Treat Anxiety Disorders: Polyherbal Formulations

In Ayurveda, compound formulations are generally used in the therapy as the combination of many drugs provides a synergistic therapeutic effect and also includes ingredients which help to minimize the adverse effects of few other major drugs. A recent study demonstrated adaptogenic potential of a compound natural health product which had Withania as the main herb in an open label human trial. An open-label and uncontrolled clinical trial evaluated the impact of OCTA© on known parameters of stress (OCTA©, an aqueous-based liquid herbal preparation consisting of eight herbs as follows: W. somnifera, Lagerstroemia speciosa, Bacopa monniera, Zizyphus jujuba, Morinda citrifolia, Punica granatum, Shisandrae chinensis and Lycium barbarum). Another herbal formulation, Sumind is (Ayurvedic nomenclature and the quantity of each ingredient are given in parentheses), Nardostachys atamans (Jatamansi), Acorus calamus (Vacha), Celastrus paniculata (Jyotishmati), Convolvulus microphyllus (Shankapushpi), Bacopa monnieri {Brahmi), Withania somnifera (Ashwagadha), Valerian wallichii (Tagara), Eclipta alba (Bhringaraja). Sumind showed antidepressant activity as indicated by reduced immobility time in rats subjected to swim stress. It also restored biogenic amine levels to normal levels and reduced corticosterone levels in stressed rats.

Mentat (BR-16A) is an herbal medication contains 20 different ingredients. The main herbs present in the mentat are Brahmi (Bacopa monnieri), Mandookparni (Centella asiatica).

Ashwagandha (Withania somnifera), Jatamansi (Nardostachys jatamansi), Shankhapuspi (Evolvulus alsinoides), Tagar (Valeriana wallichi). Vach (Acorus calamus), Guduchi (Tinospora cordifolia), Malkangni (Celastrus paniculatus), Kuth (Saussurea lappa) Amla (Embelica officinalis), Terminalia chebula and Terminalia belerica. Some of these plants namely, B. monnieri, C. asiatica, W. somnifera, N. jatamansi, E. alsinoides, V. wallichi, A. calamus, T cordifolia and C. paniculatus, have been classified in Ayurveda as Medharasayanas and claimed to improve memory and intellect. Polyherbal formulations are generally used in Ayurveda, based on the concept that such combinations provide synergistic therapeutic effect. Mice show a natural aversion to open and high spaces and therefore, spend more time in enclosed arms. Mice receiving chronic treatment with BR-16A-Mentat (100 mg/kg) followed by ethanol failed to show any withdrawal-induced anxiety. There was a significant decrease in the time spent in closed arms. The duration and the number of entries in open arms increased significantly as compared with the ethanol withdrawn group. Also, the anti-stress effect of mentat was evident against social isolation-induced stress in mice.

Agrawal et al. reported that BR-16A improves memory parameters and decreases anxiety parameters in normal volunteers. Also, mentat (BR-16) brought about marked improvement in memory in all age groups and caused decrease in anxiety level and neuroticism index. Mentat in the form of syrup was given to patients of anxiety neurosis and depression in a placebo controlled study. Both anxiety and depressive patients showed memory impairment and also increased fatiguability. 3 month treatment with Mentat improved memory and decreased fatiguability in these patients. Psychological problems like stress, anxiety and depression play an important role in the prognosis, quality of life as well as the survival rate of cancer patients. Treatment with mentat in cancer patients reduced stress, anxiety and depressive symptoms.

Another polyherbal formulation Geriforte showed significant anxiolytic effect in clinical studies. Geriforte contains Chyavanprash concentrate and the extracts of Asparagus adscendens, Withania somnifera, Glycyrrhiza glabra, Centella asiatica, Mucuna pruriens, Shilajeet, Asparagus racemosus, Terminalia arjuna, Makardhwaj and Piper longum, besides some others. An earlier open study demonstrated the beneficial effects of Geriforte in anxiety patients as per DSM III R criteria. There was significant reduction in the total Hamilton Anxiety Rating Scale (HARS) score at the end of four weeks. Another double-blind, placebo-controlled study authors have observed improvement in HARS scores in patients of mixed anxiety-depression following 4 weeks of Geriforte treatment in comparison with placebo. Preclinical studies show that Geriforte stimulates antioxidant defense system in both mice and rats. Various studies have demonstrated the efficacy of Geriforte as an anti-stress adaptogen. The prolongation of survival time and prevention of stress-induced changes in adrenals, prevention of stress-induced ulcers and milk-induced leucocytosis, indicate the anti-stress properties of Geriforte.

Another common polyherbal formulation Euphytose, which is a combination of six extracts: Crataegus, Ballota, Passiflora and Valeriana, which have mild sedative effects, and Cola and Paullinia, which mainly act as mild stimulants. Euphytose reduced HAMA scores in outpatients with adjustment disorder with anxious mood in multicenter, double-blind, placebo-controlled study.

