16%) are the major bio-active compounds of the EOs of H. officinalis that are insecticidal to Spodoptera littoralis (cotton leafworm). They also reported that H. officinalis EOs have no inhibitory effect on the germination of Lactuca sativa L. var. Carrascoy and Lolium perenne L., but have a slight inhibitory effect on the root and leaf growth of L. perenne.

Orthosiphon
Orthosiphon is another small Lamiaceae genus that comprises around 40 species, distributed throughout the tropical and sub-tropical Asia, Southern Africa, Madagascar, and some parts of Australia [100]. Some species of this genus have medicinal properties (Table 1); among them, Orthosiphon aristatus, Orthosiphon thymiflorus, Orthosiphon pallidus, and Orthosiphon stamineus are very well known [100]. To date, the allelopathic properties of only two species Orthosiphon stamineus and Orthosiphon aristatus have been reported in the literature. Suwitchayanon et al. [307] observed 75% root and 45% shoot growth inhibition of Lactuca sativa by the dried powder of Orthosiphon aristatus with a modified sandwich method, under laboratory conditions. While, the aqueous methanol extract of Orthosiphon stamineus showed inhibitory activity on the seedling growth of Lepidium sativum and L. sativa, and a novel allelopathic substance 13-epi-orthosiphol N was identified by Kato-Noguchi et al. [200]. This compound inhibited the root and shoot growth of L. sativum and L. sativa at concentrations higher than 10 µmol L −1 , and the concentrations required for 50% growth inhibition ranged 41-102 µmol L −1 [200].

Tectona
Tectona is a genus of tropical hardwood trees and comprises three species: T. grandis, T. hamiltoniana, and T. philippinensis [104]. T. hamiltoniana and T. philippinensis are now considered endangered species and confined to Burma and the Philippines, respectively. The most common species, T. grandis is native to South and Southeast Asia and is widely distributed to tropical Asia, Africa, and Central and South America, due to its quality timber [308][309][310][311][312]. Besides its high-quality timber properties, the genus Tectona is well known for its ethnobotanical and toxicological properties [40,104].
Recently, Kato-Noguchi [104] reviewed the allelopathic properties of Tectona grandis L.f. The leachate, leaves, EOs, and underground soil of T. grandis had allelopathic properties and inhibited the morpho-physiological growth of several crop species (Tables 2-4). Kole et al. [313] applied the powder of fallen T. grandis leaves (100 g 7.2 m −2 ) in a wheat field and observed a 45% reduction in weed population at 21 days after application, but interestingly the powder did not affect the wheat growth. Macías et al. [245] reported two diterpenes; 2-oxokovalenic acid and 19-hydroxyferruginol from the water extract of the dried leaves of Tectona grandis, which inhibited the germination and growth of Lactuca sativa. The highest inhibitory effects on the germination were caused by 2-oxokovalenic acid, which showed activity values similar to the herbicide Logran ® at the highest concentrations (89% inhibition at 10 −3 M concentration). However, both compounds stimulated the root growth of Lycopersicum esculentum, with values higher than 20% for all concentrations.
Lacret et al. [314] isolated naphthotectone from the dried leaves of T. grandis that inhibited the germination and seedling growth of Triticum aestivum L., Allium cepa L., Lycopersicon esculentum L., and Lactuca sativa L. Macías et al. [315] on the other hand isolated 3β-hydroxy-7,8-dihydro-β-ionol and 3β-hydroxy-7,8-dihydro-β-ionone from the dried leaves. Both compounds inhibited the seedling growth of Triticum aestivum, Allium cepa, and Lycopersicum esculentum. All these compounds showed an activity similar to the commercial herbicide Logran ® . It is important to note that all the above mentioned bioactive compounds were isolated from the water extract of T. grandis dried leaves, and their activity was examined only against crop species. Hence, it may be necessary to evaluate the phytotoxic potential of those compounds against weed species.

