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Pharmaceutical companies invest vast sums of money in discovering substances that could be used in the future to alleviate or treat mental disorders affecting people worldwide. The potential beneficial substances from plants, known as phytochemicals, are still being explored. Several species of plants have been selected for testing as nootropic agents because of their use in traditional medicine, and research has already identified several promising natural substances that could act as cognitive enhancers ( ) [3,165,166].
Despite the continuous improvement in the production of synthetic drugs, herbal compounds still have considerable use, but the important ones come from commercial plantings. The consumption of popular species is high, and it is impossible to cover it only by collecting wild plants. Bred varieties generally provide higher yields and reduce the risk of confusion or falsification [ 40 , 41 ]. Nowadays, the collector often encounters difficulties that were not present before, such as chemical damage or contamination of the growing plants [ 167 ]. The composition and total content of complex active constituents are variable during plant development and vegetative growth. Choosing a suitable period for harvesting or collecting is essential. Plants should not be harvested in humid or rainy weather, but only when dry. During harvesting, the plants must not be damaged because breaking the leaves sometimes affects the active compounds in an undesirable manner. Many compounds, such as vitamin C or tannins, can also react with metals. Therefore, if possible, the plants or parts are collected in their entirety. The leaves and stems are usually harvested just before flowering or during flowering. The flowers are harvested shortly before full development, but some may still be in the bud stage. The fruits and seeds are harvested at the time of full ripeness. For roots and rhizomes, the suitable period is the developmental dormancy of the plant, which is usually autumn or spring. The bark is harvested in the temperate zone at the beginning of vegetative growth in early spring, or, in the tropics, throughout the year [ 168 , 169 ].
The extraction of plant material to produce an effective drug usually involves many technical steps. Contaminants on aboveground parts can be removed by sieving or winnowing, while underground organs are decontaminated by washing and brushing. The common method of preservation continues to be drying, preceded by fermentation in some cases. By removing water, enzymes are inactivated, and the growth of fungi and bacteria is limited [ 170 , 171 ]. Most plants should be dried in the shade, and the temperature should not exceed a specific limit. For plants containing volatile essential oils, this limit is 40 °C [ 172 , 173 ]. Freeze-drying or lyophilization is also frequently used. For this method, fresh plant material is rapidly frozen at a temperature of &#;20 °C to &#;50 °C and then dried under a high vacuum. However, in some cases, freeze-drying imperfectly preserves important classes of medicinal compounds such as phenolics and volatile substances, reducing the effectiveness of some plant drugs. Additionally, the material dried in this way is very hygroscopic [ 174 , 175 ]. Freeze-dried drugs have to be stored away from moisture, as well as dust, insects, and light [ 172 , 173 ]. The drug is usually processed or cut after drying. Active compounds are used either directly in the form of medicinal products or indirectly as raw materials to obtain active compounds, which become part of medicinal products. Medicinal products produced directly from drugs can be in the form of tea for water infusion, granules, tablets, extracts, and divided or undivided powders. Active compounds are obtained from herbal materials often by extraction (alkaloids, glycosides), distillation (essential oils), or pressing (oils, fats) [ 176 , 177 ].
As a drug, ginseng is prepared in two different ways, which affect the content of active components and the degree of medicinal effects. It can be modified either by peeling and drying the root, after which it is called white ginseng, or the root can be steamed without peeling when it is referred to as the &#;hotter&#; red ginseng [215].
Ginsenosides have been shown to stimulate nitric oxide (NO) production in several systems. Purified ginsenoside Rb1 induced NO production in human aortic endothelial cells in vitro. The effect on the NO pathway is responsible for ginseng&#;s vasorelaxant and mildly hypotensive effect [182].
Ginseng increased the activity of the antioxidant enzymes superoxide dismutase and glutathione peroxidase in rats in vivo. Thus, supplementation may prevent increased oxidant accumulation and age-related oxidative protein and nucleic acid damage [178]. Experimental data from tests on male chicks suggest that Rb1 may improve memory for the task of visual discrimination and that the nootropic effect may be associated with changes in anxiety [179]. Ginsenoside Rb1 also reduced simulated Alzheimer&#;s disease in a rat model. Thus, it could be used in the future as a therapeutic agent for patients with memory impairment [180]. Ginsenoside Rg1 supplementation improved the performance of old mice in the behavioral test, significantly increasing the expression of proteins associated with synaptic plasticity in the hippocampus, including synaptophysin and N-methyl-D-aspartate receptor subunit 1 [181]. Oral administration of a combination of Ginkgo biloba and Panax ginseng extracts improved memory in rats. Data on test drug effects suggested the involvement of a serotonergic transporter as an important neurochemical correlate of rat behavior and memory effects of study drugs [216].