Recent preclinical studies have shown anxiolytic activity of several herbal drugs. Securidaca longepedunculata is a savannah shrub commonly used by traditional medicine practitioners in Nigeria. The aqueous root extract of Securidaca longepedunculata showed anxiolytic activity in the elevated plus maze (EPM) by significantly increasing time spent in the open arms as compared to control. Another herbal medicine yokukansan improved age related anxiety in the open filed and EPM. Petiveria alliacea L has been traditionally used in South America and Brazil for anxiety and whole plant extract of Petiveria alliacea caused anxiolytic-like effects in mice subjected to the EPM. Cirsium rivulare (Jacq.) All. (Asteraceae) is an herbaceous perennial plant traditionally used in Polish folk medicine to treat anxiety. In a recent study, methanolic extracts from flowers and leaves of Cirsium rivulare produced anxiolytic activity in the EPM. Extract from flowers in addition to its anxiolytic effects, improves memory of the appetitively and aversively motivated tasks. In Brazil, Erythrina mulungu and Erythrina velutina (Fabaceae) are widely used as a tranquilizer and/or sedative, and their extract exerts an anxiolytic-like effect profile in animal models. In herbal medicine, a leaf or bark decoction or tincture from mulungu is considered to calm agitation and other disorders of the nervous system, including insomnia and depression. Chronic Erythrina mulungu exerted anxiolytic effect in the elevated T maze inhibitory avoidance and in the light/dark transition model. Erythrina velutina administration increased the percentage of open arm entries in the elevated plus maze. No clinical data is available to substantiate anxiolytic effect of these herbs.

Our own studies have demonstrated the role of different herbs and herbal formulations namely Euphorbia hirta, Celastrus paniculatus Willd and Sumind in amelioration of anxiety, depression, cognitive deficits and associated neurodegeneration in these disorders. Recent studies have shown that treatments with the crude extract of Astragalus membranaceus reduced repeated stress induced anxiety and memory loss. In similar lines, our previous work demonstrated that Euphorbia hirta (Eh) reverses chronic immobilization stress-induced anxiety behavior in elevated plus maze and open field test. Extracts of Eh Linn have been found to possess central analgesic, antipyretic, anti-inflammatory properties in addition to its central antidepressant, sedative and anxiolytic effects. The anxiolytic activity of this drug has been established in mice subjected to two-compartment, staircase and light/dark choice situation tests. Euphorbia hirta produces its anxiolytic effect in an animal model of chronic stress through GABAa receptor-benzodiazepine receptor-CL channel complex. Eh also appears to mediate its anxiolytic action through this complex since all of the three antagonists, flumazenil, bicuculline and picrotoxin inhibited Eh-induced increase in open arm exploration and also recovered the acetylcholinesterase (AChE) activity in discrete regions of the brain.

Celastrus paniculatus Willd has been known for centuries as “the elixir of life”. Ayurveda describes drug the Jyotishmati (Celastrus paniculata) as early as 1500BC in Charaka samhita (the most ancient and authoritative text book of ayurveda) for diseases of the brain and as buddhiprada (enhancing intellect), smritiprada (enhancing memory). Jyotishmati translates as Jyoti and mati (enlightens intellect). Celastrus paniculatus (CP), a plant belonging to Celastraceae was in use from time immemorial to treat brain related disorders and to enhance learning and memory. CP treated rats exhibited a significantly increased learning curve compared with vehicle treated animals in the avoidance paradigm. In another study, rats treated daily with 850 mg/kg of CP oil for 15 days exhibited a significant improvement in their retention time in a two-way passive avoidance task. CP also produced a significant decrease in the content of norepinephrine, dopamine and serotonin and certain of their respective metabolites in the brain. Previous findings indicate that the aqueous extract of CP seed has cognitive-enhancing properties and an antioxidant effect might be involved. CP enhanced learning and memory in naive rats when tested in a partially baited radial arm maze task by altering acetyl cholinesterase activity in the hippocampus and frontal cortex. Acute and chronic immobilisation-induced oxidative stress was restored back to normal after CP oil treatment. Recently we have demonstrated that chronic stress-induced learning impairment in radial arm maze task was restored by chronic CP oil treatment. The behavioural recovery was associated with restoration of both hippocampal long-term potentiation and cholinergic activity. This opens up the possibility of developing novel agents from nature to enhance synaptic plasticity as a means of treating a variety of psychiatric diseases, including depression (Unpublished data). An in vitro study has demonstrated neuroprotective effect of CP water extract in forebrain primary neuronal cell cultures. Pre-treatment of neuronal cells with CP-water extract significantly attenuated glutamate-induced neuronal death. Also, CP significantly and reversibly inhibited whole-cell NMDA currents.