Schisandra

Schisandra chinensis (of the family Schisandraceae) is a deciduous woody climbing vine that can grow up to 8 meters and bears flowers (yellowish-white to pinkish) and small 5-8mm fruits of a deep red color;^[1] the plant itself is sometimes referred to as Chinese Magnolia Vine (not to be confused with Magnolia officinalis) and the fruits, referred to as fructae or fructus shisandra, are used in Traditional chinese medicine for the treatment of cough (antitussive) and asthma as well as to expel mucus from the lungs (expectorant), urinary and genital disorders, feminine health, sedative, astringent, and a general wellness tonic to counter fatigue.^[1] Due to the fatigue fighting properties, it is referred to as 'Qi-Invigorating'^[2] in the 'Yang' family of herbs^[3] whereas Qi refers to an abstract concept of vital energy and Yang refers to an overal manifestation of bodily functions (with reference to organ function).^[3]

Schisandra chinensis is a plant which bears some small fruits, and these fruits are used in both chinese and russian traditional medicine to fight fatigue and promote general well being

At times, the related species Schisandra sphenanthera is also used in traditional chinese medicine under the name of Wuweizi, although recently it is called Nan-Wuweizi whereas schisandra chinensis is called Ban-wuweizi and the two are not considered perfectly interchangeable.^[4] Both contain lignans which are seen as the main bioactives of schisandra chinensis (albeit different lignans) and sphenanthera contains triterpenoids not present in chinensis.^[4]

Shisandra chinensis (fruits unless otherwise specified) usually contain:

• (Lignans) Schisandrin (synonymous with Schisandrin A) in the range of 3.9-9.39mg/g (0.4-0.9%) of the dry fruit weight^[5][6][7] as well as Schisandrin B (2.1-5mg/g; 0.2-0.5%^[5][7]) and Schisandrin C (up to 1.4%, at times undetectable^[5]); the only difference between the three being whether a phenyl group has one (Schisandrin B), two (Schisandrin C), or no (Schisandrin A) catechol groups in place of the desmethoxy groups
• (Lignans) γ-Schisandrin at 0.1-0.3% of the fruits dry weight^[5][6] Schisandrol A (4.26% fruit dry weight^[7]), Schisandrol B (Aka. Gomisin A; 1.1-4.7mg/g; 0.1-0.5%^[5] yet elsewhere up to 1.18%^[7]), and Deoxyschisandrin (0.9-3.4mg/g; 0.09-0.3%^[5])
• (Lignans) Schisandtherin A (up to 0.66mg/g 0.06%^[5] and elsewhere 0.14%^[7]) and Schisantherin B (0.9-2.14mg/g; 0.09-0.2%^[5]) as well as Schisantherin D,^[4] although C and E are only present in schisandra sphenanthera^[4]
• (Lignans) Gomisin G (up to 0.88mg/g; 0.09%^[5]) and angeloylgomisin G,^[8] Gomisin J (0.4-0.9mg/g; 0.04-0.09%^[5]), M₁ and M₂,^[4] K₁ through K₃ (where K₃ is synonymous with schisanhenol, and is at 0.06-0.12mg/g fruit dry weight^[8]),^[4] L₁ and L₂,^[4] and Angeloylgomisin Q^[8]
• Gomisin O, Epigomisin O, Angeloylgomisin O, Angeloylisogomisin O, 6-O-Benzoylgomisin O, Isobenzoylgomisin O^[4][8]
• Gomisin H, Tigoylgomisin H, Benzoylgomisin H, and Angeloylgomisin H (the latter at 1.7-5.4mg/g; 0.2-0.5%^[5])^[8][4]
• (Lignans) Pregomisin,^[9] Chamigrenol,^[9] meso-dihydroguaiaretic acid,^[4] and nordihydroguaiaretic acid^[4]
• Micrantherin A^[8]

The above lignans total in the range of 16.09-32.38mg/g dry weight (average of 25mg/g) of the fruits^[5] and it appears that the ones in highest quantities and are likely to be relevant following oral ingestion are the Schisandrins (A-C), Schisandrols (A-B), and Angeloylgomisin H.^[8]

The lignan components are thought to be the major components of schisandra chinensis since they are active by themselves and are at high levels in the fruits; they are structurally unique, and quite different from other lignans such as sesamin

• (Triterpene; schisanartane skeleton) Preschisanartanin^[10]
• (Triterpenes; schisanartane skeleton) Schindilactone A-C^[10] and Schintrilactone A-B (interconvert in solution)^[11]
• (Triterpenes; schisanartane skeleton) Lancifodilactone C,^[10] Henridilactone D,^[10] and Micrandilactone B^[10][12]
• (Triterpene; 18-norschiartane skeleton) Wuweizidilactone A-F^[12]
• α-iso-cubebene^[13] and α-iso-cubebenol;^[14][15] while not precisely quantified, 316mg can be found in the n-hexane extract of 2,500g of fresh berry weight^[13]

The triterpenoids of schisandra chinensis are structurally very unique relative to other terpenoid structures in other plants, although their exact role in the supplementation of this fruit is not exactly known

• Dihydrophaseic acid (as 3-O-β-d-glucopyranoside^[4])
• Organic acids (citrus, tartaric, kinic, malic, fumaric, protocatechuic) at up to 18% of the fruit by weight^[16][17] and thought to explain the tart taste
• Benzyl alcohol (as the glycosides β-d-glucopyranosyl (1→6)-β-d-glucopyranoside and β-d-glucopyranosyl (1→2)-β-d-glucopyranoside^[4])
• Isoscoparin^[4]
• Quercetin (as 3-O-β-l-rhamnopyranosyl(1→6)-β-d-glucopyranoside^[4])
• Melatonin at 96ng/g dry fruit weight^[18]
• Phytosterols such as stigmasterol^[16]
• Vitamin C
• Vitamin E
• Trace elements (Nickel, Copper, Magnesium, Zinc); too low in quantity to be considered bioactive^[16]

The lignans tend to be named related to either the plant (lignans that sound like Shisandra) the Japanese tea Gomishi made from Schisandra berries (Gomisin lignans) or the Chinese name for the ethanolic extract of Schisandra, Wuweizi (some of the nortriterpenoids).

