**2.4 Ashwagandha**

Ashwagandha is a plant used in Ayeurvic medicine from which the roots and berries have been used as adaptagens and also to relieve stress. In double blind placebo controlled clinical trials Ashwagandha supplementation has been shown to reduce anxiety based reducing both scores on the Hamiltion-Anxiety (HAMA) scale and morning salivary cortisol [71] and reduce anxiety in a variety of other contexts including schizophrenia and sleep disorders [71–73]. With regard to brain neurochemistry, Ashwagandha does not appear to affect sertotonergic, GABAnergic, or glutaminergic pathways but instead increases cholinergic signaling in the cortical and basal forebrain [74]. While the specific bioactive molecule(s) in Ashwagandha that are anxiolytic have not been specifically identified, sominone, an aglycone derivative of Withanoside IV when injected into mice stimulated neurite outgrowth in the hippocampus and increased production of the neurotrophin, Glial Derived neurotrophic Factor (GDNF) [75]. Further injection of sominone into mice enhances spatial memory, again suggesting that anxioloytic phytochemicals that are neurotrophic may ease anxiety by providing signals to enhance neural plasticity and learning [75].

## **2.5 Passion flower**

Passion flower also shows anxiolytic properties in clinical trials that are as effective as midazolam and oxezepam [76, 77] and can reduce anxiety associated with ambulatory surgery and dental extraction [77–79]. The anxiolytic molecule from passion flower has not been identified and the effects of passion flower on brain neurochemistry is not well studied. It is interesting to note however that C-dideoxyhexosyl flavones from passion flower have been shown to enhance NGFinduced neurite outgrowth in PC12 cells [80].

#### **2.6 Cannabidiol**

Cannabidiol (CBD) is anxiolytic and has been shown in clinical trials to reduce social stress [81] and reduces anxiety in social phobia patients [82]. CBD also reduces anxiety associated with drug-craving during recovery from heroin addiction [83]. With regard to brain neurochemistry in clinical trials, CBD reduction in SAD was associated with increased blood flow in the limbic and paralimbic brain areas [84]. CBD is anxiolytic through direct binding of the GABAA receptor and activating the GABAnergic pathway [85–87]. CBD also bind to the NGF receptor, TRKA which signals the ERK1/2 signal transduction pathway and stimulates neurite outgrowth in PC12 cells [88]. Indeed the mechanism of action of CBD is recognized to help with the neuronal plasticity through autophagy and neuritogenesis and may help not only with anxiety, but also with other psychiatric disorders [88, 89]. Due to the lipophilicity of CBD, there is interest in developing emulsification techniques to increase CBD bioavailability when taken in the diet. For example, nanoemulsification [90] and lipid extractions [91] and lipid-vehicles [92] and piperine nanoliposhperes of CBD [93, 94] have been investigated for better oral absorption and better bioavailability for cellular targeting. Nanoemulsified, versus lipid emulsified CBD were tested for their ability to stimulate neurite outgrowth in PC12 cells (**Figure 1**). Continuous lipid extracted CBD shows greater bioavailability and activity compared to nanoemulsification and piperine nanoliposheperes (**Figure 1**).

### **2.7 Valerian root**

The anxiolytic activity seen in patients supplementing with Valerian root extract [95], is known to be due to the sesquiterpene, valerenic acid [96]. While there is evidence to suggest that valerenic acid activates the GABAnergic pathway [97, 98],

#### **Figure 1.**

*The effects of CBD on PC12 cell neurite outgrowth. PC12 cells were seeded on tissue culture plastic in a serum free defined medium and the percentage of cells that formed neurites were counted by visual inspection over a five day period. Cells were either untreated (blank) or treated with 100 ng/ml nerve growth factor (NGF) or with 10 uM of five different CBD formulations (CBD1-CBD5). CBD designations are as follows: CBD isolated by continuous lipid extraction, (CBD1), CBD1 + vitamin C (CBD2), nano-emulsion CBD (CBD3), liposomal-emulsion CBD (CBD 4) and piperine nanoliposhpere preparation CBD (CBD5). CBD1 and CBD2 were statistically significantly more neuritogenic at 95% confidence (\*) on days three and five (p < 0.05, t-test) compared to any of the other CBD formulations.*

*Physiological and Cellular Targets of Neurotrophic Anxiolytic Phytochemicals in Food… DOI: http://dx.doi.org/10.5772/intechopen.97565*