Satureja (Savory)
Satureja, a well-known genus from the Mediterranean area, Asia and some parts of USA, includes more than 200 aromatic species [105]. The species of this genus has also traditionally been used for gastrointestinal cramps, diarrhea, nausea, muscle pains, and some other infectious diseases, because of their various medicinal properties [316] (Table 1). Due to their characteristic smell, a few species of this genus are also used for culinary purposes and herbal tea [317]. A negligible number of allelopathic reports of Satureja species have been published so far. The aqueous extract of Satureja montana L. [185,187], Satureja thymbra L. [186], Satureja khuzestanica Jamzad, S. bachtiarica Bunge, and S. rechingeri Jamzad [189], Satureja hortensison L. [190] aerial parts significantly inhibited the germination and growth of the tested species (Table 2). Beside these, two allelopathic compounds; carvacrol and γ-terpinene have been isolated from the aerial parts of Satureja hortensis L., which inhibited the germination and growth of Lollium rigidum L. and Phalaris brachystachys L. [218], and from its EOs, which inhibited the germination, root and shoot growth, and chlorophyll content of Amaranthus retroflexus and Chenopodium album [244]. In addition, Taban et al. [107] isolated carvacrol and thymol from the EOs of Satureja spp., S. khuzestanica, S. bachtiarica, S. rechingeri, and S. spicigera, which inhibited the germination and growth of Secale cereale and Lycopersicon esculentum at different inhibition values. Among them, EOs isolated from S. khuzestanica were highly phytotoxic and were suggested for bio-herbicide development [107].

Conradina
Conradina, a small aromatic genus of the Lamiaceae family, is mainly found in the xeric environments with well drained sandy soil of the United States [109]. The family consists of six endemic species: Conradina canescens A. Gray, C. cygniflora C.E. Edwards, Judd, Ionta & Herring, C. etonia Kral & McCartney, C. glabra Shinners, C. grandiflora Small, and C. verticillata Jennison [319]. The species of this genus has colonizing ability in xeric disturbed soils [109]. Among the six species of Conradina, only the allelopathic potential of C. canescens has been reported in the literature to date.
Water leachate of C. canescens fresh leaves have germination and growth inhibitory potential, and eight monoterpenes: 1,8-cineole, camphor, borneol, myrtenal, myrtenol, α-terpineol, carveol, and carvone were identified from this leachate [320]. The saturated aqueous extract of these monoterpenes showed strong phytotoxicity against Leptochloa dubia, Schizachyrium scoparium, and Lactuca sativa, except 1,8-cineole, which did not affect L. dubia [321,322]. Dosoky [323] observed the inhibitory activity of C. canescens essential oil and isolated ursolic acid on the germination of Lactuca sativa and Lolium perenne. The presence of ursolic acid has a major role in the allelopathic potential of this species. This compound is thought to act as a natural detergent, by leading water-insoluble monoterpenes to form micelles, rendering them water-soluble; thus, boosting their ability to leach into rainwater for delivery into the soil [324]. Moreover, this compound helps co-solubilize the allelopathic monoterpenes in water and make them more effective [325].

Coleus
Coleus, another medicinal and aromatic genus of Lamiaceae [326,327], comprises 294 species found in the tropics and subtropics of Europe, Asia, Africa and Australia [115] ( Table 1). The allelopathic properties of a few Coleus species have been reported ( Table 2). Kathiresan [204] observed that a water suspension of Coleus amboinicus L. leaf dried powder at 40 g L −1 reduced the fresh and dry weight of Echhornia crassipes by 81 and 76%, respectively, within a week. The lowest dose required to kill E. crassipes was 10 g L −1 . The extract was even injurious at 0.1 g L −1 when applied to cut leaves of E. crassipes. In another study, Gnanavel and Kathiresan [203] reported the allelopathic properties of Coleus spp. varied among their different parts. For example, dried leaf powder at 25 g L −1 of water was found to be most effective in reducing the fresh weight and chlorophyll content of E. crassipes and showed a 100% reduction on 9 and 6 days after treatment, respectively [203]. The second highest inhibitory activity was found when 3/4th of dried leaf powder at 18.75 g L −1 + 1/4th of dried whole plant powder at 6.25 g L −1 was applied. Interestingly, dried stem powder at 25 g L −1 showed a minimum reduction on those two parameters [203]. The aqueous leaf extracts of Coleus forskohli significantly inhibited the seed germination, root-shoot length and dry weight, and sugar and protein content of Triticum aestivum, while the opposite activity was found for total amino acid contents [205].

