SCIENCE
References:
1. Butterweck, Böckers, Korte, Wittkowski, Winterhoff – Long-term effects of St. John’s wort and hypericin on monoamine levels in rat hypothalamus and hippocampus.
Hypericum perforatum L. (St. John’s wort) is one of the leading psychotherapeutic phytomedicines and, because of this, great effort has been devoted to clarifying its mechanism of action. Chronic effects of St. John’s wort and hypericin, one of its major active compounds, on regional brain amine metabolism have not been reported yet. We used a high-performance liquid chromatography system to examine the effects of short-term (2 weeks) and long-term (8 weeks) administration of imipramine, Hypericum extract or hypericin on regional levels of serotonin (5-HT), norepinephrine, dopamine and their metabolites in the rat brain. We focused our interest on the hypothalamus and hippocampus, as these brain regions are thought to be involved in antidepressant drug action. Imipramine (15 mg/kg, p.o.), Hypericum extract (500 mg/kg, p.o.), and hypericin (0.2 mg/kg, p.o.) given daily for 8 weeks significantly increased 5-HT levels in the hypothalamus (P<0.05). The 5-HT turnover was significantly lowered in both brain regions after 8 weeks of daily treatment with the Hypericum extract (both P<0.05). Consistent changes in catecholamine levels were only detected in hypothalamic tissues after long-term treatment. Comparable to imipramine, Hypericum extract as well as hypericin significantly decreased 3,4-dihydroxyphenylacetic acid and homovanillic acid levels in the hypothalamus (P<0.01). Our data clearly show that long-term, but not short-term administration of St. John’s wort and its active constituent hypericin modify levels of neurotransmitters in brain regions involved in the pathophysiology of depression.
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2. Butterweck V – Mechanism of action of St John’s wort in depression : what is known?
Extracts of Hypericum perforatum L. (St John’s wort) are now successfully competing for status as a standard antidepressant therapy. Because of this, great effort has been devoted to identifying the active antidepressant compounds in the extract. From a phytochemical point of view, St John’s wort is one of the best-investigated medicinal plants. A series of bioactive compounds has been detected in the crude material, namely flavonol derivatives, biflavones, proanthocyanidines, xanthones, phloroglucinols and naphthodianthrones. Although St John’s wort has been subjected to extensive scientific studies in the last decade, there are still many open questions about its pharmacology and mechanism of action. Initial biochemical studies reported that St John’s wort is only a weak inhibitor of monoamine oxidase-A and -B activity but that it inhibits the synaptosomal uptake of serotonin, dopamine and noradrenaline (norepinephrine) with approximately equal affinity. However, other in vitro binding assays carried out using St John’s wort extract demonstrated significant affinity for adenosine, GABA(A), GABA(B) and glutamate receptors. In vivo St John’s wort extract leads to a downregulation of beta-adrenergic receptors and an upregulation of serotonin 5-HT(2) receptors in the rat frontal cortex and causes changes in neurotransmitter concentrations in brain areas that are implicated in depression. In studies using the rat forced swimming test, an animal model of depression, St John’s wort extracts induced a significant reduction of immobility. In other experimental models of depression, including acute and chronic forms of escape deficit induced by stressors, St John’s wort extract was shown to protect rats from the consequences of unavoidable stress. Recent neuroendocrine studies suggest that St John’s wort is involved in the regulation of genes that control hypothalamic-pituitary-adrenal axis function. With regard to the antidepressant effects of St John’s wort extract, many of the pharmacological activities appear to be attributable to the naphthodianthrone hypericin, the phloroglucinol derivative hyperforin and several flavonoids. This review integrates new findings of possible mechanisms that may underlie the antidepressant action of St John’s wort and its active constituents with a large body of existing literature.
