Schizandra, Studies

The traditional liver remedy Schisandra chinensis contains constituents with antihepatitis activity, and has been shown to reduce circulating monocyte counts (although with no effects on other white blood cell counts) after 2 weeks’ treatment of human subjects infected with hepatitis B.

Schisandra has emerged as a key herb for boosting phase 1 and especially phase 2 detoxification processes by the liver. Despite being a powerful inducer of phase 1 enzymes, Schisandra does not cause harmful bioactivation in vivo and in vitro studies have indicated that constituents of Schisandra decrease the mutagenicity of benzo(alpha)pyrene by influencing hepatic metabolism. The probable reason is that Schisandra powerfully induces phase 2 enzymes as well, which results in the rapid clearance of the potentially toxic metabolite.

HIV

Immunomodulatory

Insomnia

Schisandra possesses potent sedative and hypnotic activity, which supports its therapeutic use for insomnia.

Liver Effects

Menopause

A randomized, double-blind, placebo-controlled trial of Schisandra chinensis for menopausal symptoms.

Memory

Schisandra inhibits the acetylcholinesterase enzyme, which may explain its positive effect on memory. -

Microbiome

Schisandra chinensis fruit modulates the gut microbiota composition in association with metabolic markers in obese women: a randomized, double-blind placebo-controlled study

Neuroprotective

Pneumonia

A combination of Rhodiola, Schisandra and Eleutherococccus (Siberian Ginseng) improves patients with acute non-specific pneumonia.

Sepsis

Therapeutic effects of alpha-iso-cubebenol, a natural compound isolated from the Schisandra chinensis fruit, against sepsis.

Stress

- Schisandra and Scutellaria baicalensis (Chinese skullcap) counter stress behavior in mice.

Other Effects

Clinical pharmacology

Studies on healthy subjects

Oral administration of 5–10.0 mg/kg bw of a 70% ethanol extract of the fruits, reduced fatigue and increased the accuracy of telegraphic transmission and reception by 22% . In another study, healthy male volunteers were given an oral preparation of the fruit (dose and form not specified), and were required to thread a needle at the same time as taking a message delivered through headphones. The results demonstrated that when compared to other undefined stimulants, the extract increased the accuracy and quality of work.

Other uncontrolled investigations have demonstrated that oral administration of the fruits increases physical performance in human subjects. A decrease in fatigue and acceleration of recovery after exercise were reported for athletes, such as long-distance runners, skiers and gymnasts, after consuming 1.5–6.0 g of the fruits daily over a 2-week period.

The effect of the fruits on physical stress was investigated in a controlled study involving 59 airline stewardesses (aged 22–29 years) during seven nonstop 9-hour fl ights. The study measured several stress parameters before and after the flights, with and without treatment with 0.5 g of an undefined extract of the fruits. Control subjects displayed a significant increase in heart rate (P < 0.001) and blood pressure (P < 0.01) during flights, while those taking the extract did not. The report further described the effect of oral administration of 2.0 g of an extract of the fruits to 58 untrained soldiers (aged 19–23 years) and 62 highly trained sportsmen (aged 19–30 years). Physical work capacity as measured by a step-ergometer, significantly increased 24 hours after treatment (P < 0.05), while that of the controls remained the same.

A double-blind, placebo-controlled clinical trial assessed the effects of a standardized extract of the fruits on the concentration of nitric oxide in human saliva, blood neutrophils, lymphocytes and monocytes, and working capacity, as a measure of adaptogenic potential in heavy exercise. The level of nitric oxide in the saliva of beginner athletes was found to increase after exercise while that in the saliva of well-trained athletes was high and did not increase further after exercise. Tablets containing an extract of the fruits, 91.1 mg standardized to 3.1 mg of schisandrin and γ-schisandrin, were administered twice daily for 8 days. There was a significant increase in the pre-exercise levels of nitric oxide in both beginners (n = 17) and athletes (n = 46) (P < 0.05); there were no changes in the other parameters.

