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Ginseng (Panax ginseng)


Ginseng (Panax ginseng) Image
Synonyms / Common Names / Related Terms
Ginseng (American ginseng, Asian ginseng, Chinese ginseng, Korean red ginseng, Panax ginseng:Panaxspp., includingP. ginsengC.C. Meyer andP. quinquefoliusL., excludingEleutherococcus senticosus), Acetylenic alcohol, acidic polysaccharides, acupuncture-moxibustion, aglycones, Allheilkraut, American ginseng (AG), American wild ginseng, Araliaceae (family), Asian ginseng, Asiatic ginseng, chikusetsaponin-L8, chikusetsu ginseng, chosen ninjin, CPPQ (coarse polysaccharide from Panax quinquefolius), CVT-E002, dae-jo-hwan (DJW), dwarf ginseng, five-fingers, five-leaf ginseng, G115®, ginsan, ginsenan PA (phagocytosis-activating polysaccharide), ginseng acidic polysaccharide, ginseng radix, ginseng saponins, ginseng tetrapeptide, Ginsengwurzel (German), ginsenoside, ginsenosides (Rb1, Rb2, Rc, Rd, Re, Rf, and Rg1), ginsenosides compound (shen-fu), GTTC, hakusan, hakushan, higeninjin, hongshen, hua qi shen, hungseng, hungsheng, hunseng, insam, jenseng, jenshen, jinpi, kao-li-seng, Korean ginseng, Korean red ginseng (KRG), Kraftwurzel (German), man root, memory enhancer, minjin, nhan sam, ninjin, ninzin, niuhan, North American ginseng, notoginsenoside, oleanolic acid, Oriental ginseng, otane ninjin, panax de chine, Panax ginseng, Panax ginseng C.A Meyer, Panax notoginseng, Panax, psuedoginseng, Panax quinquefolium (common misspelling), Panax spp., Panax trifolius L., Panax vietamensis (Vietnamese Ginseng), panaxadial, panaxans, panaxatriol, panaxydol, panaxynol, panaxytriol, pannag, polyacetylenic compounds, poly-furanosyl-pyranosyl-saccharides, protopanaxadiol ginsenosides, quinqueginsin, racine de ginseng, red ginseng, renshen, sang, sanchi ginseng, san-pi, schinsent, sei yang sam, seng, shanshen, shen-fu, shenghaishen, shenlu, shen-sai-seng, shenshaishanshen, siyojin, stress-buster, sun ginseng, t'ang-sne, tartar root, tienchi ginseng, to-kai-san, triterpenoids, true ginseng, tyosenninzin, vanillic acid, Vietnamese ginseng, Western ginseng, Western sea ginseng, white ginseng, wild ginseng, woodsgrown (wild-stimulated) ginseng root, xi shen, xi yang shen, yakuyo ninjin, yakuyo ninzin, yang shen, yeh-shan-seng, yuan-seng, yuansheng, zhuzishen.
Siberian ginseng (Eleutherococcus senticosus) synonyms: Acanthopanax senticosus, ci wu jia, ciwujia, devil's bush, devil's shrub, eleuthera, eleuthero, eleuthero ginseng, eleutherococ, eleutherococci radix, Eleutherococcus, Eleutherococcus senticosus, phytoestrogen, shigoka, touch-me-not, wild pepper, wu-jia, wu-jia-pi, ussuri, ussurian thorny pepperbush.
American ginseng (Panax quinquefolius L.) synonyms: American ginseng, amerikan ginseng, amerikanischer Ginseng (German), amerikkalainen ginseng, Anchi ginseng, Aralia quinquefolia Decne. & Planch (botanical synonym), Araliaceae (family), Canadian ginseng, CVT-E 002, five fingers, five leafed ginseng, garantoquen, ginseng, ginseng d'Amérique (French), ginsenosides poly-furanosyl-pyranosyl-saccharides, man-root, man's health, North American ginseng, Occidental ginseng, Ontario ginseng, Panax quincefolium, Panax, quinquefolium, red berry, redberry, sang, shang (TCM), tartar root, western ginseng, wild American ginseng, Wisconsin ginseng, xi yang shen (TCM, Chinese).
Panax ginseng synonyms: Aralia (botanical synonym), Aralia ginseng Mey., Araliaceae (family), Asian ginseng, Asiatic ginseng, Chinese ginseng, G115®, Gincosan, Ginsai®, ginseng asiatique, ginseng radix, ginseng root, ginsengjuuri, guigai, Japanese ginseng, jintsam, Korean ginseng, Korean Panax ginseng, Korean red, Korean red ginseng, kuhuang shenmai injection (KHSM), ninjin, Oriental ginseng, Panax, Panax ginseng, Panax ginseng C. Meyer, Panax schinseng, Panax schinseng Nees, Panax spp., radix ginseng rubra, red ginseng, ren shen (TCM), renshen (TCM), Renxian, sang, schinsent, seng, shen, shengmai, shengmai chenggu capsule, shengmai injection (SI), shengmai san (SMS), shengmai-san, shengmaisan, shengmaiyin, shenmai, shenmai huoxue decoction (SMHXD), shenmai injection (SMI), white ginseng.
Note: This review is focused on Panax ginseng species. Avoid confusing with Eleutherococcus senticosus, which is also known as Siberian ginseng. In Russia, Siberian ginseng was promoted as a cheaper alternative to ginseng as it was believed to have identical benefits. However, it is void of the ginsenosides contained in Panax spp. Other species may be referred to as ginseng as well, but they are from either a different family or genus; examples include Eleutherococcus senticosus (Siberian ginseng), Pseudostellaria heterophylla (prince ginseng), Angelica sinensis (female ginseng, or dong quai), Withania somnifera (Indian ginseng or ashwagandha), Pfaffia paniculata (Brazilian ginseng), Lepidium meyenii (Peruvian ginseng or maca), Gynostemma pentaphyllum (southern ginseng or jiaogulan). Siberian ginseng is not covered in this review.