Ginseng&#;s effect on the human body can be described as adaptogenic. It increased the physical and mental resilience of the organism, eliminated fatigue, and helped the body to adapt to any current needs [217]. It is recommended to use a standardized ginseng extract at a dose of 200 mg per day ginseng for an extended period of time. Standardization refers to the content of ginsenosides, which usually ranges from 1.5 to 7 percent. Alternatively, 0.5 to 2 g of dry root per day is recommended, with ginseng taken in tea or chewed [218]. Ginseng is contraindicated in patients with acute asthma and hypertension. In large doses, it can cause excessive body stimulation, restlessness, insomnia, increased blood pressure, nervousness, inability to concentrate, headaches, and nosebleeds [218,219].
The leaves and ripe fruit are harvested from spring to early autumn. Leaves are used to make alcohol extracts (tinctures) or dried and ground [220]. Hulled and roasted ginkgo kernels are also consumed [221]. Mechanisms of action of Ginkgo biloba compounds include free radical scavenging for antioxidant activity, antagonistic effects on platelet-activating factor, vasodilation, and an overall reduction in blood viscosity [183,187].
Results of an ex vivo rat experiment showed that Ginkgo biloba extract had specific neuroprotective effects that may be useful in treating chronic cerebral hypoperfusion. The extract&#;s pharmacological mechanism involved modulating inflammatory mediators and the cholinergic system [184]. The triterpene lactones (ginkgolides A, B, C, and bilobalide) in the Ginkgo biloba extract have antioxidant, anti-inflammatory, and neuroprotective effects. In addition, in an experiment on mice, the extract had an antagonistic effect on glycine and GABA type A receptors [185].
A double-blind, placebo-controlled clinical trial in which participants received validated neuropsychological tests before and after treatment with Ginkgo biloba extract indicated significant improvement in working memory and information processing speed [186]. In contrast, a critical review of the evidence from several randomized clinical trials did not provide convincing evidence that Ginkgo biloba extracts taken either in a single dose or over a long time had a positive effect on any aspect of cognitive performance in healthy human subjects under sixty years of age [222].
Still, Ginkgo biloba extracts are widely prescribed to treat cerebral dysfunction and neurological disorders. Doses of 120&#;300 mg of standardized Ginkgo biloba 761 extracts (24% flavone glycosides and 6% terpene lactones) per day should be administered [183,223,224]. No side effects have been reported at regular doses, but mild stomach irritation and headaches occasionally occur with excessive consumption. It causes blood thinning, so people taking some anticoagulants should not take the drug before surgery [219,225].
Centella&#;s use in traditional medicine is diverse and varies regionally. In the countries of origin, fresh leaves are consumed as a salad, as part of curry spice mixes, or cooked as a vegetable [226].
An ethanol extract of C. asiatica mediated protection against amyloid-β-induced aggregated neurotoxicity by modulating the antioxidant defense system in cells in vitro, including superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and glutathione and glutathione disulfide levels. C. asiatica is a traditional medicinal herb with strong antioxidant activity that reduces amyloid-β deposition in the brain. Amyloid-β is the major component of senile plaques and neurofibrillary tangles found in the brains of patients with Alzheimer&#;s disease. This highlights the potential therapeutic and preventive value of C. asiatica in treating Alzheimer&#;s disease [189].
The results from in vivo experiments on rats in a maze, monitoring social interactions, locomotor activity, and cage tests, showed that pure asiaticoside, and methanol or ethyl acetate extracts of Centella asiatica had anxiolytic activity. In addition, asiaticoside did not affect locomotor activity, suggesting that this compound does not have sedative effects [227]. Another in vivo study in mice revealed that a NO modulating mechanism may be involved in the protective effect of Centella asiatica against anxiety caused by sleep deprivation, oxidative damage, and neuroinflammation [188]. A study in juvenile and young adult mice demonstrated the nootropic effect of an aqueous extract of C. asiatica. Treatment resulted in increased hippocampal acetylcholinesterase activity and dendritic arborization of hippocampal CA3 neurons. Thus, treatment with C. asiatica during the postnatal developmental stage can affect neuronal morphology and support brain function [190].