Calamintha
Calamintha, a small aromatic genus of Lamiaceae, is mainly distributed in the Mediterranean region [29,117]. The species of this genus also are traditionally used as folk medicines. Some Calamintha species are used for culinary purposes and herbal tea [117]. The allelopathic properties of Calamintha spp. with weeds and crop species under laboratory and field conditions have been reported in the literature (Tables 2-4).
Tanrisever et al. [328] isolated and identified menthofuran, calaminthone, terpenoids (+)-evodone, caryophyllene oxide, and ursolic acid from the aerial parts (through NMR and MS), and menthofuran and 2,3-dihydroevodone from the volatiles (through GC-MS) of C. ashei. The seed germination of Schizachyrium scoparium was strongly inhibited by the evodone and calaminthone volatiles. While, 100% inhibition on the seed germination of S. scoparium was observed when the seeds were subjected to a fraction of the aqueous solution containing calaminthone, evodone, and caryophyllene oxide. Interestingly, these fractions had no significant effects on Lactuca sativa seed germination. On the other hand, a stimulatory activity on S. scoparium was observed when a saturated aqueous solution of pure evodone was applied. In contrast, the opposite activity was found when evodone was applied together with the saturated aqueous solution of ursolic acid. Weidenhamer et al. [329] isolated and identified (+)-evodone and desacetylcalaminthone as the major constituents of C. ashei leaf soaks and washes through reversed-phase HPLC. They reported that an equimolar mixture of desacetylcalaminthone and (+)-evodone inhibited the germination of Rudbeckia hirta L. by 17% at a combined concentration of 0.025 mM, while the germination of S. scoparium (Mich x.) Nash cv. Cimarron and Leptochloa dubia (H.B.K.) Nees. was not affected below the concentrations of 0.125 and 0.25 mM, respectively. Besides the allelopathic properties of Calamintha spp., their species have insecticidal and antimicrobial properties. Božoviè and Ragno [117] reviewed the biological properties of C. nepeta (L.) Savi and its essential oils. The bioactive EOs constituent 'pulegone' of C. nepeta is considered as one of the three most toxic insecticides naturally occurring in many Lamiaceae species [273,330], because of the repellent, antifeeding, antidevelopment, and anti-reproduction behavior of pulegone for different harmful insects [331][332][333].

Knowledge Gaps and Future Prospects
In general, plants with medicinal properties are considered important sources of bioactive compounds [5]. Scientists are, therefore, showing interest in this category of plants for searching for novel bioactive compounds. The easier screening process for allelopathic plants and the possibility of having more bioactive compounds from medicinal plants than other plants are the two main reasons for this interest [142]. It is assumed that, due to the presence of many pharmacological, pharmaceuticals, and toxicological properties, Lamiaceae occupies 43% of the total studied species among the plant families examined for their bio-herbicidal potentialities [334]. Although this is a huge number compared to other plant families, there is a lot of empty space for researchers to work with the species of this family, to explore their allelopathic potential. However, the structural complexity, cost and time involvement in structure determination, labile characteristics of some compounds, and drawbacks in obtaining sufficient quantities for structure elucidation are amongst the major constraints for the isolation and characterization of allelopathic substances.
Beside these issues, most of the works were conducted in different laboratories with different setups, and thus it is rather difficult to compare the effectiveness of crude extracts, dried plant materials, or purified allelochemicals from different species as potential natural herbicides. Some purified allelochemicals were examined for their inhibitory activities on seed germination and/or the plant growth of crops and weeds, and they were far less active than commercial pesticides; although in most cases, commercial herbicides were not included as positive controls in the assays. The most effective allelochemicals appear to be volatile monoterpenoids, but some of these are also toxic to animals [13], and must, therefore, be used with caution. In fact, the challenges of finding greener herbicides have been discussed across fields [13,335,336]. If these limitations can be overcome, there is huge potential for using allelopathy/allelopathic substances of Lamiaceae plants in agriculture, as detailed below: (i) Organ-specific: The allelopathic activities of some plants of this family are organspecific. For example, the allelopathic activity of N. meyeri depended on whether the extract was derived from the leaves or roots, and maximum inhibitory activity was found with leaf extracts [135]. Similarly, dried leaf powder of Coleus spp. at 25 g L −1 of water significantly reduced the fresh weight and chlorophyll content of E. crassipes, while dried stem powder at the same concentration showed a minimal reduction on these two parameters [203].