There is a polysaccharide within the fruits of shisandra chinensis temporarily dubbed SCP-IIa which shows immunomodulatory properties.^[19]

The lignans are also found in the shoot and leaves, just in a higher concentration in the fruits.^[16][20] Some of them possess an anti-oxidant capacity.^[21] It has been estimated that maximum value of total lignans reaches 6-11% at flowering in the stem and bark of Schisandra Chinensis, in which 3-8% was either Schisandrin, Schisandrol, or Gomisin A.^[6]

The main bioactives are the 'lignans', and all 30+ lignans seem to be categorized into 5 more precise categories; three bearing a name related to Shisandra and two bearing a name of Gomisin

Russian medicine has used air-dried fruits and 95% ethanol in a 1:6 w/v ratio to create tinctures, which are administered at 20-30 drops daily, and the seeds have also been used in a separate tincture with the same ratios.^[6] Water infusions at a 1:20 w/v ratio with the fruits have been used, and drank at 150mL twice daily, and the fruits themselves or a powdered fruit extract eaten at 1-3g a day separated into two doses of 0.5-1.5g usually before lunch and the evening meal.^[6] Consumption of schisandra chinensis in this manner is done over a period of 20-30 days, with max efficacy peaking at 3-7 days into the period.

The seed extract can be extracted with 95% ethanol at a 1:1 w/v ratio and administered in single (acute) doses of 0.05-0.2mL/kg.^[6]

Ethanolic extracts of schisandra chinensis have also been reported to be used in traditional chinese medicine under the name of Wurenchun.^[22] At times, a wine can be produced (usually in Korea) which is referred to as omija cha, somewhat similar to traditional usage of rubus coreanus (also a wine thought to bear medicinal properties in Korean medicine).

Russian traditional medicine tends to air dry the fruits and then extract them with ethanol to create tinctures to be used over the course of one month, whereas the seeds have also been used but for acute usage

There is a Kampo (Japanese medicine) formulation known as shoseiryuto (小青竜湯) which contains the fruits of shisandra alongside other herbal supplements, and is used for the purpsoes of the common cold and nasal drip as well as allergic rhinitus and pollinosus. The alleged antiallergic immune booster Shoseiryuto contains:

• Pinellia ternata (tuber) at 6g (10.1% yield after decocting)
• Shisandra chinensis (fruits) at 3g (25.2% yield after decocting)
• Ephedra sinicus (source of ephedrine) at 3g (12.9% yield after decocting)
• Licorice at 3g (25.9% yield after decocting)
• Asiasarum sieboldii or heterotropoides (root) at 3g (12.8% yield after decocting)
• Peony root (paeonia genera) at 3g (22.6% yield after decocting)
• Cinnamon (bark) at 3g (6.6% yield after decocting)
• Ginger (processed) at 3g (10.6% yield after decocting)

In where all components totally 24g are boiled in 20-fold as much water for 40-60 minutes or until the water has been half boiled off (in the decoction process), and then the supplements are then removed and the powder used as a supplement. This processing method leaves the yield mentioned above, and the final weight of products is around 18.5% with shisandra chinesis totalling 25.2% of what remains suggesting it plays a major role.^[23]

Shisandra chinensis appears to be a major component of the Kampo formulation Shoseiryuto (小青竜湯) claimed to increase immunity and exert antiallergic properties

Anti-oxidative capacity of Schisandra appears to be related to Hormesis; a phenomena similar to exercise where damage is induced only to subsequently protect and repair to a greater extent. The result of hormesis, described below, tends to be elevation of Heat Shock Proteins and increased expression of anti-oxidative enzymes in mitochondria such as Glutathione Reductase.

It was mechanistically demonstrated that mitochondria get an increase in glutathione status and the cell increases Heat Shock Protein expression secondary to ROS-stress from Schisandrin B interacting with P450; basically, Schisandrin B induces oxidation and the mitochondria responds with a empirically greater anti-oxidant response.^[24] This study was repeated with the same effects in liver cells^[25] and appears to be effective in neurons as well.^[26] It should be noted that the effects seen here extend to other lignans in Schisanda Chinensis (γ-Schisandrol, (+)Schisandrol B and (-)Schisandrol B, Schisandrol C), but the two Schisandrol B isomers appear to be more potent and thus the focus. Efficacy of a molecule is determined by the methylenedioxy group and on the Schisandrol B molecule it appears to be critical in these effects,^[27] dealkylation by CYP enzymes (P450) causes production of up to three metabolites^[28] which ultimately form a pro-oxidative quinone molecule;^[27] this pro-oxidative quinone appears to induce the hormetic and beneficial effects in mitochondria.^[29][30]

Gomisin lignans have also been implicating in interacting with Quinone Reductase in liver cancer cells, which was found to increase activity of the anti-oxidant response element (ARE) of the genome via enhanced Nrf2 translocation.^[31] This enhanced Nrf2 translocation can manifest itself as Heme-Oxygenase 1 induction and confer anti-inflammatory effects as well.^[32]

Schisandra lignans as hormetic anti-oxidants underlies most of the therapeutic, preventative, and (theoretically, not yet demonstrated) life enhancing properties of Schisandra Chinensis in most organ systems Schisandra has been demonstrated to reach (brain, liver, lungs, kidneys, spleen, and heart)

Circulation has been shown to be improved by approximately 9% after consumption of Schisandra at 130mg daily in persons who, although otherwise healthy, had slightly impaired blood flow.^[33]

The direct mechanism may be (in part) due to weak agonism of estrogen receptors,^[34] which increases activity of the NO-cGMP pathway and induces endothelial relaxation. Increase Nitric Oxide circulating after ingestion of about 360mg Schisandra Chinensis extract has been noted in human athletes of both novice and elite caliber.^[35]

Another mechanism has been noted as well, Myosin-Light Chain dephosphorylation, which works in concert with the above estrogenic agonism in rat aortic cells.^[36][37]

Increased blood flow may underlie improvements in physical performance (not too thoroughly demonstrated), and may in part contribute to neural and hepatic benefits.

