InteractionsGuide Index Page
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Ginseng
Botanical Name: Panax ginseng C.A. Meyer.
Pharmacopoeial Name: Radix ginseng.
Synonym: Panax ginseng T. Nees.
Common Names: Ginseng, Korean ginseng, Chinese ginseng, Asian or Oriental ginseng.
Family
Araliaceae.
Related Species
Panax quinquefolius L. (American ginseng) or Xi Yang Shen .
Habitat and Cultivation
Slow-growing woodland perennial native to northern China and Korea, now widely cultivated in those countries and in Japan.
Parts Used
Main and lateral roots.
Common Forms
Dried peeled root (white ginseng); steamed dried root (red ginseng) by decoction, or infusion if powdered.
Tincture or Fluid extract.
- Standardized Extract: Dried concentrates, typically standardized to 4% to 5% ginsenosides (with ginsenosides Rg1/Rb1 ratio ≥ 0.5).
Overview
Ginseng is economically the most important herb in world commerce and has generated more scientific studies and a larger general literature than any other herb. Although used in Asia for more than 2000 years, ginseng has now become widely incorporated into consumer products as well as the herbal materia medica in the West. Ginseng is the archetypal adaptogenic herb. Adaptogens have no equivalent among conventional pharmaceutical agents. The term was coined by Soviet researcher Lazarev in 1947 and subsequently defined by Brekhman in terms of three salient qualities. Adaptogens are nonspecific (in relation to a wide range of stressor stimuli), nontoxic (cause minimal disturbance to normal physiological function), and normalizing (direction of action varies depending on the prior state of response to stressor and always normalizes). 1 The general properties of adaptogens have been reviewed by Panossian et al. 2 and Wagner and Norr. 3 As with its companion adaptogen eleuthero (see Eleuthero monograph), ginseng and its constituent ginsenosides have a broad range of immunomodulating, chemopreventive, neuroendocrine, and antineoplastic activities, as well as behavioral effects on athletic, sexual, and cognitive performance.
The literature on ginseng is voluminous; recent accessible Western resources include therapeutic monographs by the World Health Organization (WHO), 4 British Herbal Medical Association (BHMA), 5 and European Scientific Cooperative on Phytotherapy (ESCOP), 6 as well as literature reviews by McKenna et al. 7 and Court. 8 Recent monographs from the Chinese medicine perspective include Bensky et al. 9 and Chen and Chen. 10 Ren shen is a transliteration of the Chinese name for “peeled, dried root,” also known as “white ginseng.” Hong shen, or “red ginseng,” is the root steamed before drying. Red ginseng is considered more Yang (i.e., warmer and stronger) than white ginseng. The ginsenoside profile of the two forms is different. The separate species Panax quinquefolius L. (American ginseng or wild American ginseng) is known as Xi Yang Shen and is regarded as closer to Japanese-cultivated Panax ginseng , or Dong Yang Shen , and has less warming properties than Ren shen . 10 The Western literature does not usually observe these energetic distinctions, although P. quinquefolius and P. ginseng , despite similarities, are not considered interchangeable by most authoritative Western sources, and the scientific literature on P. quinquefolius is considerably less than that for P. ginseng .
In consumer product marketing, the term “ginseng” has been confusingly used to refer to related species such as American ginseng (P. quinquefolius) as well as unrelated species such as Siberian ginseng (now known as eleuthero). Correct recording of the Latin binomial is always essential to identify an herb accurately, and failure to properly identify the species is a persistent defect of mainstream medical discussions of ginseng-related adverse events and drug interactions. A further problem, endemic to the dietary supplement market, is the variable quality and composition of commercial products containing, or claiming to contain, ginseng. 11 Because of the high price of the root, adulteration can occur, and several contaminating species have been identified in China. 9
Historical/Ethnomedicine Precedent
In classical Chinese medicine, ginseng is a major qi tonifying herb, addressing general deficiencies of yuan qi (“source qi”) to replenish jing (“vital essence”), as well as deficiencies of blood (xue), spleen (Pi) , lung (Fei), and kidney (Shen) qi . As a shen herb, it also calms the “Spirit/Mind” and improves mental function. Ginseng has been progressively integrated into Western use in the last 30 years, primarily as an adaptogenic tonic herb to treat fatigue and neurasthenia, enhance general wellness, and improve physical, sexual, and cognitive performance. As in China, ginseng is now increasingly seen as a potentially valuable agent in Western integrative cancer protocols. 12,13
Known or Potential Therapeutic Uses
Stress reduction and neuroendocrine balancing (dysglycemia, adrenal insufficiency); fatigue, chronic fatigue immune dysfunction syndrome (CFIDS); convalescence; enhancement of exercise, athletic and work capacity, and performance; increasing mental alertness and cognitive performance; adjunct to radiation and chemotherapy treatment; immunoprotection and immunomodulation, chemoprevention, cardiotonic, hepatoprotective, hyperlipidemic, hypoglycemic.