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3. Ronald Brenner,Subramoniam Madhusoodanan,Monika Pawlowska,et alPal Czobor – St John’s Wort and Major Depression
To the Editor: Dr Shelton and colleagues1 concluded that “St John’s wort was not effective for treatment of major depression.” These authors may have been overly skeptical in interpreting their data. In the intent-to-treat analysis, according to the study’s response criterion, 26.5% of subjects receiving St John’s wort vs 18.6% of patients in the placebo group responded to treatment (P = .15), and according to the study’s remission criterion, 14.3% vs 4.9% showed remission (P = .02). If one evaluates this trial in the context of other similar studies, it is noteworthy that the comparisons of St John’s wort vs placebo in this study is in the same direction as studies with a positive outcome, although it does not reach statistical significance. What is surprising about these data is the low response rate to placebo. A placebo response of 20% to 30% is routine in studies of depression.2 Thus, an equally reasonable conclusion is that St John’s wort was perhaps better than placebo in the treatment of major depression. A third arm with an established antidepressant might have resolved these difficulties.
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4. Gaster , Holroyd J. – St John’s wort for depression: a systematic review.
To address whether St John’s wort is useful for the treatment of depression we attempted to retrieve all English-language articles with data on the efficacy, safety, and availability of St John’s wort. Randomized, controlled, double-blind trials were selected and assessed for methodological quality using a standardized checklist, and data on pharmacology, cost, regulation, and safety were extracted. Eight studies were identified, found to be of generally good methodological quality, and determined to provide a modest amount of data to suggest that St John’s wort is more effective than placebo in the treatment of mild to moderate depression. The absolute increased response rate with the use of St John’s wort ranged from 23% to 55% higher than with placebo, but ranged from 6% to 18% lower compared with tricyclic antidepressants. More data are required to assess both its use in severe depression and its efficacy compared with other antidepressants. Rates of side effects were low. As a dietary supplement, St John’s wort is currently largely unregulated, but the Food and Drug Administration is reviewing plans to tighten its regulatory oversight.
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5. Christian Ude, Mario Wurglics – Ginkgo biloba Extracts: A Review of the Pharmacokinetics of the Active Ingredients
Ginkgo biloba is among the most favourite and best explored herbal drugs. Standardized extracts of Ginkgo biloba represent the only herbal alternative to synthetic antidementia drugs in the therapy of cognitive decline and Alzheimer’s diseases. The clinical efficiency of such standardized Ginkgo biloba extracts (GBE) is still controversial, but authors of numerous international clinical studies recommended the use of GBE in the described therapies.Extracts of Ginkgo biloba are a mixture of substances with a wide variety of physical and chemical properties and activities. Numerous pharmacological investigations lead to the conclusion that the terpene trilactones (TTL) and the flavonoids of GBE are responsible for the main pharmacological effects of the extract in the therapy of cognitive decline. Therefore, the quality of GBE products must be oriented on a defined quantity of TTL and flavonoids. Furthermore, because of their toxic potential the amount of ginkgolic acid should be less than 5 ppm.However, data on pharmacokinetics and bioavailability, especially related to the central nervous system (CNS), which is the target tissue, are relatively rare. A few investigations characterize the TTL and flavonoids of Ginkgo biloba pharmacokinetically in plasma and in the brain. Recent investigations show that significant levels of TTL and Ginkgo biloba flavonoids cross the blood-brain barrier and enter the CNS of rats after oral application of GBE. Knowledge about the pharmacokinetic behaviour of these substances is necessary to discuss the pharmacological results on a more realistic basis.
(PDF) Ginkgo biloba Extracts: A Review of the Pharmacokinetics of the Active Ingredients.
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6. Zhang SJ1, Xue ZY. – Effect of Western medicine therapy assisted by Ginkgo biloba tablet on vascular cognitive impairment of none dementia.
OBJECTIVE:
To discuss the clinical effects of Western medicine therapy assisted by Ginkgo biloba tablet (GBT) on patients with vascular cognitive impairment of none dementia (VCIND).
METHODS:
A total of 80 patients with VCIND were divided into two groups randomly: Conventional treatment group (control group) and combined treatment group. Conventional treatment group was given conventional treatment with anti-platelet aggregation. In this group, 75 mg aspirin was given three times a day for 3 months. While in combined treatment group, 19.2 mg GBT was given three times a day for 3 months together with conventional treatment (anti-platelet aggregation drugs). Montreal cognitive assessment (MoCA) and transcranial Doppler (TCD) were used to observe changes of cognitive ability and cerebral blood flow in VCIND patients before and after treatment in both groups. Then the clinical data were analyzed so as to compare the efficacy in two groups.