Direct action on smooth muscle cells and estrogen receptors may mediate improvements in blood flow

In part, subjective improvements in cognition can be attributed to placebo or reductions in stress. Currently, the only human study on cognition related to Schisandra has been conducted under conditions of stress.^[38] Schisandra seems to possess adaptogenic properties, reducing the biochemical markers of perceived stress; this effect has been recorded as reductions in corticosterones, and reductions in stress-induced liver damage.

Another possible mechanisms of improved cognition is pertaining to acetylcholine, whereas consumption of Schisandra Chinensis fruits is associated with inhibiting Acetylcholinesterase (thereby increasing levels of acetylcholine) and simultaneously possessing the capacity to enhance cholinergic signalling in the presence of a ligand.^[39]

Combination of anti-stress effects, sedation, increased acetylcholine transmission, and (theoretically) increased blood flow. One rabbit study from Russia in the 1930s claimed improved glucose utilization in neurons, but aside from not being indexed online this claim has not been reinvestigated

When looking at select lignans (Schisandrin A, Schisandrol A, Schisandrin B) they are absorbed in the small intestines; all three sections but with preferential absorption in the duodenum, with Shisandrin A showing the best relative bioavailability^[40] and Schisandrin C appearing to be poorly absorbed in intestinal cells.^[41] In rats, deoxyschisandrin appears to be one of the most relatively absorbed lignans.^[42] Lignans appear to be fat-soluble, as assessed by Schisandrin (0.425+/-0.002mg/mL solubility in water at 25°C, 7.681+/-0.095mg/mL in oleic acid) and Schisandrin B (0.0346+/-0.004mg/mL water, 3.669+/-0.073mg/mL oleic acid) with slightly better solubility with Isopropyl myristate (IPM).^[22]

Studies looking to enhance bioavailability have noted that Schisandra may be rate-limited in the intestines by it's dissolution rate, as a self-emulsifying drug delivery system of oleic acid at 20%, Polysorbate 20 as surfactant at 65%, and Transcutol P as cosurfactant at 15% (Schisandra at 20% by weight) was shown to enhance bioavailability of Schisandrin and Schisandrin B by 292.2% and 205.8%, respectively.^[22]

Bioavailability of Schisandrin lignans is poor in water, and can be enhanced in the presence of fatty acids or a good solvent. Although most lignans appear to be absorbed, some have a relatively greater absorption than each other and they can increase each other's absorption (See: Nutrient-Nutrient Interactions section)

Delivered as Schisandra Chinensis extract^[42] noted the following serum parameters in rats after oral administration of a 7.5mL/kg (85% ethanolic extract) solution:

• Shisandrin (72.13 mg/kg) had a T_max of 8 hours, a C_max of 1,321ug/mL, an AUC to infinity of 13.59ug/mL/h, a half-life of 5.572 hours, and a clearance rate of 1.327L/h/kg.^[42]
• Shisantherin A (17.96 mg/kg) had a T_max of 6 hours, a C_max of 0.02395ug/mL, an AUC to infinity of 0.2872ug/mL/h, a half-life of 8.850 hours, and a clearance rate of 15.63L/h/kg.^[42]
• Deoxyshisandrin (14.56 mg/kg) had a T_max of 1 hour, a C_max of 0.1576ug/mL, an AUC to infinity of 1.549ug/mL/h, a half-life of 9.707 hours, and a clearance rate of 2.351L/h/kg.^[42] The T_max has been replicated elsewhere.^[43]
• γ-schisandrin (45.92 mg/kg) had a T_max of 8 hours, a C_max of 0.1295ug/mL, an AUC to infinity of 1.728ug/mL/h, a half-life of 12.06 hours, and a clearance rate of 6.643L/h/kg.^[42]
• Shisandrol B (22.54 mg/kg) had a T_max of 2 hours, a C_max of 0.8733ug/mL, an AUC to infinity of 6.346ug/mL/h, a half-life of 9.707 hours, and a clearance rate of 0.8824L/h/kg.^[42]
• Shisandrol C (3.99 mg/kg) had a T_max of 2 hours, a C_max of 0.08414ug/mL, an AUC to infinity of 0.7988ug/mL/h, a half-life of 6.839 hours, and a clearance rate of 1.249L/h/kg.^[42]

As the above study drug was a concentrated ethanolic extract (2g crude drug per mL of aliquot, 7.5mL aliquot per kg bodyweight), the above serum values correlate to an oral intake of 15g/kg Schisandra Chinensis dried fruit extract, which is a very large dose.^[42] thankfully, when looking directly at humans, 15mg of Schisandrin elevated plasma levels to a C_max of 96.1+/-14.1 ng/ml and remained in plasma for up to 8 hours after administration.^[44] Assuming no species differences (unproven assumption), this dose is appromixately 1/8^th what the rat study used assuming a 200lb man, and approximately 1.8^th the C_max; suggesting linearly constant absorption rates.

Other lignans, such as Gomisin A, appear to be well absorbed and reaches a peak serum concentration 15-30 minutes after oral absorption and with a half-life of 70min.^[45] Gomisin A is highly conjugated and metabolized in the blood, however, as 80% of it in serum is bound to proteins and a great deal metabolized.^[45][46]

All tested lignans appear to be absorbed by humans and rats, and their absorption is enhanced with co-consumption of the lignans with each other (as whole fruit extract; see nutrient interactions section) and when consumed with fatty acids or a proper solvent (see previous section on bioavailability) The T_max values spread from 1 hour to 8 hours, supporting a 'long-lasting' notion

Schisandra lignans have been noted in vitro to bind to plasma proteins in accordance with their retention times (most from schisandrin B, least from Schisandrol A out of the five tested) with no interspecies differences ex vivo and ranging from 30-98% binding.^[7]

The lignans that have been tested from schisandra chinensis appear to bind to human albumin (with no significant differences when compared to rat or dog albumin), and thus can be carried to peripheral tissues

Distribution of Schisandrin (the lignan) appears to favor the liver, but has also been detected in the kidneys, lungs, heart, and spleen (quantitied in descending order).^[43]