Key Constituents
- Steroidal saponins, known as ginsenosides (up to 3.0%). The ginsenosides are based on three sapogenin aglycones: 20(S)-protopanaxodiol, 20(S)-protopanaxotriol, and oleanic acid. Ginsenosides are designated by the letter “R” followed by various subscripts. The total number of ginsenosides has not been definitively determined; more than 30 have been described. Ginsenosides are present as a complex mixture, and the composition may vary with conditions of cultivation and processing.
Polyacetylene compounds, peptidoglycans, volatile oil, polysaccharides, and lipids.
Therapeutic Dosing Range
- Dried root: Western—up to 2 g daily; Chinese—up to 9 to 10 g daily.
- Tincture/Fluid extract: Up to 3 mL/day, 1:1 equivalent.
- Standardized Extract: 100 mg 5:1 4% ginsenosides (e.g., G115, Pharmaton S.A.) solid extract twice daily, i.e., 8 mg ginsenosides total daily.
Strategic Considerations
The “normalizing” effect of ginseng on homeostatic parameters, coupled with a broad spectrum of activities and minimal toxicity, underlies a lack of pronounced pharmacodynamic drug interactions with the herb at therapeutic doses. In a recent review of the safety and toxicity of ginseng, including adverse drug interactions, Coon and Ernst 14 concluded that the herb was rarely associated with adverse events or drug interactions. Authoritative monographs either report no interactions (German Commission E) 15 or cite the often-repeated but unlikely adverse interaction with phenelzine (see later discussion) and a possible interaction with warfarin (WHO, ESCOP). 4,6
Secondary sources often suggest theoretical or speculative interactions based on extrapolations from the pharmacology of the herb. However, pharmacological data for ginseng often reveal apparently opposing effects, such as hypertensive/hypotensive, central nervous system (CNS) stimulant/CNS depressant, and antihistamine/histamine-like actions. 16 These opposing effects extend to genomic activity. 17 Such apparently conflicting data and the correlation of the direction of many ginseng effects with baseline physiological state before consumption are explained partly by the opposing action of the separate ginsenoside components of the herb. 18 This also applies to more complex processes, such as angiogenesis; ginseng can promote angiogenesis in wound healing but inhibit it in tumorigenesis. 19,20As with steroidal hormones, the ginsenosides are capable of exerting complex actions at genomic and proteomic levels, exhibiting membrane intercalation and nuclear localization, as well as more rapid actions at a signal transduction and second-messenger level. 18 Many of the observed downstream effects of ginsenosides may result from these levels of activity. There is evidence that ginsenosides may reverse the classic downregulation of glucocorticoid receptor (GR) by dexamethasone, although evidence for direct binding to the GR is equivocal. 21 This should not be read so much as evidence for a “dexamethasone-ginseng” interaction, but rather as an indication of the complexity of actions of the herb. For example, diverse effects of the ginsenosides may be downstream consequences of GR modulation, including several antineoplastic effects. 22 Similarly, putative estrogenic activity by some ginsenosides 23 may be caused by crosstalk between GR and ER, 24 rather than direct “phytoestrogen” effects, which have not historically been attributed to the herb, in contrast to recent data on isolated ginsenoside components. 25,26
In conclusion, the documented literature on ginseng interactions largely fails to account for the complex, pleiotropic and nonspecific effects of the herb, particularly on stress-related homeostasis and neuroendocrine and immune parameters. Practitioners versed in botanical medicine are likely to emphasize precisely these adaptogenic aspects in therapeutic practice, whereas the mainstream view continues to regard ginseng narrowly as some type of mild stimulant, although an exotic one.
Effects on Drug Metabolism and Bioavailability
The effects of ginseng (and isolated ginsenosides) on cytochrome P450 (CYP450) has not been fully characterized, but the balance of available data from rodent, in vitro, and preclinical in vivo studies suggests that the herb has minimal effects on the mixed-function oxidase system, lacking pronounced induction or inhibition effects that may contribute to metabolic drug interactions. 27 Two in vivo human CYP450 studies are available to date. Anderson et al. 28 found no effect of 14 days’ administration of standardized (G115) ginseng in 20 healthy volunteers on urinary 6-β-OH cortisol/cortisol ratios, suggesting lack of induction of the herb on CYP3A4. Gurley et al. 29 used a probe cocktail methodology in 12 healthy volunteers to examine the effects of 28 days’ administration of Panax ginseng at a high dose of 500 mg three times daily. They found no significant changes in CYP450 1A2, 2D6, 2E1, or 3A4. 29 Two recombinant human CYP450 enzyme studies suggest a possible weak inhibition of isoforms 1A1, 1A2, and 1B1 by G115 extract. 30 Another study using isolated component ginsenosides found that R
In contrast to the Phase II drug metabolism, there is preliminary experimental evidence for a modulating effect of ginseng on P-glycoprotein (Phase III drug metabolism), and substrates of this transporter protein may be subject to pharmacokinetic interactions. 35 The mechanisms of drug resistance modulation have not been fully characterized; cell line evidence examining the effects of ginsenoside components on drug efflux with vinblastine and doxorubicin suggests a competitive inhibition mechanism rather than transcriptional induction/inhibition. 36-39Confirmed clinical correlations of drug resistance modulation or other efflux pump-mediated interactions with ginseng or ginsenosides are not available to date, although doxorubicin (Adriamycin) cardiotoxicity was reduced in a rodent model when ginseng was coadministered with the drug. 40
Finally, evidence suggests that in both rodents and humans, certain intestinal bacteria may hydrolyze ginseng saponins into novel ginsenoside metabolites with antineoplastic activity, suggesting a prodrug bioactivation aspect to the action of the herb under certain circumstances. 41,42The clinical significance of this bioactivation mechanism has not been established.