Bioactive products found in Panax ginseng

Mechanism of Action

Pharmacology:

  • Constituents: The major active components of ginseng are a diverse group of steroidal saponins, labeled ginsenosides125,126,127, the mechanisms of which are still largely unknown. Ginsenosides are thought to be adaptogenic and are transformed into pharmacologically active substances (compound K or M4) by intestinal microorganisms.128 Compound K is derived from protopanaxadiol ginsenosides, whereas M4 is derived from protopanaxatriol ginsenosides. Recent reports show that ginsenosides act as pro-drugs for these metabolites and that the ginsenoside Rg2 regulates human 5-hydroxytryptamine3A receptor channel activity.129 Every part of the plant has pharmacological action. However, the root is most commonly used and has higher ginsenoside content.130 Generally, the saponin content is higher in Panax notoginseng and Panax quinquefolius than in Panax ginseng.131 However, there is controversy in this area as some believe that Panax ginseng has a higher saponin content, which is why it is considered stronger than American ginseng. Oriental red ginseng was found to have a low concentration of ginsenosides in one study.79 Methylxanthines (caffeine, theophylline, theobromin, and others) were extracted from a commercial sample of ginseng supplements in one study.132
  • Ginseng components include 20(S)-Ginsenoside Rg3, acetylenic alcohol, aglycones, alpha-maltosyl-beta-D-fructofuranoside, aluminum, antioxidants, calcium, chikusetsaponin-L8, citral, cobalt, copper, dammarane-type tetracyclic triterpenoid saponins, essential amino acids (especially arginine), fatty acids, ginsenan PA, ginseng acidic polysaccharide, ginsenosides (e.g., F1, F2, F3, R0, Ra1, Ra2, Rb1, Rb2, Rb3, Rc, Rd, Rd2, Re, Rf, Rg1, Rg2, Rg3, Rh1, Rh2, Rh3, and Rs4), notoginsenoside-Fe, ginsenoside-Ia, ginsenoside-Ra1, ginsenoside-Re, ginsenoside-Rg2 (20R), ginsenoside-Rh1 (20R), ginsenoside-Rh1 (20S), ginsenoside-Rs3, iron, limonene, manganese, magnesium, molybdenum, notoginsenoside-R4, oleanolic acid, panaxadial, panaxans, panaxatriol, panaxosides, panaxydol, panaxytriol, peptidoglycans, phosphorus, polyacetylenes, polyacetylenic compounds, poly-furanosyl-pyranosyl-saccharides, polysaccharides, potassium, protopanaxatriol, protopanaxadiol ginsenosides, quinqueginsin, saponins, sodium, terpineol, triterpenoids, vanadium, vitamins (especially ascorbic acid and B vitamins), volatile oil (b-elemene, panaxydol, panaxytriol, falcarinol, and falcarintriol), and zinc.49,14,133,134,135,136,137,138,139
  • In various chemical analyses, shenmai has been found to contain up to 39 ginsenosides as well as seven ophioponins.16,17
  • Panax ginseng: Panax ginseng has much higher amounts of Rg1 than American ginseng, which has more Rb1. Rg1 and Rb1 are thought to have opposing pharmacological roles. Rg1 is thought to be a slight central nervous system stimulant (activates brain activity), hypertensive, anti-fatigue agent, anabolic (stimulates deoxyribonucleic acid (DNA), protein, and lipid synthesis), and mental acuity and intellectual performance enhancer.
  • American ginseng (Panax quinquefolius): This herb's constituents include poly-furanosyl-pyranosyl-saccharides.52 American ginseng typically has higher levels of ginsenoside Rb1 and no ginsenoside Rf. Ginsenoside Rb1 is believed to limit or prevent the growth of new blood vessels, depress the central nervous system (anticonvulsant, analgesic, tranquilizing), and have hypotensive, anti-stress (protecting gastrointestinal tract from ulcers), antipsychotic (inhibition of conditioned avoidance response), weak anti-inflammatory, and antipyretic (fever-reducing) activity, as well as facilitate small intestine motility, and increase liver cholesterol synthesis. American ginseng is thought to be higher in acidic, or malonyl, ginsenosides.140 Malonyl and neutral ginsenosides are reduced when drying temperature is raised from 32-44°C.141
  • Alcohol clearance effects: Ginseng improves alcohol clearance in humans by 30-50%, likely by enhancing metabolic activity of alcohol dehydrogenase.111
  • Analgesic effects: In a two-phase formalin pain test, 23 ICR mice fed orally with polyfuranosyl-pyranosyl-saccharides extracted from American ginseng root (Cold-fX®) for four days spent significantly less time in licking and biting their injured paws in the second phase of pain than the water-fed placebo mice.39 There was no difference in the first phase of pain between the groups. In animal studies, ginseng total saponins antagonized morphine-induced analgesia, an action that also inhibits the development of analgesic tolerance to and physical dependence on morphine.104 In mice, ginseng has been shown to inhibit tolerance formation to opioids and psychostimulants.115,44 Ginsenosides administered intrathecally, intraperitoneally, or intracerebroventricularly have also produced analgesia against capsaicin-induced pain in mice.142
  • Angiogenic effects: In in vivo and in vitro studies, Rg1 and Re, compounds isolated from Panax ginseng, significantly increased human umbilical vein endothelial cell proliferation, migration, formation of a capillary-like network of cells, and increased neocapillary density.143,33 In addition, shenmai may also have angiogenic effects, as low-dose shengmai chenggu capsule-treated rabbit serum significantly stimulated vascular endothelial growth factor (VEGF) secretion of the ECV304 human umbilical cord cells in vitro .144 However, Panax ginseng is traditionally used to treat cancer and is thought to have antiangiogenic effects.31
  • Angiotensin-converting enzyme (ACE) effects: In an in vitro study, Panax ginseng extract inhibited angiotensin-converting enzyme (ACE) activity, but did not affect nitric oxide (NO) production.110
  • Antiaging effects: The combination of Panax ginseng C.A. Meyer and du-zhong leaf stimulates collagen synthesis and prevents the decrease in protein metabolism that occurs with aging.145
  • Antiallergic effects: In laboratory studies, ginsenoside Rh2 has exhibited antiallergic activity originating from cell membrane-stabilizing activity and anti-inflammatory activity by the inhibition of nitric oxide (NO) and PGE2 production.102
  • Antiasthmatic effects: An in vitro study indicates that ginsenoside induces relaxation of human bronchial smooth muscle via stimulation of nitric oxide (NO) generation, predominantly from airway epithelium and cyclic guanosine monophosphate (GMP) synthesis.13
  • Anti-cancer effects: Antineoplastic effects of ginseng have been found in vitro, in vivo146, 147,148,149,30,150,151,152,153,154,155, and in epidemiological studies29. The nature of this mechanism is poorly understood, but ginsenosides Rg3, Rg5, and Rh2 are active components that may prevent cancer either singularly or synergistically.156
  • In epidemiological study, ginseng consumers had a decreased risk for most cancers compared with nonconsumers.157,158,159,160 Preliminary evidence suggests that patients treated with ginseng plus chemotherapy showed symptomatic improvements in their general condition (fewer symptoms, improved appetite, weight gain), but also improvements in various clinical parameters (hemoglobin, immunoglobulin, and lymphocyte levels).161 This has not been confirmed with a primary reference.