Preliminary, but it appears to favor the organs that Traditional Chinese Medicine mentions it invigorates or replenishes

Shisandra chinensis fruits (both water and ethanolic extracts) have been noted to activate the Pregnane X Receptor (PXR) at a concentration of 1mg/mL with a potency nonsignificantly less than 10μM rifampicin.^[47] This receptor is known to regulate Phase I enzymes such as CYP3A4^[48][49] and CYP2C9^[50] and is also the target for some well known CYP3A4 inducers such as hyperforin from St. John's Wort^[50] and PXR activation was also noted with some other Kampo herbs such as angelica sinensis and licorice.^[47]

The molecules of shisandra chinensis thought to mediate the above include Schisandrol A (40μM but not 10μM), Schisandrins A and B (EC₅₀ of 1.25μM).^[47]

Shisandra chinensis is known to activate the xenobiotic sensing PXR thought to be due to its lignan components

Perhaps secondary to the activation of PXR, Shisandrins A and B as well as Shisandrol B have been noted to induce the mRNA of CYP3A4 while Schisandrol A was weaker.^[47] Shisandra whole fruit has been tested in vitro in a CYP3A4 inhibitory assay, with 100-1,000µg/mL dose dependently inhibiting CYP3A4 activity (assessed by the 6β-hydroxylation of testosterone) with an IC₅₀ of 123µg/mL.^[23]

Schisandria Chinensis fruit extract is able to inhibit the CYP3A4 enzyme^[51] which metabolizes over 50% of pharmaceuticals; this inhibition may be due to the Lignan components, specifically Schisandrin A and B^[52] and more potently with Gomisin A.^[53]

Shisandra appears to induce the activity of CYP3A4 which is thought to be secondary to PXR activation, and while it appears very low doses of the fruits may not have this effect (due to a high concentration needed paired with a low oral intake) high doses of the fruits or any extract concentrated for the lignans are likely to be more potent

Schisandrin B has been noted to induce the mRNA of CYP3A11 in isolated rat hepatocytes,^[47] and both CYP2C9 as well as CYP2C29 were induced by the overall schisandra chinensis extracts thought to be due to the lignans acting on PXR.^[47]

Other enzymes also mediated by PXR appear to be influenced by the lignans of shisandra

Lignans of this structural class (Dibenzocyclooctadiene) in general tend to be P-glycoprotein inhibitors^[54] and lignans from schisandra chinensis (Schisandrin A being more potent than the other Schisandrins and Schisandrols) have been noted to reverse P-glycoprotein mediated drug efflux in various cancer cells at 25µM associated with reducing the mRNA for MDR1 which encodes for P-glycoprotein.^[55] Gomesin A is also active in cancer cells (20µM)^[56] and this inhibitory effect on P-glycoprotein appears to also influence intestinal cells where Schisandrol A^[57] and Deoxyschisandin^[58] amongst other lignans where it appears to reduce P-glycoprotein activity but not by allosteric modulation but may partially block the active site.^[57] Interestingly some lignans are also subject to P-glycoprotein mediated efflux themselves^[41] and a mixture of lignans appears to have better absorption overall due to this inhibition.

In rats circulating paclitaxel concentrations are increased with isolated Schisandrol B (10-25mg/kg oral intake) with the higher dose reaching a 163% increase in C_max and a 182% increase in AUC.^[59] This has been replicated in otherwise healthy humans where 300mg of the fruits appears to increase the C_max (51%) and AUC (47%) of talinol thought to be due to the P-glycoprotein inhibition.^[60]

The lignans in schisandra chinensis, due to their structure, appear to be inhibitors of P-glycoprotein mediated efflux and thus may increase the absorption of drugs that are subject to this efflux; this may also underlie anti-cancer properties in particular cancer cell lines

In vitro in isolated rat hepatocytes, shisandra chinensis due to the lignan component can actiate the transcription of the efflux protein MRP2 possibly secondary to PXR activation.^[47]

Secondary to the PXR activation mentioned above, the MRP2 efflux protein appears to be increased in activity

When investigated, the Kampo therapy Shoseiryuto (50mg/kg; of which the ethanolic extract of schisandra chinesis was 25.2% of it) failed to significantly alter the pharmacokinetics of nifedipine in rats although it trended to do so.^[23] This is thought to be related to shisandra chinensis since it is known to activate the PXR^[47] which influences CYP2C9 activity,^[50] the enzyme mediating warfarin metabolism.^[61]

Limited in vivo evidence assessing the CYP3A4 inhibitory properties have failed to find a significnat inhibitory effect following oral ingestion of shisandra chinensis, although the dose was low and there was a trend towards inhibiting its activity

Schisandra chinensis water extract at 500mg/kg is able to reduce the pharmacokinetic profile of warfarin injections by reducing the AUC by 29% and the half-life by 11.5% while increasing the clearance rate by 37.3%.^[47]

The fruits of shisandra appear to increase the rate of warfarin efflux from the body, suggesting that it can reduce the overall therapeutic efficacy of warfarin by lowering bodily exposure

In isolated heart cells, it was mechanistically demonstrated that mitochondria get an increase in glutathione status and the cell increases Heat Shock Protein expression secondary to ROS-stress from Schisandrin B interacting with P450; basically, Schisandrin B induces oxidation and the mitochondria responds with a empirically greater anti-oxidant response.^[24] This study was repeated with the same effects in liver cells^[25] and appears to be effective in neurons as well.^[26] It should be noted that the effects seen here extend to other lignans in Schisanda Chinensis (γ-Schisandrol, (+)Schisandrol B and (-)Schisandrol B, Schisandrol C), but the two Schisandrol B isomers appear to be more potent and thus the focus. Efficacy of a molecule is determined by the methylenedioxy group and on the Schisandrol B molecule it appears to be critical in these effects,^[27] dealkylation by CYP enzymes (P450) causes production of up to three metabolites^[28] which ultimately form a pro-oxidative quinone molecule;^[27] this pro-oxidative quinone appears to induce the hormetic and beneficial effects in mitochondria.^[29][30]

Due to these effects, Schisandrin B is being investigated as a hormetic anti-aging molecule.^[3][2] Studies in rats sugges that a low dose Schisandrin B content (0.012% w/w of the diet) can ameliorate the aging process and improve relative functional capacity of the organs that are usually deemed to be a target of Schisandra Chinensis; the brain, heart, kidney, and liver.^[62] There appear to be differing effects in young and old rats^[63] with more pronounced protective effects (induction of heat shock proteins) in younger rats.^[62]

In aged rats, Schisandrin B consumption was shown to increase neural ATP synthesis.^[62] One review^[3] noted that improved energy metabolism beneficially influences sirtuin expression;^[64] Sirtuins have been implicated in longevity theory every since resveratrol was thought to be a direct inducer of them (since proven to be false).