RESULTS:
After 3 month-treatment in combined treatment group, the scores of executive ability, attention, abstract, delayed memory, orientation in the MoCA were significantly increased compared with those before treatment and those in control group after treatment. Besides, blood flow velocity of anterior cerebral artery increased significantly than that before treatment and that in control group after treatment.
CONCLUSIONS:
GBT tablet can improve the therapeutic efficacy as well improve cognitive ability and cerebral blood flow supply of patients with VCIND.
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7. Santos, Galduróz, Barbieri, Castiglioni, Ytaya, Bueno – Cognitive performance, SPECT, and blood viscosity in elderly non-demented people using Ginkgo biloba.
The aging process is associated with several cognitive alterations. This study looks at the effects of taking dried extract of Ginkgo biloba, which has been used in several countries in an attempt to minimize these effects. The subjects were 48 men aged 60 – 70 matched between control and experimental groups for educational level. Evaluation was based on a number of neuropsychological tests in an attempt to cover the largest possible number of functions including Single Photon Emission Computer Tomography (SPECT) and measures of blood viscosity. The study was run on a double-blind basis with placebo and Ginkgo biloba groups evaluated over a period of 8 months. After treatment, the experimental group showed a reduction in blood viscosity, improved cerebral perfusion in specific areas and improved global cognitive functioning. The control group showed the opposite – higher blood viscosity, a reduction in cerebral perfusion (in specific areas), and cognitive deterioration in different functions. Although the mechanisms by which Ginkgo biloba may contribute to overall enhancement of the parameters evaluated have not been specified, this plant extract certainly appears to be effective in the treatment of cognitive deficits in older people. Further research into its use is called for on the basis of the results obtained here.
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8. Jose Miguel Rubio-Perez and Juana Maria Morillas-Ruiz – A Review: Inflammatory Process in Alzheimer’s Disease, Role of Cytokines
Alzheimer’s disease (AD) is the most common neurodegenerative disorder to date. Neuropathological hallmarks are β-amyloid (Aβ) plaques and neurofibrillary tangles, but the inflammatory process has a fundamental role in the pathogenesis of AD. Inflammatory components related to AD neuroinflammation include brain cells such as microglia and astrocytes, the complement system, as well as cytokines and chemokines. Cytokines play a key role in inflammatory and anti-inflammatory processes in AD. An important factor in the onset of inflammatory process is the overexpression of interleukin (IL)-1, which produces many reactions in a vicious circle that cause dysfunction and neuronal death. Other important cytokines in neuroinflammation are IL-6 and tumor necrosis factor (TNF)-α. By contrast, other cytokines such as IL-1 receptor antagonist (IL-1ra), IL-4, IL-10, and transforming growth factor (TGF)-β can suppress both proinflammatory cytokine production and their action, subsequently protecting the brain. It has been observed in epidemiological studies that treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) decreases the risk for developing AD. Unfortunately, clinical trials of NSAIDs in AD patients have not been very fruitful. Proinflammatory responses may be countered through polyphenols. Supplementation of these natural compounds may provide a new therapeutic line of approach to this brain disorder.