  • Saponins, polysaccharides, and polyacetylenes are likely to contribute and possibly to act in synergy on neoplastic processes162 and may act as immunomodulators163. Constituents of ginseng have been shown to inhibit the production of tumor necrosis factor in mouse skin36, inhibit the growth and proliferation of cancer cells in animal models 98, inhibit cell proliferation, induce differentiation, and stimulate c-fos expression, intracellular cAMP, p21 and p53 expression, mitomycin C accumulation, caspase-1 activation, caspase-3 activation, Bax upregulation, and interferon levels, and reduce levels of cyclin D protein, and activity of cyclin/Cdk complex kinase activity, phosphorylation of pRb, and E2F release, in vitro164,9,114. Another laboratory study indicates that (20S)Rg3 prevents endothelial cell apoptosis via Akt-dependent inhibition of the mitochondrial apoptotic signaling pathway.32 Other tumor cell processes may also be interfered with by ginseng constituents or their intestinal bacteria metabolites.99,165
  • Panax quinquefolius L. was found to synergistically inhibit cancer cell growth when used in combination with breast cancer therapeutic agents (cytoxan, doxorubicin, fluorouracil, methotrexate).166 Triol saponins in combination with polysaccharides from Korean red ginseng exhibit a protective effect on the formation and growth of tumors in mice.167
  • Cell line study of a related species showed that Panax japonicus, which contains saponins (chikusetsusaponins IV, IVa, V, polysciasaponin P5), may relieve cutaneous symptoms caused by excessive apoptotic cell death in the skin through the Fas/FasL pathway.168
  • Shengmai injection has also shown anti-tumor effects in mice.169 The inhibition mechanism might be related to IL-2 receptor levels.170
  • The role of cancer-preventative effects of ginseng have been discussed in various reviews.171,162
  • Antiemetic effects: The results of an in vitro study indicate that ginseng saponins, especially the panaxatriol saponin fraction, have substantial inhibitory effects on the recombinant serotonin type 3A receptor, suggesting that some specific ginsenosides might have an antagonistic action against serotonin type 3A receptor related to nausea and vomiting.12 These antiemetic results are supported by an animal study using Korean red ginseng total extract.28
  • Anti-inflammatory effects: Panax ginseng may reduce muscle injury and inflammation following exercise in humans, as demonstrated by reduced levels of creatine kinase, beta-glucuronidase, and glucose-6-phosphate dehydrogenase (G6PDH) following oral Panax ginseng administration.172 In a clinical trial of patients with obstructive jaundice, postoperative Salvia miltiorrhiza and shengmai decreased the postoperative levels of plasma LPs, ET, TNF-alpha, IL-6 and IL-8, and inhibited inflammatory mediator and improved blood dynamics.42 Administration of shenmai injection also significantly reduced the expression of TNF-alpha mRNA in peritoneal macrophages.173
  • Antimicrobial effects: In an animal study, mice treated with ginseng before a bacterial challenge of Staphylococcus aureus were protected from sepsis, possibly due to early suppression of acute inflammatory responses and later enhancement of macrophage activity.174 Juzen-taiho-to, a Japanese traditional medicine containing ginseng radix, enhanced the anti-Candida activity of macrophages in Candida albicans infected mice.175 Belogortseva et al. found polysaccharide fractions from the root of Panax ginseng to inhibit Helicobacter pylori hemagglutination.176 Patients treated with ginseng exhibited a significant improvement in clearance of Pseudomonas aeruginosa from the lungs (p<0.04), lower lung abscess incidence (p<0.01), and lower mast cell numbers in the lung foci (p<0.005).34
  • Antioxidant effects: Panax ginseng and Panax quinquefolius have antioxidant activity.177,19 This is thought to be due to ginsenoside content178 and saponins, which can decrease oxidation of low density lipoprotein in vitro122, 179. In addition, Panax ginseng extracts have antioxidant activity in vitro in brain tissue180, and its properties may be enhanced by using a heat treatment on the ginseng36. Benzoic acid derivatives, salicylic acid, and vanillic acid also showed antioxidant activity in assays.181 Not surprisingly, shenmai (Panax ginseng, Schizandra fruit, Ophiopogon) has also shown antioxidant activity in vitro, in rats, and in heart attack patients.46, 182 Lee et al. found a reduction of oxidative deoxyribonucleic acid (DNA) damage and protein oxidation in smokers who were supplemented with ginseng183, the compounds that mediate such effects remains unclear.