A placebo-controlled clinical trial involving 134 healthy subjects assessed the effects of a single administration of the encapsulated fruits on night vision and acceleration of adaptation to darkness. Visual function was assessed 15–20 minutes prior to administration and 3 hours after. Administration of a single dose of 3.0 g of the fruits increased visual acuity under low illumination and extended the visual field margins for white and red colors by 8–25° . In a second study of 150 subjects, a single administration of 3 g of the fruits increased visual acuity in 90% of subjects. Administration of the drug decreased the time recognition of an object in darkness (from 32.3 seconds to 18.4 seconds), 4.5 hours after administration.

Clinical trials in patients

In an uncontrolled study, a tincture of the fruits was used for the treatment of stomach and duodenal ulcers in 140 patients with acute and chronic ulcers, who had been ill for 1–10 years. Patients were treated with 30–40 drops per day for 3–4 weeks. All subjects reported a reduction in symptoms within a few days, with ulcer healing reported in 96.5% of

patients after 35 days of treatment. Recurrent episodes of peptic ulcer disease were reported in only 9 of 90 patients followed over a period of 1–6 years.

A review of the Chinese literature mentioned reports of more than 5000 cases of hepatitis treated with preparations of the fruits, which had resulted in reductions of elevated liver enzymes. Elevated SGPT activities returned to normal in 75% of treated patients after 20 days of treatment. In subjects with elevated SGPT due to drug toxicity, SGPT levels reportedly returned to normal in 83 of 86 cases after 1–4 weeks of treatment. Enzyme levels reportedly decreased even without the discontinuation of the hepatotoxic drugs . It must be stressed that these are uncontrolled observational studies with questionable methodology. Further well designed, controlled clinical trials are needed to ascertain their validity.

In a controlled trial involving 189 patients with chronic viral hepatitis B and elevated SGPT levels, an ethanol extract of the fruits, containing 20 mg of lignans and corresponding to 1.5 g of the fruits, was administered orally to 107 of the patients daily, while the control group (n = 82) received liver extracts and vitamins . Normal SGPT levels were observed

in 72 (68%) of patients receiving the extract after 4 weeks. In the control group, normal SGPT levels were observed in 36 (44%), with an average recovery time of 8 weeks. However, improvements in SGPT were only temporary, and levels rose again 6–12 weeks after treatment was discontinued. Relapse rates were highest (46–69%) in chronic persistent hepatitis, elderly patients, and in those receiving long courses of treatment with hepatotoxic drugs. Most patients responded to resumption of treatment with a return to their previously reduced SGPT levels.

Experimental pharmacology

Anti-inflammatory activity

External application of gomisin A (schisandrol B), 0.6 mg/ear, inhibited inflammation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in mice. External application of gomisin J and schisandrin C also inhibited the inflammation induced by TPA in mice. The median effective dose (ED50) of these compounds ranged between 1.4 μmol and 4.4 μmol, with gomisin A having the strongest anti-inflammatory effect.

Antihepatotoxic activities

In vivo studies have demonstrated that the fruits have liver-protectant effects. Intragastric administration of 80.0 mg/kg bw of a lignan-enriched extract of the fruits to rats prevented hepatotoxicity induced by carbon tetrachloride, prevented glutathione depletion and stimulated the activity of glutathione reductase. In experimental models, the activity of serum glutamic pyruvic transaminase (SGPT) induced by the administration of carbon tetrachloride or paracetamol in mice, thioacetamide in rats, and ethinyl estradiol 3-cyclopentylether in rabbits was reduced by oral administration of 1.0–10.0 g/kg bw of a 95% ethanol extract of fruits . A 95% ethanol extract of the fruits lowered elevated SGPT levels in mice treated with carbon tetrachloride or thioacetamide . Lignans, isolated from the fruits, have also been shown to have liver-protectant activities in vivo . Intragastric administration of the lignans to mice, specifically 50.0 mg/kg bw of gomisin A, 50.0 mg/kg bw of gomisin B, 50.0–100.0 mg/kg bw of schisandrin A, 50–100.0 mg/kg bw of schisandrin B and 50.0–100.0 mg/kg bw of γ-schisandrin, decreased elevated SGPT levels in mice treated with carbon tetrachloride. Treatment with the lignans also prevented the elevation of SGPT levels and the morphological changes in the liver, such as inflammatory infiltration and liver cell necrosis, induced by carbon tetrachloride.