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9. J. Klein, O. Weichel, M. Hilgert, J. Rupp, S. S. Chatterjee, H. Nawrath – Excitotoxic Hippocampal Membrane Breakdown and its Inhibition by Bilobalide: Role of Chloride Fluxes
We have previously shown that hypoxia and N-methyl-D-aspartate (NMDA) receptor activation induce breakdown of choline-containing phospholipids in rat hippocampus, a process which is mediated by calcium influx and phospholipase A2activation. Bilobalide, a constituent of Ginkgo biloba, inhibited this process in a potent manner (Weichel et al., Naunyn-Schmiedeberg’s Arch. Pharmacol. 360, 609 – 615, 1999). In this study, we used fluorescence microscopy and radioactive flux measurements to show that bilobalide does not interfere with NMDA-induced calcium influx. Instead, bilobalide seems to inhibit NMDA-induced fluxes of chloride ions through ligand-operated chloride channels. In our experiments, substitution of chloride in the superfusion medium fully blocked the effect of NMDA on choline release from hippocampal slices, while the presence of chloride transport inhibitors (furosemide, DIDS) was partially antagonistic. The inhibitory effect of bilobalide and of HA-966, a glycine B receptor antagonist, on NMDA-induced choline release was attenuated in the presence of glycine. The inhibitory effect of bilobalide, but not that of HA-966, was also antagonized by GABA. The inhibitory effect of MK-801, an NMDA channel blocker, on choline release was insensitive to glycine. We conclude from our findings that bilobalide inhibits an NMDA-induced chloride flux through glycine/GABA-operated channels, thereby preventing NMDA-induced breakdown of membrane phospholipids. This effect is expected to contribute to the neuroprotective effects of ginkgo biloba extracts.
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10. Yoshitake, Yoshitake, Kehr – The Ginkgo biloba extract EGb 761(R) and its main constituent flavonoids and ginkgolides increase extracellular dopamine levels in the rat prefrontal cortex.
BACKGROUND AND PURPOSE:
Experimental and clinical data suggest that extracts of Ginkgo biloba improve cognitive function. However, the neurochemical correlates of these effects are not yet fully clarified. The purpose of this study was to examine the effects of acute and repeated oral administration of the standardized extract EGb 761((R)) on extracellular levels of dopamine, noradrenaline and serotonin (5-HT), and the dopamine metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the prefrontal cortex (PFC) and striatum of conscious rats.
EXPERIMENTAL APPROACH:
Monoamines and their metabolites were monitored by the use of microdialysis sampling and HPLC with electrochemical or fluorescence detection.
KEY RESULTS:
A single oral dose of EGb 761 (100 mg.kg(-1)) had no effect on monoamine levels. However, following chronic (100 mg.kg(-1)/14 days/once daily) treatment, the same dose significantly increased extracellular dopamine and noradrenaline levels, while 5-HT levels were unaffected. Chronic treatment with EGb 761 showed dose-dependent increases in frontocortical dopamine levels and, to a lesser extent, in the striatum. The extracellular levels of HVA and DOPAC were not affected by either acute or repeated doses. Treatment with the main constituents of EGb 761 revealed that the increase in dopamine levels was mostly caused by the flavonol glycosides and ginkgolide fractions, whereas bilobalide treatment was without effect.
CONCLUSIONS AND IMPLICATIONS:
The present results demonstrate that chronic but not acute treatment with EGb 761 increased dopaminergic transmission in the PFC. This finding may be one of the mechanisms underlying the reported effects of G. biloba in improving cognitive function.
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11. He´ le`ne Amieva, Ce´ line Meillon, Catherine Helmer1, Pascale Barberger-Gateau1, Jean Franc¸ois Dartigues – Ginkgo Biloba Extract and Long-Term Cognitive Decline:A 20-Year Follow-Up Population-Based Study
BACKGROUND:
Numerous studies have looked at the potential benefits of various nootropic drugs such as Ginkgo biloba extract (EGb761®; Tanakan®) and piracetam (Nootropyl®) on age-related cognitive decline often leading to inconclusive results due to small sample sizes or insufficient follow-up duration. The present study assesses the association between intake of EGb761® and cognitive function of elderly adults over a 20-year period.
METHODS AND FINDINGS:
The data were gathered from the prospective community-based cohort study ‘Paquid’. Within the study sample of 3612 non-demented participants aged 65 and over at baseline, three groups were compared: 589 subjects reporting use of EGb761® at at least one of the ten assessment visits, 149 subjects reporting use of piracetam at one of the assessment visits and 2874 subjects not reporting use of either EGb761® or piracetam. Decline on MMSE, verbal fluency and visual memory over the 20-year follow-up was analysed with a multivariate mixed linear effects model. A significant difference in MMSE decline over the 20-year follow-up was observed in the EGb761® and piracetam treatment groups compared to the ‘neither treatment’ group. These effects were in opposite directions: the EGb761® group declined less rapidly than the ‘neither treatment’ group, whereas the piracetam group declined more rapidly (β = -0.6). Regarding verbal fluency and visual memory, no difference was observed between the EGb761® group and the ‘neither treatment’ group (respectively, β = 0.21 and β = -0.03), whereas the piracetam group declined more rapidly (respectively, β = -1.40 and β = -0.44). When comparing the EGb761® and piracetam groups directly, a different decline was observed for the three tests (respectively β = -1.07, β = -1.61 and β = -0.41).