  • Antiplatelet aggregation effects: Ginseng acts as an antagonist to platelet activating factor84 and dose-dependently to thrombin87, which may be due primarily to ginsenoside Rg17 or panaxynol89. Ginseng inhibits platelet aggregation regulation of cGMP and thromboxane A2 levels. The platelet aggregation inhibiting action of ginseng may mediate its therapeutic effect in diabetic nephropathy.81 In addition to inhibiting aggregation of rabbit platelets, panaxynol, a compound found in Panax ginseng, inhibits the release reaction and thromboxane formation, while ginsenosides R0, Rg1, and Rg2 only suppress the release reaction.88 Furthermore, dietary supplementation of rats with the lipophilic fraction from Panax ginseng has an antithrombotic effect.86
  • In vitro, notoginsenoside R1 can induce a profibrinolytic response85 and R0 and Rg1 decrease the creation of fibrin and stimulate fibrin antagonistic enzymes90.
  • On the other hand, in a hemorrhagic rat model, Panax notoginseng (powder and total saponin extract) applied topically exhibited a hemostatic effect.82 The Korean herbal combination medicine dae-jo-hwan, which contains Panax ginseng Meyer, showed similar anti-thrombotic characteristics.11 Panax quinquefolius also exhibits antithrombotic activity in vitro, which may be due to nitric oxide (NO) release.83 However, co-administration of warfarin with ginseng did not affect the pharmacokinetics or pharmacodynamics of either S-warfarin or R-warfarin.184 Likewise, in a small randomized, controlled study, co-administration of Panax ginseng and warfarin did not influence the pharmacologic action of warfarin in ischemic stroke patients without a history of warfarin use.105
  • Antiulcer effects: A polysaccharide fraction of the leaves from Panax ginseng prevented gastric ulcer formation in rats after administration of necrotizing agents (HCl-ethanol, ethanol) and after pylorus ligation.185 This effect was observed not only after oral, but also after systemic administration, suggesting a non-local effect. Rats administered tissue cultured and cultivated ginseng had reduced gastric secretion and acid output.186 However, pepsin activity was not affected. Specifically, the cultivated ginseng blocked histamine induced acid secretion.
  • Antiviral effects: A few studies indicate that ginseng may have antiviral activity in both humans and animals. When given in combination with 6-MFA, an interferon inducing antiviral agent, ginseng was found to protect 82-100% of mice infected with Semliki forest virus.187 Ginseng also has a level of effectiveness similar to that of zanamivir and oseltamivir, and may reduce duration of a cold.52
  • Aphrodisiac effects: Traditionally, ginseng has been used as an aphrodisiac and some research supports this. It is thought that Panax ginseng enhances nitric oxide synthesis in corpora cavernosa endothelium and ginsenosides enhance acetylcholine-induced and transmural nerve stimulation-activated relaxation associated with increased tissue cyclic guanosine monophosphate.38
  • Cardiovascular effects: Ginsenoside-induced smooth muscle relaxation57,61,62,63 might explain the improvement of symptoms of coronary artery disease including typical electrocardiogram (ECG) changes, such as repolarization disturbances188. Implications have been made that Ca2+ plays a role in ginseng's cardiovascular effects.189,62 Ginsenosides Rb1 and Rg1 appear to have vasodilatory effects, possibly mediated by the proportion of nitric acid release.61 Enhanced nitric oxide synthesis from the endothelium of the lung, heart, kidney, and corpus cavernosum contributes to the vasodilation.3 The total saponins of Panax notoginseng may improve myocardial relaxation secondary to an enhancement of the calcium pump activity and inhibiting intracellular calcium overload.190
  • The left ventricular function was improved in rats that were administered yi-qi huo-xue, consisting of ginseng, astragalus, and Angelicae sinensis.191 Panax notoginseng saponins inhibit the proliferation of aortic smooth muscle cells stimulated by hypercholesterolemic serum.192 Rats treated with ginseng were less susceptible to arrhythmias than controls.193 Panax ginseng and American ginseng were found to increase the higher harmonic Fourier components of the pulse.58 Rb1 decreases the contraction force in pigs without affecting the action potential or amplitude.194 Rg 1 and Re showed vasodilator action in dogs, while Rc and Rb2 only showed very weak vasodilator actions but Rb1 did not.57 In dogs, ginseng aqueous extract significantly decreased the cardiac output, stroke volume, and central venous pressure and significantly increased the total peripheral resistance.60 Although both red and white ginseng similarly affect the cardiovascular system, red ginseng has stronger effects than white.195
  • In congestive heart failure patients, shengmai injection (Panax ginseng, Schizandra fruit, Ophiopogon) lowered serum levels of DR4 and DR5, the death receptor of soluble tumor necrosis factor-related apoptosis inducing ligand (TRAIL).196 Shengmai powder may also improve left ventricular performance in cases of coronary heart disease.197,198 Shenmai injection has also increased cardiovascular output in another clinical trial.97 In addition, shenmai injection in rats had a marked protective effect in systemic inflammatory reaction syndrome (SIRS), which might be related to the lowering of lipopolysaccharide levels and reducing of tumor necrosis factor (TNF) alpha secretion in rats.35
  • In vitro study indicates that ginsenoside Re from Panax ginseng uses nitric oxide (NO) actions to increase cardioprotection, specifically through direct S-nitrosylation of channel proteins to enhance K+ current and utilizing a cGMP-dependent pathway to suppress L-type Ca2+ current.199
  • Cellular effects: A polysaccharide from the root of Panax notoginseng has reticuloendothelial system activating properties.200 According to evidence from an assay, various ginsenosides have different effects on intracellular gap junction-mediated intercellular communication (GJIC), including inducing GJIC reductions and inhibiting GJIC reductions, due to tyrosine phosphatase inhibitor vanadate or interleukin 1 alpha (IL-1alpha).14 Panax ginseng may improve nitric oxide synthesis in endothelium of the heart, lung, kidneys, and in the corpus cavernosum.73 Ginsenosides Rh2 and Rh3 can induce differentiation of HL-60 cells into granulocytes.201 Modulation of protein kinase C isoform levels may contribute to differentiation of HL-60 cells by Rh2.