A lignan from Schisandra, Schisandrin B, has been shown in vitro to downregulate a wide-variety of pro-inflammatory cytokines released from microglia such as TNF-a, IL-1β, IL-6, PGE(2) and NO.^[65] These effects were theorized to be downstream from Toll-Like Receptor 4 interacting with its ligands, the proteins MyD88, IRAK-1 and TRAF-6. The demonstrated prevention of this signalling pathway in microglia prevented activation of NF-kB translocation, and may have prevented upregulation of the cytokines that were demonstrated to have been downregulated.^[65]

Schisandrin C (1-20μM) appears to have antiinflammatory effects in activated microglia due to inhibiting NF-kB activation, which was due to the ability of schisandrin C to induce Nrf2 transcription and HO-1 production (via signalling through the PKA, STAT, and MAPK pathways);^[66] Schisandrin C can induce Nrf2 at 10-20μM over 24 hours of incubation to 500-600% of baseline values without the presence of an inflammatory factor.^[66]

A study in rats suggest that one of the lignans from Schisandra, Deoxyschizandrin, was able to increase memory and cognition in mice with excessive beta-amyloid pigmentation; this was hypothesized to be secondary to its anti-oxidative abilities, and suggests Schisandra may help Alzheimer's Disease symptoms.^[67] Schisandrin B also exerts a general protective effect on scopolamine-induced memory impairment.^[68] In this latter study, a preservation of glutathione levels was seen in rats subject to Schisandra.

In isolated brain homogenates, Schisandrin B at 25mg/kg bodyweight (oral administration, dissolved in olive oil, for 7 days) was as effective as Tetrahydroaminoacridine (THA) at 10mg/kg in inhibiting acetylcholinesterase, and was more effective in raising acetylcholine levels in these mice. The IC₅₀ of Scopalamine in inhibiting acetylcholinesterase was approximately 667uM.^[68] These memory preserving effects have also been observed with Schisandrin at 1 and 10mg/kg bodyweight in water extract, a feasible oral dose.^[39]

Schisandrin was also implicated in enhancing M1 receptor (cholinergic) neurotransmission as assessed by oxotermorine-induced tremors, able to enhance the tremoring effects of the drug while not confering any tremors on its own at this dose; oral doses of 1 and 10mg/kg bodyweight water extract were insignificantly different. ^[39] Injections of 175mg/kg Schisandrin do induce convulsions, however.

There is biological basis for Schisandra Chinensis in improving memory and focus related to acetylcholine, although studies are preliminary. The enhancement of cholinergic neurotransmission is particularly intriguing

In accordance with traditional usage of Schisandra as a hypnotic and sedative (and to treat insomnia, historically^[69]), a study in mice found that oral administration of 100-200mg/kg bodyweight Schisandra extract was able to attenuate rises in catecholamines and cortisol associated with restraint stress and increase the amount of anxiolytic behaviours of mice (relative to control).^[69] Schisandra was more effective than Diazepam at normalizing adrenaline and serotonin changes in stress, but not dopamine.^[69] This reduction in activation of the HPA (Hypothalamus-Pituitary-Adrenal) axis seems to extend to exerise, where there is also noted attentuations in cortisol.^[70] In rats subject to the same restraint mentioned previously (a research model for anxiety and stress), it was found that stress was able to increase tumor growth in rats already harboring tumors; 100-200mg/kg oral Schisandra fruit was able to normalize the immune system biomarkers and oxidation in test rats and reduced the amount of hepatic metastatic nodules.^[71] This anti-stress effect has been somewhat replicated in a human study using Schisandra which noted that cognition, accuracy and attention was increased during periods of study by stressed persons using the supplement relative to placebo, but this study was confounded by Siberian Ginseng and Rhodiola Rosea which also share an adaptogenic property.^[38]

Without a prior stress, administration of Schisandra at 25-100mg/kg demonstrated an anxiolytic effect and promoted sedation and sleepfulness in rats.^[72]

Appears to exert sedative and anxiety-reducing effects, in accordance with it's title as an adaptogen that reduces stress

Schisandrin B appears to be an active lignan in protecting the heart tissue from myocardial infarction damage via glutathione (primarily in the cardiac mitochondria^[73]), but only when preloaded suggesting a preventative effect rather than rehabilitative.^[29] An intragastric dose of 1.2mmol/kg Schisandrin B (0.48g/kg) was demonstrated protective in Myocardial reperfusion injury, and while Alpha-Lipoic Acid at the same dose was more protective against LDH leakage Schisandrin B was better able to aid in contractile recovery.^[74] Schisandrin B has been demonstrated to reduce Ca²⁺ permeability of mitochondria after oxidative insult via these protective mechanisms,^[75] and these protective effects may extend to Schisandrin C and γ-Schisandin, although not to Schisandrin A.^[76] Although Schisandrin B is seen as the most potent at this, the (-) isomer is more potent than the (+) isomer.^[77]

This increased glutathione content in cardiac mitochondria appears to be secondary to heat shock protein induction, particular Hsp25 and Hsp70, and an overall hormetic effect in heart cells (H9C2 cardiomyocytes) associated with P450.^[78] Incubation of Schisandrin B at 7.5 and 15uM is able to increase reactive oxygen species by 24% and 32%, respectively, which increased intracellular glutathione levels by 40 and 47%, respectively.^[24] Incubation with P450 inhibitors preventing ROS, and subsequently prevented both glutathione and Heat Shock Protein induction.^[24]