The reported typical daily dose of C. asiatica is approximately 600 mg of dried leaves, or from 60 mg to 120 mg of standardized extract of C. asiatica (contains at least 85% of triterpenoid glycosides) [228,229].
Based on clinical studies, the reported tolerability of orally administered extracts of Centella is high, and no interactions with other drugs are known. Although no teratogenic effects have been reported, the drug should not be used during pregnancy and lactation. Use by children is also not recommended [230].
The roots and the leaves are harvested and used mainly in dried form. An infusion is prepared from the leaves and a decoction from the root. Fruit is sometimes used as an emetic [231].
A study in mice indicated that ashwagandha increased the content of hemoglobin, platelets, and red as well as white blood cells. An increase in red blood cells increases the blood&#;s ability to transport oxygen to the peripheral system, ensuring greater maximum aerobic capacity [194]. In another study, rats were used as a model of tardive dyskinesia, a disorder characterized by involuntary neurological triggering that leads to spontaneous, repetitive body movements, such as grimacing, sticking out the tongue, or lip movements that were simulated by injection of reserpine. Oxidative stress and lipid peroxidation products are involved in the pathophysiology of this disease. Long-term administration of Withania somnifera root extract to the rats significantly reduced lipid peroxidation, restored reduced glutathione levels, and reversed the decrease in brain superoxide dismutase and catalase levels induced by reserpine treatment. Thus, Withania somnifera root extract could be a helpful drug for treating drug-induced tardive dyskinesia [192]. Several tests in animal models have confirmed the nootropic effect of ashwagandha and its potential as a treatment for Alzheimer&#;s disease [191,193]. In another study, the steroidal lactone withaferin, a bioactive compound from the group of withanolides showed significant anticancer properties both in vitro and in vivo [232].
The dosage can be from 6 to 10 g of ground roots of ashwagandha per day or the equivalent of 750 mg to mg of extract per day [233]. Ashwagandha is not recommended in cases of hyperthyroidism or pregnancy. It is a relatively safe drug when used at the recommended doses. Overdoses can cause gastrointestinal problems and vomiting; therefore, treatment should be started with small doses and gradually increased. Ashwagandha is best taken in the evening because, in substantial doses, the herbal extract can act as a sedative [234].
In countries of natural occurrence, it is sometimes used as a leafy vegetable in salads or soups [235].
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In vitro treatment of rat astrocytes with methanol extract of Bacopa monnieri significantly reduced damage caused by high NO concentrations. It has been suggested that glial cells may produce NO by an enzyme-independent mechanism when stimulated by superoxide radicals, and the study results verified the antioxidant activity of Brahmi plant extract [196].
Treatment of albino rats with an alcoholic extract of Bacopa monnieri increased protein kinase activity and caused an increase in protein in the hippocampus. Overall, the extract has improved learning ability by enhancing cognitive function and memory retention. The chemical compounds responsible for this facilitating effect have been identified as a mixture of two saponins, bacosides A and B [197]. Choline acetyltransferase expression in the hippocampus was studied in olfactory bulbectomy mice compared to controls. Olfactory bulbectomy reduced cholinergic activity and thus choline acetyltransferase expression in the hippocampus. However, subsequent administration of Bacopa monnieri alcohol extract reversed this effect and gradually improved the induced cognitive dysfunction [195]. In a rat model of Alzheimer&#;s disease, Bacopa monnieri alcohol extract improved escape latency in the Morris water maze test. In addition, the loss of neurons and the density of cholinergic neurons were also mitigated [198]. Experiments have shown inhibition of the degeneration of cholinergic neurons by Bacopa monnieri, suggesting that the herb is a cognitive enhancer and neuroprotectant and may serve as a potential adjunctive drug for treating Alzheimer&#;s disease [195,198].
The Bacopa monnieri liquid extract dosage (ratio 1:2) is 5&#;12 mL per day for adults and 2.5&#;6 mL per day for children aged 6&#;12 years. For Bacopa monnieri extracts standardized at 20% content of bacosides A and B, 200&#;400 mg in divided doses for adults and 100&#;200 mg daily in divided doses for children is recommended [236,237].
No serious side effects have been reported. Rarely, mild sedation or digestive problems may occur after ingestion [238,239].
The seeds, the so-called guarana nuts, are harvested at full maturity. They are first roasted, then sifted by sieving, mechanically crushed, and mixed with water to make a bitter paste with high caffeine content. A coffee-like beverage is prepared by simmering guarana paste with hot water. Guarana paste is also added to syrups, and various non-alcoholic and alcoholic drinks are prepared from it, mainly popular in Brazil. Sometimes, the guarana paste is dried, ground into a powder, and used to make tablets [240,241].