  • Cerebroelectrical effects: Panax ginseng can directly modulate cerebroelectrical activity, based on encephalographs of healthy volunteers.21
  • Cholesterol effects: Ginseng may possess lipid-lowering properties. In animals and hyperlipidemic humans, oral administration of ginseng reduced plasma total cholesterol, triglyceride, LDL-cholesterol, and non-essential fatty acids, while increasing levels of HDL91,202, which may be due to the stimulation of cholesterol enzymes203. Another study found ginseng to lower blood triglyceride levels in obese rats compared to controls.204 Although ginsenoside Re may reduce cholesterol, Rb1 may actually raise it.203 Cholesteryl ester transfer protein inhibitors inhibit human cholesteryl ester transfer protein with IC50 values of 20-35mg/mL.205 No effect on plasma lipids was found in a study on type 2 diabetics.76
  • Circulation effects: Shenfu injection (ginseng and aconite root) increased the auricle micro-artery diameter and the density of capillary and blood velocity in mice, more so than shenmai injection.206
  • CNS/Neurological/Cognitive effects: CNS stimulating effects have been found in animal models for ginseng extracts207 and for all studied ginsenosides alleviating fatigue57. The ginsenoside Rb1 may exert its memory effects by minimizing the inhibitory effects of β-amyloid peptides, thought to play a role in memory degeneration208, although neither Rb1 nor Rg1 reversed β-amyloid-induced cell death209. Rb1 and Rg1 increased neuron growth and reversed 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine-induced cell death.209 Panax ginseng extract also improves amnesia induced by scopolamine administration.210, 211 In mice, ginseng has been shown to have anxiolytic properties.212 In rats, ginseng has been shown to antagonize the acute pharmacological actions of morphine.213 and to inhibit the development of morphine tolerance44. Ginsenosides Rb1 and Rg1 were found to inhibit hyperactivity, conditioned place preference, and postsynaptic dopamine receptor supersensitivity in mice.116 These observations indicate a possible use of ginseng in the treatment of drug dependence.115
  • The metabolism of dopamine and norepinephrine in the cerebral cortex and serotonin in the corpus striatum and cerebellum was enhanced in mice that were administered Panax ginseng root.214 Dopamine in the corpus striatum and serotonin in the hypothalamus and midbrain were inhibited. However, mice treated for seven weeks had inhibited metabolism of dopamine, norepinephrine, and serotonin in all brain areas with the exception for the enhancement of serotonin metabolism in the cerebellum. Ginseng extract also inhibits the uptake of gamma-amino butyric acid (GABA), glutamate, dopamine, noradrenalin, and serotonin in rat brain synaptosomes.215 An in vitro study suggested that ginsenosides regulated GABA(A) receptor expressed in Xenopus oocytes and implied that this regulation might be one of the pharmacological actions of Panax ginseng.216 Ginseng total saponin 100mg/kg decreased the release of striatal dopamine induced by intrastriatal nicotine infusion by 41%.217 Ginseng is thought to normalize disturbances in the sleep-wake cycle218 and Rb1, Rb2, and Rc ginsenosides can prolong hexobarbital sleeping time and exhibit additional depressant effects on the central nervous system (CNS) in mice.
  • Consumption of a softdrink containing ginseng and ginkgo extract resulted in alterations in electroencephalogram (EEG) recordings from healthy human volunteers.219 In an in vitro study, American ginseng extract tonically and reversibly blocked the Na(+) channel in a concentration- and voltage-dependent manner, possibly due to an interaction with the channel when it was inactive.120 Ginsenoside Rb1 alone had similar results to the total extract. These results, and the results from another in vitro study, indicate that American ginseng may protect neurons from oxidative and ischemic injury.220 Shenmai (Panax ginseng, Schizandra fruit, Ophiopogon) has also shown protective effects in rats after cerebral ischemia-reperfusion injury, circulatory shock, and brain damage during heatstroke.15,221,222,37 An explanation for this effect is due to shenmai's antioxidant activity.15,221,222,37 A rat study has also shown that sensory nerve conduction velocity increased after shenmai huoxue decoction administration in a diabetes model.40 In animal study, shenmai (ginseng, Ophiopogon, and Schisandra) may offer protective effects in intracerebral hemorrhage223 and neurocytes224.