(ii) Test plant-specific: It is assumed that the allelopathic plants or their allelochemicals that will be used for crop protection should be non-toxic or stimulatory to the crops. Nevertheless, in reality, this is not always true. However, many essential oils (EOs) of Lamiaceae species showed test plant-dependent inhibitory activity, where crops were less affected than weeds. For instance, linalool and linalyl acetate of Lavandula × hybrida showed phytotoxic activity against weeds (Lolium rigidum and Phalaris brachystachys) and no activity against crops (Triticum aestivum and Hordeum vulgare) [218]. The EOs of Satureja hortensis inhibited the germination of A. retroflexus at a lower concentration, while tomatoes were unaffected at the same concentrations. At the highest tested concentration, tomato germinations were affected, but less than A. retroflexus [34]. Similarly, when applying EOs of Origanum onites and Rosmarinus officinalis to the germination and seedling growth of Avena sterilis, Sinapis arvensis, and wheat cultivars, the wheat cultivars were less affected [37]. Kole et al. [313] reported a 45% reduction in weed population at 21 days after application but no effect on the Triticum aestivum growth by Tectona grandis fallen leaf powder in field conditions. In contrast, Lacret et al. [314] and Macías et al. [315] reported the germination and seedling growth inhibition of Triticum aestivum by EOs isolated from the dried leaves of T. grandis under laboratory conditions. The root and leaf extracts of Nepeta meyeri showed an allelopathic effect on the germination and seedling growth of barley and sunflower, while having no inhibitory activity on Triticum aestivum [135].
(iii) Phytotoxic under natural settings: Although thousands of species from different families or their isolated allelochemicals have been reported as allelopathic in the literature, most of them were laboratory experiments, and a few were greenhouse or field trials. A negligible number of reports are found in the literature where plant species showed allelopathic activity under natural settings. The Lamiaceae species, Salvia leucophylla and Nepeta meyeri belong to this short list that showed allelopathic activity under natural settings [119,209]. Leucas aspera and Hyptis suaveolens also form colonies under natural settings that suppress the growth of surrounding neighboring species, where allelopathy might play a vital role [30,32].
(iv) Presence of ursolic acid: Ursolic acid is present in some Lamiaceae species, which has a great role in their allelopathic activities. This ursolic acid is considered a natural detergent that makes the water-insoluble monoterpenes water-soluble and, consequently, boosts their ability to leach into rainwater for delivery into the soil [324].
(v) Terpenes as the major compounds: Terpenoids are the major group of plant specialized metabolites with allelopathic properties [181,337]. These compounds use IPP as a substrate which derives from either the MEP pathway [338] or the MVA pathway [339]. There are several types of terpenes, e.g., monoterpenes, sesquiterpenes, diterpenes, triterpenes, and polyterpenes [340]. Among them, monoterpenes (major elements of EOs) are most often reported to have herbicidal activity [181,334]. It is evident from this re-view that Lamiaceae species are rich sources of several allelopathic monoterpenes, e.g., camphor, α-pinene, β-pinene, 1,8-cineole, carveol, carvone, and camphene. Cinmethylin, a monoterpene-based commercial herbicide derived from 1,4-cineole, is already available on the market [341]. However, among the monoterpenes, the ketone-containing compounds, camphor and pulegone, are the most toxic, followed by alcohol compounds (cineol and citronellol), while ether, diene, and monoene compounds (α-pinene) are the least toxic [341,342]. In addition, pulegone is considered one of the three most toxic natural insecticides in the world [273,330].
(vi) Presence of volatile compounds: Although plant volatiles are considered an important tool for pest management in organic agriculture [343], unlike other mechanisms of allelopathy, very little research has been conducted to date to examine the effects of volatiles in plant-plant interactions [208]. It has been reported that plant volatiles mainly belong to the terpenoids, fatty acid derivatives, and phenolics groups [344]. As stated earlier, Lamiaceae species are rich sources of volatile EOs that are phytotoxic; for example, pulegone, α-pinene, limonene, 1,8-cineole, carvacrol, camphor, thymol, etc. [27,[41][42][43]341,345]. Several plant-originated monoterpenoids are more toxic to nematodes than commercial nematicides. Compounds such as thymol and carvacrol have been found to be the most effective, with 100% mortality [346]. Furthermore, eugenol, geraniol, isoeugenol, and methyl isoeugenol also have nematicidal properties [347].