CONCLUSION:
Cognitive decline in a non-demented elderly population was lower in subjects who reported using EGb761® than in those who did not. This effect may be a specific medication effect of EGb761®, since it was not observed for another nootropic medication, piracetam.
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12. Kennedy, Scholey, Wesnes – Modulation of cognition and mood following administration of single doses of Ginkgo biloba, ginseng, and a ginkgo/ginseng combination to healthy young adults.
It has previously been demonstrated in separate studies that single doses of Ginkgo biloba, Panax ginseng, and a combination of the two extracts can improve different aspects of cognitive performance in healthy young volunteers. The present study directly compared the effects of single doses of G. biloba, ginseng, and a product combining the two on aspects of mood and cognitive performance in the same cohort of healthy, young adult volunteers. The study followed a randomised placebo-controlled, double-blind, balanced, cross-over design. Twenty participants received 360 mg of ginkgo, 400 mg of ginseng, 960 mg of a product combining the two extracts, and a matching placebo. Treatment order was dictated by random allocation to a Latin square, with a 7-day wash-out period between treatments. Cognitive testing comprised completion of the Cognitive Drug Research (CDR) computerised assessment battery and two serial subtraction mental arithmetic tasks. Mood was assessed with Bond-Lader visual analogue scales. Following a baseline cognitive assessment, further test sessions took place 1, 2.5, 4, and 6 h after the day’s treatment was taken. The results largely supported previous findings. All three treatments were associated with improved secondary memory performance on the CDR battery, with the ginseng condition evincing some improvement in the speed of performing memory tasks and in the accuracy of attentional tasks. Following ginkgo and the ginkgo/ginseng combination performance of both the Serial Threes and Serial Sevens, subtraction tasks was also improved at the later testing sessions. No modulation of the speed of performing attention tasks was evident. Improvements in self-rated mood was also found following ginkgo and to a lesser extent the combination product.
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13. Ginkgo biloba
Ginkgo (Ginkgo biloba) is one of the oldest living tree species. It is also one of the best-selling herbal supplements in the United States and Europe.
Ginkgo has a long history of use in treating blood disorders and memory issues. It is best known today as way to potentially keep your memory sharp. Laboratory studies have shown that ginkgo improves blood circulation by opening up blood vessels and making blood less sticky. It is also an antioxidant.
For those reasons, ginkgo may improve vein and eye health. Although not all studies agree, ginkgo may help treat dementia (including Alzheimer disease) and intermittent claudication, or poor circulation in the legs. It may also protect memory in older adults.
Ginkgo leaves contain flavonoids and terpenoids, which are both antioxidants. In your body, harmful particles called free radicals build up as you age, and may contribute to heart disease, cancer, and Alzheimer disease. Antioxidants like those found in ginkgo fight off free radicals, and stop them from damaging DNA and other cells.
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14. Hemmeter, Annen, Bischof, Brüderlin, Hatzinger, Rose, Holsboer-Trachsler. – Polysomnographic effects of adjuvant ginkgo biloba therapy in patients with major depression medicated with trimipramine.