- Evidence: Cocaine, methamphetamine, morphine sulfate (Astramorph PF, Avinza, Duramorph, Infumorph, Kadian, MS Contin, MSIR, Oramorph SR, RMS; Roxanol, Roxanol Rescudose, Roxanol T).
- Extrapolated, based on similar properties: Narcotic analgesics: Butorphanol (Stadol, Stadol NS), codeine, fentanyl (Actiq Oral Transmucosal, Duragesic Transdermal, Fentanyl Oralet, Sublimaze Injection), hydrocodone, hydromorphone (Dilaudid), levorphanol (Levo-Dromoran), meperidine (Demerol), methadone (Dolophine, Methadose), opium tincture, oxycodone (Endocodone, OxyContin, OxyIR, Percolone, Roxicodone), oxymorphone (Numorphan), paregoric, pentazocine (Talwin, Talwin NX), propoxyphene (Darvon, Darvon-N).
- Combination drugs: buprenorphine and naloxone (Suboxone); codeine and acetaminophen (Capital with Codeine; Phenaphen with Codeine; Tylenol with Codeine); codeine and acetylsalicylic acid (Empirin with Codeine); codeine, acetylsalicylic acid, caffeine, and butalbital (Fiorinal); hydrocodone and acetaminophen (Anexsia, Anodynos-DHC, Co-Gesic, Dolacet, DuoCet, Hydrocet, Hydrogesic, Hy-Phen, Lorcet 10/650, Lorcet-HD, Lorcet Plus, Lortab, Margesic H, Medipain 5, Norco, Stagesic, T-Gesic, Vicodin, Vicodin ES, Vicodin HP, Zydone); hydrocodone and acetylsalicylic acid (Lortab ASA); hydrocodone and ibuprofen (Reprexain, Vicoprofen); opium and belladonna (B&O Supprettes); oxycodone and acetaminophen (Endocet, Percocet 2.5/325, Percocet 5/325, Percocet 7.5/500, Percocet 10/650, Roxicet 5/500, Roxilox, Tylox); oxycodone and acetylsalicylic acid (Endodan, Percodan, Percodan-Demi); pentazocine and acetaminophen (Talacen); pentazocine and acetylsalicylic acid (Talwin Compound); propoxyphene and acetaminophen (Darvocet-N, Darvocet-N 100, Pronap-100, Propacet 100, Propoxacet-N, Wygesic); propoxyphene and acetylsalicylic acid (Bexophene, Darvon Compound-65 Pulvules, PC-Cap); propoxyphene, acetylsalicylic acid, and caffeine (Darvon Compound).
Interaction Likely but Uncertain Occurrence and Unclear Implications |
Probability: 3. Possible
Evidence Base: Preliminary
Effect and Mechanism of Action
Ginseng extracts may interfere with analgesic effects of morphine and related opioids while preventing or reversing drug-induced tolerance, according to animal data. The mechanism and clinical significance of the interaction are not established, although theoretically the herb may be of value in preventing or modulating drug adverse effects, including drug tolerance.
Research
Investigators have conducted experimental studies into the effects of ginseng pretreatment and coadministration with psychostimulant and opioid drugs, principally morphine but also methamphetamine and cocaine, in rodent behavioral models (conditioned–place preference tests). The general conclusions were that drug-induced hyperactivity was reduced by ginseng, with ginsenosides fractions Rg1 and Rb1 being primarily responsible for the antiopioid activity. The effect may be related to dopaminergic pathway modulation but has not been established. 70-76
Clinical Implications and Adaptations
At least one author has suggested that ginseng extracts hold the potential to prevent and treat the effects of abuse of cocaine, methamphetamine, and morphine. 77 These extrapolations from rodent models to drug abuse behavior and tolerance mechanisms in humans require supporting clinical data, which are unavailable at present.
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