**2. Clinically relevant anxiolytic phytochemicals with neurotrophic activity**

In this chapter we present only plants and plant extracts that contain phytochemicals that are both shown to be anxiolytic in human clinical trials and also *Physiological and Cellular Targets of Neurotrophic Anxiolytic Phytochemicals in Food… DOI: http://dx.doi.org/10.5772/intechopen.97565*

possess neuroplastic properties (**Table 1**). The specific anxiolytic nutraceutical or phytochemical in the plant is in most cases not known, in part because neuroactive plants usually contain many nervine agents. Often however there is a suspected phytochemical or group of phytochemicals thought to be responsible for the anxiolytic activity. In some cases the anxiolytic nutraceutical in the plant extract is the same phytochemical that has the neurotrophic activity, while in other cases it may be a different phytochemical in the plant extract. Anxiolytic drugs adjust neurotransmitter and neurotransmitter receptors levels which leads to increased drug insensitivity, extreme withdrawal effects and a return to imbalance neurotransmitter and neurotransmitter receptor levels when and if the drug is removed. In addition to altering neurotransmitter and receptor levels neuroplastic anxiolytics also stimulate the new neurite connections associated with learning and remembering appropriate responses to stressors. If a new response to a threat is learned, then treatment of the anxiety disorder may not require dosage increases and the newly learned healthy perceptions of threats could remain with the patient even if the drug or treatment is removed or reduced. This would represent a tremendous advancement in the treatment of anxiety disorders. **Table 1** is a list of the fourteen clinically supported anxiolytic plants that also have neuroplastic properties.

#### **2.1 Theanine**

Theanine is an amino acid that when taken as a green tea extract or in a purified form is able to reduce anxiety in clinical trials [38–40]. When administered in a double blind placebo controlled study, theanine was shown to reduce stress-induced salivary cortisol levels [39]. However in other studies, while theanine did improve the sleep in people with GAD, theanine did not reduced anxiety scores on the HAMA scale [41]. Both animal and in vitro studies have suggested that theanine supplementation increases brain serotonin, dopamine and GABA levels and that the cellular target for theanine includes glutamate receptors to which theanine binds and antagonizes the stimulating action of glutamate on neurons [42–44]. With regard to neuroplasticity, theanine facilitates neuritogenesis in the developing rat hippocampus and enhances object learning memory [45]. Further, dietary theanine increases nerve growth factor (NGF) levels in the developing rat brain [46]. Theanine is not the only green tea molecule that can affect neurotrophin activity. The catechins from green tea have been show to potentiate BDNF binding to TRKB receptors in PC12 cells and enhance neurite outgrowth [47], and potentiate NGF signaling through TRKA receptors and enhance neurite outgrowth also in PC12 cells [48]. Further, the green tea catechin, green tea polyphenol (−)-epigallocatechin-3 gallate (EGCG) also stimulates neurite outgrowth in cultured PC12 neurons [49].

#### **2.2 Chamomile**

In clinical trials, chamomile has been shown to decrease the symptoms of general anxiety disorder [50, 51], in part by exerting an effect on diurnal cortisol changes [52]. While not yet known, apigenin is a plant flavone component of chamomile which is thought to contribute to the anxiolytic effects of chamomile [53]. Interestingly, apigenin increases neurite formation in murine N2a cells [54] and reverses PTZ induced behavioral impairments in mice by increasing hippocampal levels of brain derived neurotrophic factor (BDNF) [55]. Apigenin also has been shown to increase hippocampal BDNF levels in a chronic corticosteroid treatment model of depression in mice [56]. Apigenin also activates the ERK1/2 pathway in PC12 cells and while not sufficient to stimulate differentiation in PC12 cells [57], apigenin does increases neurite outgrowth in estrogen receptor


*All plants listed above have been shown to be anxiolytic in human clinical trials. In some cases the anxiolytic molecules and neurotrophic activities have not been determined (N.D.). Neurotrophic activities are those associated with activating neurotrophin signaling pathways by increasing levels of neurotrophin (NGF, BDNF, NT3, GDBF) synthesis, or by directly binding to neurotrophin receptors (TRKA, TRKB, TRKC and NGFR) or by activating the ERK1/2 signaling pathway. Another neurotrophic activity is the induction of neurite outgrowth or neuritogenesis in neuronal cell cultures and in. In these cases the names of the cells or tissues showing a neuroplastic response is provided.*

#### **Table 1.**

*The neurotrophic activities of anxiolytic plant extracts and phytochemical nutraceuticals.*

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

expressing PC12 cells [58] again linking dietary phytochemicals that are anxiolytic to neural plasticity.