Sleep disturbance and cognitive impairment are frequent complaints of depressed patients under standard antidepressant medication. Therefore, additional therapies are required which specifically focus on the improvement of these deficits without exerting major side effects. Ginkgo biloba extract (EGb) has been shown to improve cognitive abilities in elderly subjects and in patients with disorders of the dementia spectrum. Animal studies surmise that EGb may reduce CRH activity, which is substantially related to depressive mood and behavior, predominantly cognition and sleep. An open non-randomized pilot study has been conducted to investigate the effects of ginkgo biloba extract (EGb Li 1370) on cognitive performance and sleep regulation in depressed inpatients. 16 patients were treated with a trimipramine (T)-monotherapy (200 mg) for six weeks. In eight of the 16 patients, an adjunct EGb therapy (240 mg/d) was applied for four weeks after a baseline week, the other eight patients remained on trimipramine monotherapy (200 mg) during the entire study. Polysomnography, cognitive psychomotor performance and psychopathology were assessed at baseline, after short-term and long-term adjunct EGb treatment, and after one week of ginkgo discontinuation (at the respective evaluation times in the eight patients on T-monotherapy). This report focuses on the results of EGb on sleep EEG pattern. EGb significantly improved sleep pattern by an increase of sleep efficiency and a reduction of awakenings. In addition, sleep stage 1 and REM-density were reduced, while stage 2 was increased. Non-REM sleep, predominantly slow wave sleep in the first sleep cycle, was significantly enhanced compared to trimipramine monotherapy. Discontinuation of EGb reversed most of these effects. Based on the animal data, these results suggest that EGb may improve sleep continuity and enhance Non-REM sleep due to a weakening of tonic CRH-activity. The compensation of the deficient Non-REM component in depression by the EGb application may provide a new additional treatment strategy, especially in the treatment of the depressive syndrome with sleep disturbance.
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15. Woelk H1, Arnoldt KH, Kieser M, Hoerr R. – Ginkgo biloba special extract EGb 761 in generalized anxiety disorder and adjustment disorder with anxious mood: a randomized, double-blind, placebo-controlled trial.
Ginkgo biloba special extract EGb 761, an anti-dementia drug, enhances cognitive functioning and stabilizes mood in cognitively impaired elderly subjects. Moreover, EGb 761 had been found to alleviate symptoms of anxiety in people with mental decline, therefore it was now tested for clinical efficacy in younger patients suffering from anxiety. One hundred and seven patients with generalized anxiety disorder (GAD, n=82) or adjustment disorder with anxious mood (ADWAM, n=25) according to the diagnostic and statistical manual of mental disorders, third edition – revised (DSM-III-R) were randomized to daily doses of 480 mg EGb 761, 240 mg EGb 761 or placebo for 4 weeks. Intention-to-treat (ITT) analyses were performed on the primary outcome measure, the Hamilton rating scale for anxiety (HAMA), and the secondary variables, the clinical global impression of change (CGI-C), the Erlangen anxiety tension and aggression scale (EAAS), the list of complaints (B-L’), and the patient’s global rating of change. The HAMA total scores decreased by -14.3 (+/-8.1), -12.1 (+/-9.0) and -7.8 (+/-9.2) in the high-dose EGb 761, the low-dose EGb 761 and the placebo group, respectively. Changes were significantly different from placebo for both treatment groups with p=0.0003 (high-dose group) and p=0.01 (low-dose). Regression analyses revealed a dose-response trend (p=0.003). EGb 761 was significantly superior to placebo on all secondary outcome measures. It was safe and well tolerated and may thus be of particular value in elderly patients with anxiety related to cognitive decline.
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16. Müller, Rolli, Schäfer, Hafner – Effects of hypericum extract (LI 160) in biochemical models of antidepressant activity.
Since the mechanism of the antidepressant activity of hypericum extract is not yet understood, we tested possible effects of standardized hypericum extract (LI 160) in several biochemical models relevant for the mechanism of action of other antidepressant drugs. While LI 160 was only a weak inhibitor of MAO-A and MAO-B activity, it inhibited the synaptosomal uptake of serotonin, dopamine and norepinephrine with about equal affinity-2 micrograms/ml). Moreover, subchronic treatment of rats with hypericum extract led to a significant down-regulation of beta-receptors and to a significant up-regulation of 5-HT2-receptors in the frontal cortex. The data might suggest that hypericum extract acts via similar biochemical mechanisms to other antidepressants (e.g. tricyclics).
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17. World Health Organization 2011 – International Statistical Classification of Diseases and Related Health Problems
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