In an in vivo study, the aqueous fraction of Paullinia cupana seeds was repeatedly administered to rats who were then placed in a T-maze, a model of generalized anxiety and panic disorders, and the guarana was shown to have anxiolytic and panicolytic effects [242]. The impact of long-term administration of Paullinia cupana seed extract by gavage to rats at various doses on their cognitive behavior was studied using the Morris water maze test, which showed identical results in rats with scopolamine-induced amnesia compared with controls [200]. Mice that ingested guarana suspension showed a significant increase in physical capacity when exposed to stressful situations such as forced swimming. After both single and chronic administration, guarana partially reversed the amnesic effect of scopolamine, as measured by a passive avoidance test in rats and mice, indicating a positive impact on memory acquisition [199]. Studies have shown that oral administration of processed Paullinia cupana seeds had a significant nootropic effect. Herbal drugs that exhibit this property may offer a useful adjunct therapeutic option for preventing or treating memory deficits, such as those seen in Alzheimer&#;s or Parkinson&#;s disease [199,200].
A typical dose is 75 mg of guarana extract (approximately 12% caffeine) administered as a tablet [243]. Guarana should not be used in persons with cardiovascular disease, who are pregnant or breastfeeding, have chronic headaches, diabetes, insomnia, mental disorders, stomach ulcers, or are taking theophylline [244].
The root is ground to a powder and formed into tablets or used in the form of a tincture. Infusion of the above-ground parts is also sometimes used [245].
In vitro experiments showed the antioxidant and antiradical activity of eleuthero [208], including the inhibition of lipid peroxidation [207].
In an in vivo study, an aqueous extract of eleuthero reduced acute stress in mice [210]. A study in normal mice examined the effects of an aqueous extract from eleuthero leaves on memory function. These in vivo tests showed that oral administration of the extract improved memory functions, and ex vivo confirmed that the active compounds of the extract, such as eleutheroside M and ciwujianoside B and C3, were able to penetrate the BBB and act on the brain. These three compounds and the leaf extract showed dendritic elongation activity against primary cultured cortical neurons, which may be related to improved memory [211].
Tests on healthy volunteers have also concluded that the active compounds of eleuthero affect cell defense, physical fitness, and lipid metabolism [209]. The detoxification properties of the extract have been used in treating chronic lead poisoning in mine workers [246]. Siberian ginseng has also been used in cosmetics [207].
The recommended daily dose of eleuthero is 2&#;3 g of dried root or an equivalent preparation [247]. According to the Russian Pharmacopeia, a standardized liquid extract of roots and rhizomes of Eleutherococcus senticosus (10 mg of the extract is equivalent to 120 mg of the crude herb) is currently available as an over-the-counter drug in a ratio of 1:1 with 40% ethanol. In the Russian medical system, this extract is recommended for oral use at a daily dose of 20&#;40 drops for an adult. However, further research is needed to investigate the appropriate dosing regimen to improve healthy adults&#; cognitive function and physical performance [246,248]. Side effects occur infrequently. Eleuthero increases blood pressure, so its use in hypertension is not recommended [249].
Rhizomes and roots from older plants are collected, dried, and subsequently used for extract preparation [250].
According to an in vitro study, salidroside, a phenylpropanoid glycoside isolated from R. rosea L., showed a protective effect in cultured PC12 neuronal cells against hypoglycemia and serum-restricted cytotoxicity, probably through modulation of gene expression associated with apoptosis, restoration of mitochondrial membrane potential, and inhibition of intracellular oxygen radical production [203].
An in vivo study was performed to investigate the effects of a single oral dose of an aqueous-alcoholic extract (plant material was extracted with 2% ethanol diluted with tap water) of R. rosea containing 3% rosavin and 1% salidroside on CNS activity in mice. The extract was tested for adaptogenic, antidepressant, anxiolytic, nociceptive, and locomotor activity at various doses using predictive behavioral tests in the animal model. The results showed that this extract significantly induced adaptogenic, antidepressant, anxiolytic, and stimulating effects [202], but the effects were not dose-dependent.
In a different trial, the effect of R. rosea L. extract on mood, anxiety, stress, and cognition in moderately anxious students was evaluated. Compared with the control, the experimental group showed a significant reduction in anxiety, stress, anger, confusion, and depression, and an improvement in general mood after treatment for two weeks. However, no significant difference in cognitive performance was observed between the groups [201].