  • Although human study has indicated that ginseng increases cognitive performance23, the mechanisms of this effect are not known, but may be related to the ginseng's glycemic properties22,93. Ginseng affects brain activity, specifically by increasing cortical levels of dopamine, noradrenalin, serotonin, and cAMP.214 In vitro study indicates that ginseng increases energy produced aerobically in the brain.225 Ginseng saponins showed moderate depressant actions on the EEG and the behavior in cats, although Rg1, Re, and Rb2 were more potent than the other saponins.57
  • Cytotoxic effects: Although some Panax ginseng root polysaccharides may have cytoprotective activity226, more research has been conducted on ginseng's cytotoxic effects. In in vitro study, ginseng's etheric oil and ginsenoside aglycones 20(S)-protopanaxadiol, 20(S)-protopanaxatriol, and ginsenoside Rh2 have been identified as having a strong cytotoxic effect on intestinal and leukemia cell growth.43,65,227 Panaxytriol has also been found to rapidly inhibit cellular respiration and disrupt cellular energy balance in breast cancer cells.228 However, another in vitro study did not find a cytotoxic effect in monocytes from patients with AIDS or chronic fatigue syndrome.229
  • Cytochrome P450 (CYP) effects: Based on the available evidence, Panax ginseng does not appear to alter CYP450 metabolism. In vitro, ginsenosides found in Panax ginseng have no inhibitory effects on CYP3A activities103, yet their intestinal bacterial metabolite possesses the potential for inhibitory effects on CYP3A activities117. No significant effect on CYP activity was observed for Panax ginseng in a clinical trial.230 C57BL/6J mice treated for three days with 5g/kg daily of CVT-E002, a proprietary extract from American ginseng (Panax quinquefolius), showed no effects on liver microsomal CYP catalytic activities.118 Based on in vitro laboratory studies, human hepatic recombinant cytochrome P450 (CYP) drug metabolizing isozymes 1A2, 2B6, 2C19, 2C9, 2D6, and 3A4 demonstrated no effect on activity by Cold-fX® over a wide concentration range.119
  • Dermatologic effects: The saponin content of ginseng radix rubra accelerates fibronectin synthesis through changes in transforming growth factor-β receptor expression in fibroblasts.231 This action is thought to facilitate wound healing. Topical application of an extract obtained from Korean red ginseng increases the fibronectin in the whole dermis (in mice), deoxyribonucleic acid (DNA), and protein synthesis (in human fibroblasts).232
  • Endocrine effects: Some clinicians still believe that there is a lack of evidence to attribute ginseng with a glycemic effect233, due to methodological flaws of studies234. Ginseng appears to have an insulin-mimetic78, hypoglycemic effect in type 2 diabetes, possibly accelerating glucose-utilization by the liver77,75. This hypoglycemic effect has also been seen in nondiabetic human subjects taking American ginseng74,75, although one study found no such effect, perhaps due to variable ginsenoside concentrations in the Panax ginseng used70,112. Although a hypoglycemic effect of ginseng was also found on postprandial glucose levels in healthy subjects in another study, no hypoglycemia was observed.75 Similarly, Panax ginseng (G115) significantly lowered fasting blood glucose levels; however, effects on blood glucose were opposite in the raised blood glucose state.94 One study suggests that the glycemia-lowering effect of American ginseng root may be batch dependent.235 40% of batches tested did not reduce glycemia with the anticipated magnitude. Several types of ginseng (Canadian white, American red, Korean red, and Sanchi ginseng) decrease plasma glucose levels79, possibly due to their sulfonylurea-like activity69.
  • Furthermore, ginseng seems to accelerate hepatic lipogenesis, stimulate glucose transport, enhance glycogen storage, inhibit lipolysis, and inhibit lipid peroxidation.76,236,78,101 Ginseng may elicit an elevation of plasma insulin level by increased insulin secretion from beta islet with a differing mechanism from glucose.71. At least five glycans have been isolated from Panax ginseng237 and three from Panax quinquefolius238. A small study found 50g of ginseng extract to have no effect on insulin after a standardized weight-training workout.239 Ingestion of 3g American ginseng daily for eight weeks significantly lowered fasting plasma plasminogen activator inhibitor-1.72 There is a strong relationship between glycemic control and the plasminogen activator inhibitor-1.
  • Shenfu decoction (ginseng and aconite root) and shengmai powder (ginseng root, Ophiopogon japonicus root, Schisandra chinensis fruit) had no regulating effect on blood glucocorticoid levels in hemorrhagic rats (Qi-Yang exhaustion model) or heat-stressed rats (Qi-Yin exhaustion model), but upregulated glucocorticoid receptor levels.240
  • In rats, ginseng saponin primarily affected the hypothalamus and/or hypophysis and increased corticosterone levels in the adrenal cortex by stimulating corticotropin secretion.241 Panax ginseng extract also had an affinity for progestin, mineralocorticoid, and glucocorticoid receptors.242
  • Exercise effects: American ginseng supplementation before exhaustive aerobic exercise reduced creatine kinase leakage during exercise, but did not change aerobic capacity, possibly due to American ginseng's ability to reduce cellular and muscle damage.18
  • Fertility effects: Panax notoginseng extracts enhanced sperm motility in vitro after one and two hours of incubation.243 Ginsenosides enhanced nitric-oxide release from nitrergic nerves in tissue samples of rabbit corpus cavernosum244,2 and caused relaxation of the smooth muscle245. Choi et al. found that long-term administration of Korean red ginseng enhanced erectile capacity by endothelium-derived relaxing factor.246 Use of Panax ginseng C.A. Meyer extract showed an increase in spermatozoa number/mL and progressive oscillating motility, an increase in plasma total and free testosterone, dihydrotestosterone (DHT), follicle stimulating hormone (FSH), and luteinizing hormone (LH) levels, but a decrease in mean prolactin (PRL).108 In another clinical trial, Panax ginseng decreased in the percentage of diskinetic forms of spermatozoids.107
  • Helicobacter pylori inhibitory effect: Acidic polysaccharides from Panax ginseng may inhibit Helicobacter pylori adhesion to human gastric epithelial cells.41
  • Hemological effects: Saponins from Panax ginseng, including ginsenosides Rb1, Rb2, and Rg1, inhibited the hyperosmotic hemolysis of erythrocytes in an in vitro study.247 In an in vitro trial using bone marrow from patients with aplastic anemia, the total saponins of Panax ginseng increased bone marrow cultures possibly by prompting proliferation of normal progenitor cells.248 In a clinical study, shenmai injection (Panax ginseng, Schizandra fruit, Ophiopogon) decreased the concentration of tumor necrosis factor (TNF)-alpha in blood serum and the apoptosis rate of bone marrow CD34. cell249
  • Hepatoprotective effects: The metabolite of oral ginsenosides, 20-O-beta-D-glucopyranosyl-20(S)-protopanaxadiol, protected mouse liver cells from cytotoxicity induced by tert-butyl hydroperoxide and significantly inhibited the increment of alanine amino transferase (ALT) and aspartate transaminase (AST) induced by tert-butyl hydroperoxide in mice.250 The metabolite also stabilized cell membranes.