An alternate mechanism that may offer cardioprotection is inhibition of Smad2/3 complex translocation and MAPK activation via inhibiting TGFβ1 signalling in smooth muscle cells.^[79] TGFβ1 signalling was inhibited in a dose-dependent manner with full inhibition at 500ug/mL, and Smad2/3 phosphorylation was halved at 100ug/mL with no further reduction at 500ug/mL, and reduced nuclear translocation of Smad3; this inhibition was secondary to PPM1A activation, which reduces Smad phosphorylation.^[80] These effects were best seen with Schisandrin B, since Gomisin N induced cell death.^[79]

There is biological basis for claims of Schisandra Chinensis fruit extract (some of the lignans) to benefit the heart organ itself, and it appears to induce these benefits by a hormetic (induce a bit of harm, reap a greater amount of benefit) mechanism

A lignan from Shisandra, Gomisin J, has been demonstrated to induce Nitric Oxide Synthase in the rat endothelium in the range of 1-30ug/mL.^[81] Induction of endothelial NOS has been demonstrated previously with Gomisin A^[82][37] Although the mechanism of action of endothelial relaxation is mostly due to Nitric Oxide, Myosin-Light Chain phosphatase may also be implicated.^[36] The pair of mechanisms confers a direct (MLC phosphatase) and indirect (eNOS) mechanism of relaxation, and may confer protection from heart diseases associated with blood vessels.

The relaxing effect of low doses seems to be inhibited by estrogen-receptor antagonists, suggesting that this mechanism (eNOS induction) is secondary to estrogen receptor activation.^[83] Schisandra has been demonstrated previously to activate estrogen receptors independent of estrogen.^[34]

Only one human study has been performed on this topic, with the hypothesis that improvements in liver function was secondary to increased blood circulation; it was found that 130mg Schisandra (confounded with 5mg Sesamin) daily was able to improve blood circulation by 9% in 1 week, and held roughly static during the second week of measurement at 9.7%.^[33]

Schisandra Chinensis extract appears to be able to increase blood flow and nitric oxide bioavailability, which can compliment the previously mentioned cardio-protective effects

Improvements in blood flow may also apply to the penis.^[84] Lignans were able to induce relaxation in pre-contracted (via phenylephedrine) cells by 8.0% at 0.1mg/mL and by 98.6% at 2mg/mL, suggesting an increasing dose-efficacy.^[84] The mechanisms appeared to be due to be inhibiting the influx of calcium ions, as there were no beneficial effects noted with Ca2+ preincubation.^[84]

One human study lasting 2 weeks and using 130mg Schisandra (with 5mg Sesamin) found no changes in triglycerides, HDL cholesterol, or LDL cholesterol.^[33]

Higher doses of Schisandra, especially isolated Schisandrin B, appear to elevate triglycerides; insofar that 0.5-0.8g/kg bodyweight Schisandrin B may be an experimental procedure to induce dose-dependent hypertriglyceridemia.^[85] However, Schisandrin B is able to reduce triglycerides in the liver and reduce pathology of Non-alcoholic fatty liver disease.^[86]

One fraction of schisandra chinensis (containing Schizandrin, Gomisin A, and Angeloylgomisin H at 2.8+/-0.4mg/g, 1.7+/-0.3mg/g and 0.6+/-0.1mg/g) appears to stimulate PPARγ transcriptional activity in 3T3-L1 fibroblastic cells at the concentration of 500ng/mL with a potency slightly lesser than 200-2,000nM rosiglitazone.^[87] Elsewhere (in HepG2 cells) it appears that these results have been replicated with two of the main lignans (Schisandrin A and C^[88]) whereas Gomisin N by itself exceeded rosiglitazone in potency.^[88]

Lignans from shisandra chinensis appear to be able to activate PPARγ transcriptional activity

No ethanolic fractions from schisandra chinensis appear to promote insulin secretion from isolated Min6 cells.^[87]

Limited evidence does not support the role of shisandra chinensis lignans as an insulinotrophic agent

In streptozotocin induced diabetic rats, shisandra chinensis supplementation at 5,000mg/kg was unable to significantly influence fasting glucose over the course of seven weeks.^[89]

In type II diabetic rats with reduced pancreatic capacities (90% pancreatectomy), oral intake of 200mg/kg ethanolic lignan extracts for eight weeks appears to be able to improve insulin sensitivity with a potency comparable to 20mg/kg rosiglitazone.^[87] This has been ntoed elsewhere with the compound formulation Huang-Lian-Jie-Du-Tang (normally consisting of Phellodendron Amurense, gardenia jasminoides, and rhizoma coptidis) where shisandra chinensis was added.^[90]

A review of Russian Literature^[6] cites three trials by the researcher Lupandin (in the years of 1965, 1981, 1986) that note increased work capacity in swimming mice, extending time to exhaustion from 71+/-4min to 120+/-11min, a 69% increase after a single dose of 0.05mL/kg 1:1 Schizandra:ethanol extract. Chronic administration over 2-4 weeks with 0.5mL/kg showed increased performance ranging from 39-67%, and this increased performance tended to appear 2-5 hours after administration; the original texts by Lupandin (and Lapadev, 1981) could not be located online.

One study on static physical loading noted that 1-10mg/kg total lignans of Schisandra (not the fruit extract per se) found that there was increased resistance to fatigue;^[6] like the above studies, the original text (Lupindin, 1989) could not be located.

Beyond the above Russian studies, two recent studies from China^[91][70] suggest that Fructus Chinensis prior to exercise can reduce changes in corticosterone and glucose that occur during exercise and offer a protective effect on adrenal glands, without influencing testosterone or luteinizing hormone.

Inherent problems with copious amounts of Russian Research 50 years ago are that they tend to not be indexed online, and without full text access to said Review that collects them it is hard to prove they even exist

When pre-loaded, Schizandra (2 capsules each of 94.1mg, giving 3.1mg Shizandrin and y-Shizandrin) is able to increase cortisol levels in beginner trainers to levels that would normally be reached by exercise; this effect is not seen in experienced athletes (national level) and both populations experience a decline in post-exercise cortisol relative to placebo.^[35]

Nitric Oxide (NO) levels are increased prior to exercise in both beginner and trained athletes.^[35] In neither cortisol or NO were the effects seen with Shizandra amplified with exercise, instead spiking both biomarkers to exercise levels prior to exercise.^[35] The authors claimed this was due to a preparatory effect.