#### **Figure 2.**

*The effect of valerian root extract and valerenic acid on neurite outgrowth in PC12 cell cultures. PC12 cells were seeded in serum free defined medium and treated as indicated with 10 ng/ml NGF, 100 μM valerenic acid and 50 mg/ml of 4:1 aqueous valerian root extract. The percentage of cells that formed neurites was counted by visual inspection over a five day period. More neurites were seen in PC12 cells treated with the valerian root extract and NGF when compared to NGF alone and these differences were statistically significantly at 95% confidence (\*) on days one, three and five (p < 0.05, t-test). These data suggest valerian root extract phytochemical can potentiate NGF activity.*

growing evidence suggests that valerenic acid mediates anxiolytic effects also by both antagonizing glutaminegric pathways [99, 100] and agonizing the serotonin receptor [101]. Valerenic acid also activates secretion of BDNF in cultured SH-SY5Y neurons [102]. Interestingly, germacrane, another sesquiterpene extracted from Valerian root, while not associated with an anxiolytic activity, has been shown to potentiate NGF and TRKA signaling and neurite outgrowth in PC12 cells [103]. An aqueous extract of valerian root enhances NGF-mediated neurite outgrowth and neuroplasticity but unlike CBD, the valerian extract is not neurotrophic in PC12 cells in the absence of NGF stimulation (**Figure 2**).

#### **2.8 Citrus**

Citrus plant extracts, including those from lemon, bitter orange, and bergamot relieve anxiety in clinical trials. For example, lemon inhalation reduced anxiety in myocardial infarction patients [104] and bergamot aromatherapy reduced preoperative anxiety [105] and bitter orange aroma therapy relieves anxiety in patients with acute coronary syndrome [106] and chronic myeloid leukemia [107] and preoperative anxiety [108]. Bitter orange extract contains primarily limolene and b-myrcrene, appear to act on the 5-HT serotonergic pathway [109]. When tested in PC12 cells, citrus phytochemicals such as nobilitin, gardenin A and auraptene all stimulate neurite outgrowth [110–112] and 5-Hydroxy-3,6,7,8,3′,4′-hexamethoxyflavone from sweet orange peel stimulates neurite outgrowth in and NGF-like fashion activating the ERK1/2 signaling pathway suggesting binding to TRKA [113].

### **2.9 Saffron**

Saffron has been shown to be anxiolytic in two double blind placebo controlled clinical trials. [114, 115] and while the active anxiolytic molecule in Saffron has not been identified, crocin, a carotinoid in Saffron, has been shown to increase BDNF and GDNF expression in neuronal stem cells [116] and also increase hippocampal BDNF and protect the murine brain from methamphetamine toxicity [117].

#### **2.10** *Bacopa monnieri*

In double blind placebo controlled trials, *Bacopa monnieri*, an adaptagen of Ayruvic medical tradition, has been show to enhance cognition and reduce anxiety [118, 119]. This anxiolytic adaptagen has been shown to increase nerve NGF expression in rats [120]. A saponin isolated from *Bacopa monnieri*, Bacopacide I, has been shown to have antidepressant activity in mice by modulating the HPA axis and enhancing BDNF mRNA expression in the hippocampus and prefrontal cortex of mice [121].

#### **2.11 Skullcap**

Skuttleria is a genus of plants known as the skullcaps that include scutellaria Radix and *Scutellaria lateriflora* (American skullcap). American skullcap has been shown to be anxiolytic in humans as shown by a reduction in anxiety in healthy volunteers using the Beck Anxiety Inventory (BAI) [122, 123]. The Skullcap flavone, baicalin which is found in american sckullcap and other members of the skuttleria genus has been shown to be anxiolytic by binding to GABAA receptors in mice [124, 125]. Interestingly biacalin increases hippocampal BDNF expression and in doing so protects the hippocampus from corticosterone induced depression in mice [126]. In addition biacalin stimulates neurite outgrowth in C17.2 neuronal stem cells by signaling through the ERK1/2 pathways, the known signal transduction triggered by NGF binding to TRKA [127].

#### **2.12 Rhodeola Rosea**

Rhodeola Rosea has been shown to reduce GAD in small pilot and self reporting clinical trials [128, 129]. While the effects of Rhodeola on brain neurochemistry has not been well studied, salidroside, a glycoside from Rhodiola has been shown to increase stem cells expression of neurotrophin-3 (NT-3), BDNF, NGF mRNA and induce differentiation into neurons [130] and also activates the ERK1/2 pathway in NGF treated PC12 cells [131].

#### **2.13 Hops**

One study shows Hops to be anxiolytic in clinical trials [132]. Prenylflavinoids from extracted from Hops can both bind to the benzodiazepine binding site on GABAA receptors [133, 134] and stimulate neurite outgrowth through TRKA a signaling in PC12 cells and cultures of dorsal root ganglia neurons [135, 136].

#### **2.14** *Nigella sativa*

One clinical study shows that *Nigella sativa* seeds are anxiolytic in clinical trials [137]. Oral administration of Nigella extracts increase brain serotonin level in rats [138, 139] and thymoquinone, a terpine from Nigella is anxiolytic through *Physiological and Cellular Targets of Neurotrophic Anxiolytic Phytochemicals in Food… DOI: http://dx.doi.org/10.5772/intechopen.97565*

a GABAnergic pathway when orally administered to mice [140]. Thymoquinone promotes neurite outgrowth in rat hippocampal neurons and dorsal root ganglion neurons [141, 142].