Intragastric administration of 100 mg/kg bw of gomisin A, B or schisandrin also protected against thioacetamide-induced liver damage in mice . Oral pretreatment of rats with 50.0 mg/kg bw of gomisin A prevented the rise in SGPT and serum glutamic oxaloacetic transaminase (SGOT), as well as necrosis of hepatocytes induced by paracetamol. Intragastric administration of 30.0 mg/kg bw or 100.0 mg/kg bw of gomisin A per day for 4 days, increased liver weight in normal rats or animals with liver injury. Gomisin A suppressed the increase in serum transaminase activity and the appearance of histological changes, such as hepatocyte degeneration and necrosis, inflammatory cell infiltration and fatty deposition induced by carbon tetrachloride, galactosamine or ethionine. Gomisin A also increased the activities of microsomal cytochrome B5, P450, NADPH cytochrome C reductase, aminophenazone-N-demethylase and 7-ethoxycoumarin O-deethylase, and decreased the activity of 3,4-benzopyrene hydroxylase.

Intragastric administration of 10.0–100.0 mg/kg bw of gomisin A per day for 4 days increased liver regeneration in rats after partial hepatectomy, increased the regeneration rate of the liver cells, and improved the serum retention rate of the foreign dye sulfobromophthalein. In addition, gomisin A enhanced the incorporation of radio-labelled henylalanine into liver protein and decreased hexobarbital-induced sleeping time. Ultrastructural studies of liver tissue by electron microscopy showed an increase in rough and smooth endoplasmic reticulum in the groups receiving gomisin A. Gomisin A enhanced the proliferation of hepatocytes and the recovery of liver function after partial hepatectomy and increased hepatic blood flow. Liver enlargement induced by repeated administration of gomisin A may be due to the proliferation of endoplasmic reticulum. Intragastric administration of 10.0 mg/kg bw or 30.0 mg/kg bw of gomisin A per day for 3 or 6 weeks decreased fibrosis and accelerated liver regeneration and the recovery of liver function after partial hepatectomy in rats with chronic liver damage induced by carbon tetrachloride . Intragastric administration of 100.0 mg/kg bw of gomisin A per day for 14 days promoted hepatocyte growth after mitosis during regeneration

of partially resected rat liver, and induced proliferation of non-parenchymal cells by increasing the c-myc product, a gene that precedes DNA replication in proliferating cells.

In vitro studies with cultured rat hepatocytes treated with an ethyl ether, ethyl acetate, methanol or water extract of the fruits, 0.1–1.0 mg/ ml, reduced cytotoxicity induced by galactosamine and carbon tetrachloride. Gomisin A, 0.1 g/ml, suppressed the biosynthesis of leukotrienes induced by calcium ionophore A2318 in rat peritoneal macrophages.

This effect was partially associated with its antihepatotoxic effects .

Intragastric administration of 100.0–200.0 mg/kg bw of schisandrol A or schisandrin B reduced liver malondialdehyde formation induced by the administration of 50% ethanol to rats . Intragastric administration of 4.0–16.0 mg/kg bw of schisandrin B per day for 3 days increased the activities of hepatic glutathione S-transferase (GST) and glutathione reductase in mice treated with carbon tetrachloride. The mechanism by which schisandrin B exerts its hepatoprotectant effect appears to be through the enhancement of the hepatic glutathione antioxidant status in mice with carbon tetrachloride induced hepatotoxicity. The activities of glucose-6-phosphate dehydrogenase, selenium-glutathione peroxidase and γ-glutamylcysteine synthetase were reduced in a dose dependent manner by schisandrin B. Pretreatment of mice with 1.0 mg/kg bw of schisandrin B per day for 3 days protected the animals against menadione-induced hepatic oxidative damage, and reduced the plasma level of alanine aminotransferase and the hepatic level of malondialdehyde as compared with menadione-intoxicated controls.

Intragastric administration of 12.0 mg/kg bw schisandrin B per day for 3 days to mice increased the hepatic mitochondrial glutathione concentration, whereas butylated hydroxytoluene decreased hepatic glutathione. Pretreatment with schisandrin B at the same dose sustained the hepatic mitochondrial glutathione level in carbon tetrachloride intoxicated mice and protected against carbon tetrachloride induced hepatotoxicity.Schisandrin B also increased the hepatic ascorbic acid (vitamin C) level in control animals, and sustained a high concentration of hepatic

vitamins C and E in carbon tetrachloride intoxicated mice, which may partially explain its mechanism of action. Pretreatment of mice with intragastric administration of 1.2–12.0 mg/kg bw schisandrin B per day for 3 days had a dose-dependent protective effect on carbon tetrachloride induced lipid peroxidation and hepatocellular damage.