One study. It did show benefit and was nice in how it examined both elite athletes and beginners, but it was conducted in 1999 and no studies since then have attempted to replicate it

In mice subject to a thermal chamber (research method of overheating), Schisandra fruit extract at 0.2mL/kg (1:1 ethanolic extract) was able to enhance survival; rats in the control group died at an internal body temperature of 42.5◦C and Schisandra at 43.8◦C.^[6]

In mice subject to a cold stress (10 minute swim in 12◦C water), subsequent administration of 0.2mL/kg Schisandra fruit extract was able to prolong exercise to exhaustion when swimming in normal water; higher doses in the 1-10mg/kg range of pure lignans had no effect and 100mg/kg exerted a negative influence (Lupandin 1981; Lebedev 1966).^[6]

In general, research from Russia past suggests Schisandra Fruit extract is able to exert an adaptogenic effect and reduce stress from abnormal temperatures

α-Iso-cubebene is able to promote calcium influx from the extracellular medium in neutrophils extracted from volunteers with maximal activity at 200μg/mL by a thapsigargin sensitive pathway, and is not inhibited when PKC or calcium channels are blocked.^[15] Secondary to calcium influx, there was an increase in the secretion of CXCL8 (near 20-fold after 8-16 hours)^[15] which is a chemoattractant for leuckocytes expressing the CXCR1 and CXCR2 receptors^[92] and neutrophil activating cytokine.^[93]

Schisandra Chinensis has been shown, in vitro, to act as a weak estrogen agonist and thus a phtyoestrogen, and can do so at low concentrations of 10ug/mL.^[34]

Shisandra was demonstrated, in vitro, to not influence the androgen receptor in transfected cell lines expressing the androgen receptor.^[34]

High dose Schisandrin B has been demonstrated to decrease cyclosporin-induced cytotoxicity at an oral gavage dose of 20mg/kg bodyweight in vivo and in vitro in a HK-2 cell line at 2.5-10µM concentrations.^[94] Serum parameters reflective of renal damage (MDA, creatinine, BUN) were reduced and histopathological changes attenuated.^[94] Gentamicin toxicity has also been ameliorated damage at oral doses of 1-10mg/kg bodyweight,^[95] and protection has also been demonstrated against mercucic chloride with 10mg/kg bodyweight Schisandrin B, but the mechanism appears to vary in vivo and in vitro.^[96]

Higher doses (5g/kg) have been demonstrated to decrease urinary albumin in type 1 diabetic animals.^[89] Secondary to reduced albumineria (which encourages podocyte damage^[97]) podocyte damage in these animals was reduced.^[89]

A pleiotropic protective effect of Schisandra on the kidneys appears to exist, via both anti-inflammatory mechanisms (inhibition of NF-kB) or encouraging mitochondrial integrity via Schisandrin B; that being said, the oral doses used in the above rat studies is very high and quite impractical for preventative medicine

Schisandra chinensis, in vitro and in vivo, was able to dose-dependently attenuate lung inflammation in mice insulted with lipopolysaccharide when consumed at 10, 50, or 100mg/kg daily.^[98]

Schisandra Chinensis has traditionally been known as a liver 'tonic' in Traditional Chinese medicine, and is present in higher concentrations in the liver relative to the serum and other organs.^[43] In Western Herbal Medicine, it holds a spot in hepatoprotection treatment, used in acute or chronic liver disease and poor liver function and its usage in this regard dates back to the 1970s.^[99][100] Interestingly, two pharmaceutical liver therapies have been synthesized using Schisandrin C as a model; Diphenyl Dimethyl Bicarboxylate (DDB)^[101] and Bicyclol.^[102]

A study delineating how Schisandra affects the liver practically found that both the anti-oxidative protection (mediated via glutathione induction) and anxiolytic effects of reducing corticosterone were crucial (as psychological stress may adversely affect liver function^[103]).^[99] Furthermore, Schisandra offers a protective effect on hepatic (liver) tumor cells that are responsive to stress.^[71] On the anti-oxidant side of things, induction of glutathione (S-transferase and reductase) and buffering anti-oxidant status prior to chemical insult has been demonstrated to protect against aflatoxin,^[104] cadmium,^[104] Hepatitis C,^[105] and carbon tetrachloride.^[106] It is said to confer a protective effect that is not specific for a toxin, but instead general.^[104]

In regards to liver enzymes; Schisandra lignans can reduce a stress-induced increase of ALT from 96.7±6.3IU/L to 29.70-34.76IU/L, with 100mg/kg being more effective than 200mg/kg; the control group in this study had ALT levels at 17.5 ± 4.7IU/L.^[99] These benefits have been noted in humans with 260mg Schisandra extract plus 10mg Sesamin daily, and alongside the reductions in liver enzymes (ALT, AST) the increase in anti-oxidant enzymes (glutathione, reductase) as well as a reduction in fatty liver and inflammatory markers was seen; no significant influences were noted on bilirubin.^[107] A study on blood flow in humans using half the dose of the previous study found increased blood circulation with no influence on liver enzymes; these humans were healthy, so either the dose or prior disease state may account for the discrepancy.^[33]

Appears to offer both a preventative and rehabilitative liver protection effect, which may be due to a combination of factors (anxiety and stress reduction lessens the adverse effects of stress on the liver, direct protection via anti-oxidant enzymes, increased general blood circulation). Human studies are limited, so conclusions are preliminary despite promising

Schisandra chinensis has demonstrated antiangiogenetic properties in preliminary testing (10µg/mL in quail eggs) but direct docking to VEGF receptors was not tested.^[108]

In isolated hepatocarcinoma cells, α-Iso-cubebenol (320µM) has been noted to cause apoptosis via a p53 dependent mechanism and reduce overall cell viability to less than 20% after 24 hours of incubation, although it seemed that 40-160µM failed to exert any influence at any time and the influence on p53 was concentration dependent and did not correlated with apoptosis.^[14]

A separate species of Schizandra (Schisandra Nigra) has been found to promote hair growth in mice.^[109] This study applied a 50% ethanolic extract to the back of mice (20mcg/mL, 0.2mL application for 15 days) as well as in vitro and noted a prolongation of the Anagen phase of hair (an observation similar to that of minoxidil), though to be secondary to a reduction of TGF-β2 which induces catagen and suppresses Anagen.^[109] Whether these effects extend to Schizandra chinensis are unknown.