  • Hormonal effects: The estrogenic effects of ginseng are not well defined, due to conflicting studies. Some in vitro studies indicate an estrogenic effect in human breast cancer cells, possibly by binding and activating the estrogen receptor.64,251,109,10,67,252 Other in vitro studies do not show this effect.66 This discrepancy may be due to the type of ginseng extract used, as King et al. showed that a methanol extract did have estrogenic properties in vitro in breast cancer cells, but a water extract did not.8 The traditional Japanese herbal medicine unkei-to, which contains Panax ginseng and other herbs, stimulated the secretions of 17ß-estradiol and progesterone from highly luteinized granulosa cells obtained from in vitro fertilization patients; the stimulated effect on estradiol secretion occurred with 0.3mcg/mL, while a significant effect on progesterone secretion was obtained at 10mcg/mL.50
  • Ginseng has been postulated to stimulate adrenocorticotropic hormone and thereby increase plasma cortisol levels.123 In rats fed with ginseng for 60 days, a significant increase of blood testosterone levels was found, combined with a significantly reduced prostate weight.124 An estrogen-like effect of ginseng may be due to strong competition with estradiol for estrogen and progesterone binding sites in the human myometrial cytosol.253 One study was conducted to determine whether ArginMax® (The Daily Wellness Co., Sunnyvale, CA) or the Panax ginseng extract it contains has any estrogenic activity.66 ArginMax® for Women, a nutritional supplement for sexual health, contains L-arginine, ginseng, ginkgo, damiana, multivitamins, and minerals. In a human endometrial adenocarcinoma cell line, no estrogenic activity was evident in either ArginMax® or Panax ginseng.
  • Hypotensive effects: There has been conflicting research on the effect of ginseng on blood pressure. In hypertensive individuals, 3g American ginseng had a neutral effect on all ambulatory blood pressure parameters compared with placebo, and had no effect on 24-hour blood pressure and renal function in hypertensive individuals.95,113 In another clinical trial, Panax ginseng extract 200mg daily increased the QTc interval and decreased diastolic blood pressure two hours after ingestion in healthy adults on the first day of therapy, but these effects were not considered clinically significant.59 Other authors have also described hypertensive effects of ginseng.53,54 The conflicting effects of ginseng on blood pressure may be due to the dosage used.62,254,60,54
  • The hypotensive effects in humans55,58 and animals60 may be due to a relaxing effect on smooth muscle induced by certain ginsenosides (e.g., Rb1)57,61,62,63. An animal study indicated that ginseng has simultaneous contraction and relaxation effects that may explain ginsenosides' biphasic actions on blood pressure.56,57
  • Immunomodulating activity: Both suppression and enhancement of humoral and cellular immunity have been reported, due to ginseng extracts.25,255 This discrepancy could arise from the difference in dose levels, composition, and duration of therapy. Ginseng is believed to boost immune function and, thus, has been implicated for treatment of cancer and respiratory infectious disease.256 In human or animal study, ginseng has been shown to enhance cellular immune function by stimulating natural killer cell activity257,258,259,229,157, macrophages25, tumor necrosis factor (TNF)-alpha production260, cytokine production261,26, antibody-dependent cellular cytotoxicity229,96, intracellular killing in neutrophils, blastogenesis of circulating lymphocytes262, increased antibody production257, potentiation of the effect of vaccines263, exhibition of anticomplement activity254, or exhibition of mitogenic activity towards lymphocytes264. Study suggests a lack of effect on peripheral blood leukocyte numbers and lymphocyte subsets after administration of ginseng.265
  • Immunomodulating effects of ginseng may be attributable to constituents, such as root-derived panaxanes-polysaccharides266, ginsenosides that can differentially modulate lymphocyte proliferation267, and ginsenan S-IIA, a potent inducer of IL-8 production by human monocytes and THP-1 cells268. Certain multi-ingredient preparations, such as CKBM (Panax ginseng, Schisandra chinensis, Fructus crataegi, Ziziphus jujube, and Glycine max), have also been shown to regulate intracellular signaling and the production of cytokines.24
  • The immuno-regulatory functions of a saccharide-rich proprietary American ginseng extract (Panax quinquefolius, CVT-E002) by CV Technologies Inc., may be due to stimulation of a panel of inflammatory cytokines secretion from monocytes, and augmentation of IFN-γ secretion upon influenza stimulation. In clinical study, Cold-fX®, containing CVT-002, demonstrates effectiveness in the prevention and treatment of upper respiratory infections.4,5,100 Cold-fX® may increase NK cell and macrophage activity leading to increased cytolytic and phagocytic killing of pathogens and IFN-γ secretion. Evidence from in vitro and in vivo studies indicates that Cold-fX® induced antiviral effects could be related to its immunomodulating properties.269,256,270,27,92,271
  • It has been suggested that Korean red ginseng may delay disease progression in human immunodeficiency virus type 1 (HIV-1)-infected patients and slow the decrease in CD4 T cells.272
  • Lipogenesis effects: Ginseng seems to inhibit lipolysis and promote lipogenesis.273,274
  • Nicotinic activity: In an in vitro study, Panax ginseng extract had affinity for both the nicotinic receptor and, to a lesser extent, the muscarinic receptor, but the activity is not due to choline.275 Ginsenosides might regulate nicotinic acetylcholine receptors in a differential manner.276
  • Photosensitivity: In laboratory study, Panax ginseng acted as a photoprotector in low concentration and as a photosensitizer in high concentration.80
  • Protein synthesis effects: In an in vitro study, ginseng stimulated protein synthesis in human fibroblasts.277
  • Protein tyrosine kinase effects: American ginseng ginsenosides and the non-saponin fraction of Panax ginseng roots had significant inhibitory effects on protein tyrosine kinase activation induced by hypoxia/reoxygenation in one laboratory study.134
  • Pulmonary effects: A ginsenoside-induced nitric oxide-mediated relaxation effect has also been observed in vitro in bronchial smooth muscle.13 This offers a possible mechanism for the bronchodilatory effect reported from the only trial that assessed this effect in humans.68 Promotion of nitric oxide release has also been suggested as possible mechanism in the vasorelaxation and prevention of oxygen free radical injury in pulmonary endothelium by ginsenosides.61 These effects appear to be even more pronounced after artificial gastric digestion of extract G115.®278 Shenmai (ginseng, Schizandra fruit, Ophiopogon) has increased the contraction of diaphragmatic muscle in vitro.279,45,280
  • Pulse alteration (TCM): Pulse measurement is seen in traditional Chinese medicine (TCM) as a multifaceted component of heart rate. Single doses of Panax ginseng or Panax quinquefolius extract demonstrated specific effects on the Fourier components of the pulse.58 Panax ginseng and Panax quinquefolius reported significant increases in harmonic components C6, C7, C8, and C9. Western medicine does not view pulse the same way as TCM; therefore, results may not be applicable to a Western idea of pulse and health.