Administration of the powdered fruits in the diet, 5%, to mice induced a three-fold increase in activity of hepatic cytochrome P450. Total benzopyrene metabolism was increased 1.6-fold, and phenol II formation relative to total metabolites was significantly increased as compared with the control group. In addition, 7-ethoxycoumarin O-deethylase and aryl hydrocarbon hydroxylase activities were increased and the binding of aflatoxin to DNA was decreased.

Antioxidant activity

Inhibition of lipid peroxidation in rat liver microsomes was observed after treatment with schisandrol, schisandrin C and schisandrin B, 1.0 mmol/l, in vitro. Schisandrol and schisandrin B, 1.0 mmol/l, inhibited gossypol-induced superoxide anion generation in rat liver microsomes . Schisandrol, 1 mmol/l, scavenged oxygen radicals in human neutrophils

induced by tetradecanoylphorbol acetate.Schisandrin B suppressed lipid peroxidation induced by carbon tetrachloride in hepatocytes in vitro . The release of GPT and lactate dehydrogenase was also reduced, thereby increasing hepatocyte viability and the integrity of the hepatocyte membrane. Schisandrin B, 10 mmol/l, inhibited NADPH oxidation in mouse liver microsomes incubated with carbon tetrachloride. Schisandrin B, 110.0 μmol/l, inhibited oxidation of erythrocyte membrane lipids induced by ferric chloride in vitro.

Antitumor activity

The effect of gomisin A on hepatocarcinogenesis induced by 3'-methyl-4-dimethylaminoazobenzene (3'-MeDAB) in rats was assessed. Oral administration of 30 mg/kg bw of gomisin A per day for 5 weeks inhibited the appearance in the liver of foci for GST (placental form, GST-P), a marker enzyme of preneoplasm. Gomisin A also decreased the number of altered hepatic foci, such as the clear cell and basophilic cell type, in the early stages. Administration of gomisin A in the diet, 0.03%, for 10 weeks decreased the concentration of GST-P, and the number and size of GST-P positive foci in the liver after treatment with 3'-MeDAB . This indicates that gomisin A may inhibit 3'-MeDAB-induced hepatocarcinogenesis by enhancing the excretion of the carcinogen from the liver and reversing the normal cytokinesis.

Central nervous system effects

Intraperitoneal administration of 10.0 mg/kg bw of a 50% ethanol extract of the fruits to mice potentiated the sedative effects of barbiturates. However, intraperitoneal administration of 5.0 mg/kg bw of an ethanol and petroleum ether extract of the fruits decreased barbiturate-induced sleeping times . Intraperitoneal administration of 50.0 mg/kg bw of an unspecified extract of the fruits to mice 30 minutes prior to the injection of pentobarbital, ethanol, or exposure to ether significantly reduced the sleeping time of the treated group by 41.4%, 51.5% and 27%, respectively (P < 0.001 for all differences). However, other researchers have demonstrated that the effects of the fruits on pentobarbital sleeping time depended upon the time of administration, and the type of extract or individual schisandrin derivatives administered. Schisandrin B or schisandrol B, 12.5 mg/kg bw, administered 1 hour prior to the injection of pentobarbital potentiated sleeping time. However, if the compounds were administered 24 hours prior to injection of pentobarbital, a decrease in sleeping time was observed. Administration of schisandrin C prolonged pentobarbital-induced sleeping time regardless of when it was administered.

Effects on drug metabolism

The activity of the fruits in restoring hepatic drug metabolism and phase I oxidative metabolism in livers damaged by carbon tetrachloride was investigated in vivo by assessing the pharmacokinetics of antipyrine. Intragastric administration of 160.0 mg/kg bw of a lignan-rich extract of the fruits to rats 30 minutes prior to administration of carbon tetrachloride and a single dose of antipyrine improved antipyrine elimination, decreased its clearance and reduced the half-life of the drug. In addition, normalization of the levels of SGPT and SGOT and cytochrome P450 was observed.