(vii) Scalable by biotechnology: Traditional breeding has been adopted for Lamiaceae species, especially the ones that are an important source of essential oils, such as mint [348,349] and catnip [350,351]. The recent findings in the botany and horticulture of catnip have been reviewed, and the interest in scaling up catnip to industrial scale was also discussed in Gomes et al. [352]. This evidence supports our view of further utilizing and exploring Lamiaceae in sustainable agriculture. With the recent advance in sequencing technologies, the genomes of many Lamiaceae species have been sequenced. This includes species in Salvia [353,354], Nepeta [355], Lavendula [356], Ocimum [357], and Mentha [358], whose allelopathy was described above. In addition, more transcriptomes are available on several platforms, such as the mint genome project (http://mints.uga.edu, accessed on 13 January 2022) and OneKP [359]. The availability of omics data allows scientists to gain fundamental knowledge of terpene biosynthesis and adopt biotechnology tools to increase the yield and productivity of the targeted compounds. Many synthetic biological and metabolic engineering approaches have successfully created production platforms for terpenoids. Zebec et al. [360], and more recently Zhang and Hong [361], have comprehensively reviewed the synthetic biology approach for monoterpene production in Escherichia coli and Saccharomyces cerevisiae, the industrial workhorses. The metabolic engineering attempts and significant milestones of terpenoid production in planta were also discussed by Mani et al. [362]. To date, the cell-free enzyme system from E. coli has shown the highest yield of monoterpene production, which is up to 14-15 g L −1 [363]. The fed-batch fermentation system from E. coli, which is more feasible on an industrial scale, can produce limonene up to 3.6 g L −1 [364]. Therefore, it is highly likely that the allelopathic compounds of interest in Lamiaceae can be synthesized on an industrial scale, by taking advantage of the recent discoveries in genetics, breeding, biochemistry, and synthetic biology. This advantage of these biotechnological tools may help overcome the challenges in field testing, by making the allelopathic compounds more accessible.
These special features of allelopathic plants from Lamiaceae families, or their isolated allelochemicals, may help researchers develop natural product-based crop or weed specific herbicides and insecticides. Although the utilization of allelopathy in agriculture could be achieved with the incorporation of allelopathic plant residues into soils or with mulching, the application of water extracts or essential oils from allelopathic plants, and allelochemicals produced artificially (organic synthesis, fermentation, tissue culture, etc.) [5], and extraction with organic solvents should be avoided for green allelopathy. Therefore, a huge amount of research with allelopathic Lamiaceae plant species remains to be conducted, both under controlled laboratory and field conditions, to harness their maximum potential for agricultural purposes. A significant amount of research is also needed to explore the mechanisms of action, impacts on beneficial crops, insects, and other organisms, formulations for effective application, and to assess the cost-benefits of allelochemicals identified from Lamiaceae species.

Conclusions
Researchers have always had a keen interest in the Lamiaceae plant species because of their multitude of pharmacological and pharmaceutical properties and the presence of bioactive EOs. However, considering the number of plant species, a significant amount of research is yet to be conducted, to explore the allelopathic activity of the Lamiaceae family. As for other plant families, most of the research works carried out to date have mainly focused on the inhibitory properties of Lamiaceae plant extracts and their EOs on the germination and seedling growth of several target species, under controlled laboratory or greenhouse conditions. Therefore, the transfer of laboratory and greenhouse experiments into field settings is imperative, for understanding the environmental impacts on the herbicidal/pesticidal activity of the allelochemicals of Lamiaceae plants or their EOs on target species. In addition, the biostimulatory activities of allelochemicals/EOs at lower concentrations should also be given more priority. With this review, we provide the current stage of the research in allelopathy and point out the potential of allelopathy in Lamiaceae species as a source of greener alternative herbicides, along with the gaps in knowledge that need filling for introducing natural allelopathic substances to agriculture.  Data Availability Statement: Data sharing is not applicable, as no new data were generated or analyzed during this study.