Adapt-232 is a patented blend of Rhodiola Rosea, Siberian ginseng (Eleutherococcus Senticoccus), and Schizandria Chinensis. This blend has been used in clinical trials before, on cognitive function under stress^[38] ultraweak biophoton emission,^[110] and as an adjunct therapy during pneumonia.^[111] All three herbs are considered adaptogens.^[112]

In research animals, Adapt-232 has been implicated in increasing physical endurance and time to exhaustion in mice^[113] and in increasing secretion of neuropeptide Y and Hsp72 in isolated cell cultures.^[114]

Rhodiola Rosea is a 2.8:1 concentration with 70% ethanolic extraction, Siberian Ginseng at 10.5:1 concentration and 70% ethanolic extraction, and Shizandria at 1.2:1 concentration with 95% ethanolic extraction.^[38] This gives a by weight standardization of 0.5% rosavin, 0.32% rhodioloside, and 0.05% tyrosol from Rhodiola; 0.37% schizandrin and 0.24% γ-schizandrin from Schizandria, and 0.15% eleutherosides B and E per 450mg capsule, which delivers 270mg of total bioactive compounds (the latter value is where the percentages are in reference to).^[38]

A combination of adaptogens that, although have not been shown to be synergistic, have been used alongside each other with good results

The lignans may be synergistic with each other in regards to absorption, as isolated deoxyschisandrin (at 14.56mg/kg bodyweight) confers a C_max of 0.08023ug/mL yet the same dose in a solution of lignans from Schisandra confers a C_max of 0.1576ug/mL (+96%); AUC to infinity is increased in the blend by 457%, and half-life extended by 42% with no influence on T_max at 1 hour.^[42] This study on deoxyshisandrin has been replicated^[115] and a study was conducted investigating the lignan Shisandrin and found similar results, in where the bioavailability and half-life of Schisandrin was increased almost two-fold at the same dose when consumed via Schisandra Chinensis fruit extract.^[116]

A possible mechanisms is due to less intestinal efflux, as many lignans inhibit P-glycoprotein^[54] (a protein in cells and the intestines that send molecules back out into the intestinal lumen or out of a cell) yet some lignans are actually subject to this protein.^[41] Consumption of the P-glycoprotein substrate with the inhibitors (both lignans) may decrease efflux and inadvertently increase bioavailability.

Combinations of lignans may be better absorbed than isolated lignans, thus a supplement using the whole fruit powder is likely to be more effective than taking a supplement with an isolated lignan

Sheng-Mai-San is a herbal combination in Traditional Chinese medicine consisting of Schisandra Chinensis Fruit, Radix Panax ginseng, and Radix Ophiopogon japonicus in a ratio of 3:2:6 by weight; aqueous extract. The combination is touted to treat heart diseases.^[117]

And it has been demonstrated that the combination of herbs results in better bioavailability of Schisandrin (a lignan used as biomarker) than does a basic aqueous extract of Schisandra fruit delivering the same about of Schisandrin.^[116] Whereas isolated Shisandrin at 5mg/kg delivered an AUC of 31766.4+/-7551.1ug/mL, the AUC from Schisandra was 70209.1+/-29155.0ug/mL and from the Sheng-Mai-San concoction 116697.4+/-35816.4ug/mL.^[116] This is a 121% enhancement of average AUC using the whole plant, and a 267% enhancement of average AUC using the three herbs.^[116]

Similar to the Dang-Gui Buxue Tang concotion of Angelicae Sinensis and Astragalus membranaceus, it appears that the historical combination of herbs has biological basis

Ninjin-Yoei-To, with the slightly easier to remember name of TJ-108 and equally complex name of Ren-Shen-Yang-Rong-Tang, is a herbal concoction from Kampo (Japanese medicine) that contains Schisandra Chinensis as the primary active ingredient (in regards to liver protection^[105]). Compounds in this concoction include Polygala Root, Citrus Unshiu Peel (which, alongside Schisandra, are unique to Ninjin-Yoei-To) as well as ginseng, cinnamon bark, Japanese angelica root, Astragalus membranaceus root, peony root, rehmannia root, atractylodes rhizome, poria sclerotium, and glycyrrhiza.^[118] The combination of all herbs as powdered extracts is taken at 15g daily for humans.

This particular blend appears to be protective of the liver. In rats, it has been demonstrated to protect from hepatitis C^[105] and various forms of toxicity to the liver,^[119][120] and other organs like the lung^[121] and brain.^[122][123]

The more interesting studies attributed to Ninjin-Yoei-To are recovery of lost scent in rats after 28 days supplementation.^[124]

The combination of herbs in Ninjin-Yoei-To exists, and should be noted; that being said, it is incredibly confounded and hard to delineate which bioactives do what and to what degree

There is a related mixture of herbs simply called Ninjin-To by some studies, which retains Ginseng radix, Glycyrrhizae radix, Atractylodis rhizome and adds in Zingiberis siccatum rhizoma; this concoction does not include Schisandra Chinensis.

Sesamin is a lignan from sesame seeds, which appears to exert hepatoprotective properties in rats.^[125] The combination has been used in two human studies, one on liver function^[107] and another on blood viscosity and circulation.^[33] Synergy between these two supplements has not yet been demonstrated.

The first reported oral toxicity of Schisandra Chinensis seed powder has been reported to be 3.6g/kg in mice, whereas the ethanolic extract of the fruit was was non-toxic in dogs.^[6] Schizandrin (isolated lignan) was able to induce convulsions when injected at 175mg/kg bodyweight in mice and paresis at double that dose; however, no deaths occurred.