The optimal dose of rhodiola extract for long-term use was 100&#;170 mg per day, and the rosavin content of the extract should be 3.6&#;6.14 mg per weight of the extract. This would suggest a daily dose of roughly 360&#;600 mg of standardized Rhodiola rosea extract containing 1% rosavin [251].
No serious side effects have been identified so far. Because it affects human nature, it is not recommended for patients who have manic&#;depressive psychosis. Rhodiola should also not be used by children, pregnant and breastfeeding mothers, or people with high blood pressure [252].
The often used parts are fruits and seeds. A tincture can be prepared from crushed seeds and a tea brewed from dried berries, shoots, and leaves. The fruits are consumed dried or marinated in sugar or honey to make jam, syrup, juice, or compote. They can also be stored frozen. In addition to syrups and juices, a strong sweet wine can be made from the juice of the berries [253,254]. Schisandra fruits are known to the people of the Far East primarily as a tonic and stimulant against fatigue and exhaustion [253].
An in vitro study was performed to determine the neuroprotective effects of dibenzocyclooctadiene lignan, schisantherin A, from the fruits of Schisandra chinensis against selective dopaminergic neurotoxin 6-hydroxydopamine-induced neural damage in human neuroblastoma cells. Pretreatment with schisantherin A provided neuroprotection against induced cytotoxicity, regulated the intracellular accumulation of reactive oxygen species and inhibited NO overproduction by reducing the overexpression of inducible nitric oxide synthase in cells [206].
In other in vitro and in vivo experiments, SH-SY5Y (human neuroblastoma) cells were incubated with 1-methyl-4-phenylpyridinium ion, and mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine were used to determine neuroprotection of schisantherin A. Pretreatment with schisantherin A significantly inhibited the induced cytotoxicity in SH-SY5Y cells. In addition, schisantherin A provided significant protection against induced dopaminergic neuronal loss in a mouse model of Parkinson&#;s disease [204]. These findings demonstrate that schisantherin A may have potential therapeutic value for oxidative stress-related neurodegenerative disorders, such as Parkinson&#;s disease [204,206].
In vivo cognitive tests such as the Morris water maze and the passive step-down avoidance tests were performed with rats given oral doses of aqueous or 95% ethanolic extract of Schisandra chinensis (petroleum ether fraction) and showed that the extract could partially reverse the effects of decreasing activity of superoxide dismutase, catalase and the overall antioxidant effect induced by D-galactose, and to maintain normal levels of glutathione, malondialdehyde and nitric oxide in serum, prefrontal cortex, striatum, and hippocampus. The extract improved the overall induced cognitive deficit [205].
The optimal dose of dried schisandra fruit for human administration is 2&#;6 g per day. For an average human body weight of 60 kg, the dose is 0.03&#;0.1 g of fruit per kg of body weight [253,255]. No serious side effects have been reported. Side effects have only occurred after regular ingestion of excessive amounts of fruits and included restlessness and insomnia [256].
Maca root is consumed either fresh or dried and has a distinctive taste and aroma. In South America, a sweet porridge or pudding called mazamorra de maca is made from dried roots, while the fresh root is cooked like potatoes. It can also be ground into flour, with a composition similar to cereal grains. A slightly alcoholic beverage called maca chica is made from the maca plant. Many growers mix and grind the leaves with the roots [257,258].
Polysaccharide fractions from maca leaves showed different in vitro scavenging capacities on 2,2-diphenyl-1-picrylhydrazyl, hydroxyl, and superoxide anion radicals [212].
Researchers have recently been interested in the neuroprotective effects of Lepidium meyenii. Experiments in vivo and ex vivo tests have shown the effect of Lepidium meyenii in reducing latency in untrained and trained mice. In the swimming strength test, maca shortened the immobility time. It also increased the uterine weight of mice after ovariectomy. Lepidium meyenii appeared to positively affect latent learning in ovariectomized mice and exhibited antidepressant activity [214]. Maca improved cognitive function, motor coordination, and endurance in middle-aged mice, increased mitochondrial respiratory function, and upregulated proteins associated with autophagy in the cortex [213].
These findings suggested that maca might be an effective functional food to slow age-related cognitive decline. The optimal dose has not been determined; however, the amount of maca root powder used in many studies was in the range of 1.5&#;3 g per day for the average human adult [259,260].
So far, no serious side effects or contraindications to the extracts have been reported. Maca seems to be safe, effective, and non-toxic [261].
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