Intragastric administration of 200.0 mg/kg bw of schizandrin B and schisanhenol per day for 3 days increased liver GST and microsomal cytochrome P450 levels in mice and rats. Both compounds reduced an increase in uterus weight in animals treated with estradiol, and decreased serum estradiol levels in mice. An enhancement in metabolism by liver microsomes, specifically the induction of drug-metabolizing phase I and phase II enzymes was also noted.

Ergogenic effects

The effects of the fruits on fatigue in and the endurance of horses has been assessed in a number of small studies. In one study, a dried 50% ethanol extract of the fruits or saline solution (48 g) was administered orally to thoroughbred horses prior to an 800-m race at maximum speed and to polo horses before a 12-minute gallop at a speed of 400 m/min. Treatment of the animals with the extract reduced serum lactic acid levels and increased plasma glucose levels after the test. Horses treated with the extract were also able to run faster and completed the 800-m race in 50.4 seconds compared with 52.2 seconds for the control animals (P < 0.05), indicating an increase in physical performance.

In a randomized double-blind, crossover study, 12.0 g of a dried 50% ethanol extract of the fruits, standardized to contain 1.2% schizandrins, was administered orally to 20 race horses 30 minutes prior to competition. Horses treated with the extract had significantly reduced heart rates for up to 20 minutes following the race (P < 0.01). The rate of respiration was also reduced immediately after the race, and was maintained for 15 minutes (P < 0.05). In addition, plasma glucose concentrations increased significantly (P < 0.05) and concentrations of lactic acid were significantly lower (P < 0.01) in the treated group than in the control group. Treated horses also completed the circuit in a shorter time than controls (117.5 seconds compared with 120.3 seconds). A placebo-controlled study involving 24 sports horses with performance problems, as well as high levels of serum γ-glutamyltransferase (SGT), SGOT and creatinine phosphokinase, assessed the effects of the fruits on performance. Oral administration of 3.0 g of a dried 50% ethanol extract of the fruits per day to 12 horses significantly reduced SGT, SGOT and creatinine phosphokinase levels (P < 0.05, P < 0.01 and P < 0.01, respectively), and improved performance after 7 and 14 days, as compared with 12 placebo controls.

Intragastric administration of 1.6 g/kg bw of a petroleum ether extract of the fruits to rats signifi cantly (P < 0.01) reduced exercise-induced elevation of plasma creatine phosphokinase.

Toxicology

Intragastric administration of 0.6 g/kg bw or 1.3 g/kg bw of the fruits per day for 10 days to mice resulted in only mild toxic effects, such as decreased physical activity, piloerection, apathy and an increase in body weight. The intragastric and intraperitoneal median lethal doses (LD50) of a petroleum ether extract of the fruits in mice were 10.5 g/kg bw

and 4.4 g/kg bw, respectively. The symptoms of toxicity included depressed motor activity, short cataleptic periods and a lack of coordination of motor functions, which were followed by tonic seizures and marked mydriasis . In a 7-day study, no deaths occurred after oral administration of high doses of schisandrins A and C (2000.0 mg/kg bw), and

schisandrol A (500.0 mg/kg bw); schisandrol B (250.0 mg/kg bw) and schisandrin B (250.0 mg/kg bw) showed relatively higher levels of toxicity.

The toxicity of an ethanol extract containing schisandrin B, and of the schisandrins A and C, 2000.0 mg/kg bw) and schisandrol A, 1000.0 mg/ kg bw, was reported after intragastric administration to mice. Death of mice occurred within 7 days after administration of schisandrins A and C. Schisandrol B, 500 mg/kg bw, is reported to have a relatively higher toxicity after intragastric administration to mice. The LD50 of schisandrol B in mice is reported to be 878.0 mg/kg bw by the intragastric route and 855.0 mg/kg bw after subcutaneous administration. The intragastric LD50 values for petrol-ether extracts with schisandrin contents of 10%, 40% and 80% were 10.5 g/kg bw, 2.8 g/kg bw and 1.4 g/kg bw, respectively.

(WHO-VOL3 pg 308- 315)

Schizandra, Studies

Anti-Inflammatory

Antioxidant

Blood Sugar Effects

Cancer

Cardiovascular Effect

Cartilage

Endurance / Energy Metabolism

Hair Growth

HIV