  • Radioprotective effects: Ginseng saponin significantly increased radioprotection when applied to cultured mammalian cells before gamma-irradiation.281 Ginseng has been shown to be radioprotective in mice. One study found specific fractions of ginseng to be attributable for this action: CM-A, G-1, and G-3.282 Panax ginseng also prevents irradiation-induced hair loss due to programmed cell death in the follicles.283
  • Renal effects: In a clinical trial, postoperative Salvia miltiorrhiza and shengmai in patients with obstructive jaundice inhibited inflammatory mediator and improving blood dynamics, thereby protecting renal function.42 This renal protective effect by shenmai injection has also been seen in rats with 5/6 nephrectomy.284
  • Sexual effects: Ginsenosides enhance nitric-oxide release from nitrerigic nerves in tissue samples of rabbit corpus cavernosum244,2 and causes relaxation of the smooth muscle245. In a clinical trial of 90 patients with erectile dysfunction, ginseng saponins changed early detumescence and penile rigidity, penile girth, and libido.106
  • Sleep effects: In rats, ginseng temporarily increased slow wave sleep, although this effect returned to the baseline after two weeks.285
  • Steroid-like effects: In an in vitro trial, Panax ginseng suppressed phytohemagglutinin stimulation of peripheral blood lymphocytes, indicating that Panax ginseng has a steroid-like effect.121
  • Stimulant effects: Panax ginseng extracts contain similar constituents as guarana, a known herbal stimulant.20
  • Stimulatory/growth effects: In in vitro studies, Panax ginseng and heat-treated ginseng stimulated cell growth of human fibroblasts, probably by promoting growth in younger cells.286,1,6 Irradiated animals receiving ginseng experienced accelerated recovery of the megakaryocytes in the bone marrow.48 Ginsenoside Rg1 was shown to increase both humoral and cell-mediated immune responses. Kenarova reported that spleen cells from ginsenosides treated mice injected with sheep red cells as an antigen showed significantly higher plaque-forming response and hemagglutinating antibody titers.287 In addition, Rg1 increased the number of antigen-reactive T helper cells, T lymphocytes, and NK cells.
  • Urinary effects: An International Olympic Committee (IOC) urine drug test of athletes ingesting Cold-fX® was not positive for any IOC banned or restricted substances.51
  • Wound healing effects: Ginseng has been traditionally used for wound healing, and these properties may be due to the activity of ginsenosides Rb1and Rb2. Rb1's contribution may be due to the promotion of angiogenesis by stimulating vascular endothelial growth factor production and increasing hypoxia-inducible factor-1a expression.288 Rb2 may stimulate epidermal cell proliferation and formation by increasing secretion of epidermal growth factor and its receptor, as well as fibronectin, keratin, and collagenase 1.289
  • Other: The pharmacological effects of ginsenosides have been reviewed in several publications.290,47,291 The pharmacological activity and constituents of sanchi ginseng (Panax notoginseng) have also been reviewed.292 The potential for interactions with anti-cancer agents of herbal products, including ginseng, has been reviewed.293

Pharmacodynamics/Kinetics:

  • The ginsenosides found in ginseng appear to be poorly absorbed, either after both oral and intravenous administration in rats.294,295,296 For example, the bioavailability of Rb1 and Rg1 after oral administration is 0.71% and 3.29%, respectively.294 Other unsubstantiated sources have reported that the bioavailability of beta-sitoserol, a steroid sapogenin, and ginsenoside Rg1 after oral administration to rats was 50-60%. However, intranasal administration may increase absorption.297,298 High elimination in the stomach, large intestine, and liver may contribute to the low bioavailability of these ginsenosides, but low membrane permeability is probably a greater limiting factor294,295, especially as ginsenosides may be passively absorbed by simple diffusion294 or dependent on active transport299. The low absorption rate by the intestinal wall could be enhanced by carbomer and borneol.296 Once absorbed, the distribution of ginsenosides could be described by a two-compartment model.300
  • Although several recent studies have examined the ginsenosides themselves, some researchers have focused on the intestinal metabolites of these compounds, which may have the active processes that medical researchers are interested in, such as antitumor effects. A couple of these metabolites are 20- O-(beta-D-glucopyranosyl)-20(S)-protopanaxadiol, known as compound K or IH-901, and 20(S)-protopanaxatriol, known as M4.301,302,303,304 The metabolism of ginsenoside Rb1 to compound K was shown in a rat study by Akao et al., when rats deprived of Eubacterium sp. and orally administered Rb1 had neither compound K nor any other metabolite in their plasma, intestinal tract, or feces; Rb1 was only found in fecal contents and not in the plasma.304
  • Compound K seems to be efficiently removed from blood by the liver301 and showed little excretion in the urine302. Compound K may also be passively absorbed from the digestive tract.302 The ginsenoside Rg1 may have a plasma protein binding of 24% and tissue protein binding of 48% in the liver although confirmation is needed.
  • In a study of rats administered with the metabolite M4, M4 was absorbed from the small intestine, was esterified with fatty acids, then accumulated in tissues, including the lungs and liver.303
  • The metabolism and excretion of the constituents of ginseng has not been extensively studied. It appears that ginsenosides are excreted in the urine only in trace amounts. One study has focused on the pharmacokinetics of shenmai injection (Panax ginseng, Schizandra fruit, Ophiopogon) by tracking the plasma concentrations of the ginsenosides Rg1 and Re after shenmai injection into human volunteers.305 The results indicate that the distribution and elimination of Rg1 and Re were rapid after intravenous infusion, and the pharmacokinetic characteristics indicate a two-compartment model.

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