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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.

Summary Table

Drug/Class Interaction Type	Mechanism and Significance	Management
Amoxicillin Beta-lactam antibiotics	Ginseng increases T helper cell typ. 1 (Th1) immunity and may enhance effectiveness of many antimicrobial agents, although evidence of interaction is specific to amoxicillin. Clinical significance: possibly widely applicable, although currently unknown.	Consider coadministration, especially in antibiotic-resistant conditions or immunocompromised patients.
Chemotherapy Radiotherapy /	Ginseng may decrease drug toxicities and increase drug efficacy through multiple mechanisms, including immunomodulation, chemosensitization, and specific toxicity reduction. Western clinical trial support negligible, despite anecdotal clinical support.	Pretreatment and coadministration with chemotherapy and radiation recommended, with appropriately experienced professional management.
Ethanol Antiarthritic analgesics / /	Clearance of alcohol may be increased by herb pretreatment. Interaction of questionable clinical value.	None.
Narcotics, opioids, central stimulants	Ginseng may reduce drug-induced tolerance development and decrease adverse effects of drug use. Clinical significance not established.	Consider possible use as additional support for adverse effect reduction in analgesia or withdrawal from narcotic/opioid abuse.
Phenelzine Monoamine oxidase inhibitors (MAOIs)	Ginseng effect on neurotransmitters not considered physiologically significant. Current low use of nonselective MAOIs renders clinical significance marginal. Interaction overstated.	Normal precautions regarding nonselective MAOI advice for patients adequate.
Vaccine immunotherapies	Ginseng extracts may increase antibody response and effectiveness of some vaccine therapies by enhancing antigen-presenting cell (APC) activity. In particular, ginsenosides may be a useful pretreatment and adjuvant for improving potency and immunogenicity of vaccines.	Pretreatment and coadministration worthy of consideration.
Warfarin Oral vitamin K antagonist anticoagulants	International normalized ratio (INR) reduction in a single report, probably idiosyncratic. Significance unknown, likely minimal.	Observe normal INR monitoring, especially if adding or removing any drug/herb to stable anticoagulation.

herb description

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).

herb in clinical practice

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.

interactions review

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 Rd, Rc, and Rfexerted a very weak effect on 1A2, 2C9, 2C19, 2D6, and 3A4. Ginsenosides Rcand Rfalso exerted activation effects on 2C9 and 3A4, respectively, but only at concentrations of 200 µM. The authors concluded that these small effects would be unlikely to have in vivo effects on coadministered medications. ³¹ Rodent models have also failed to reveal significant effects on CYP450 enzymes 1A2, 2B1, and 3A23. ^32-34

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.

herb-drug interactions

Amoxicillin and Related Beta-Lactam Antibiotics

Evidence: Amoxicillin (Amoxicot, Amoxil, Moxilin, Trimox, Wymox); combination drug: amoxicillin and clavulanic acid (Augmentin, Augmentin XR, Clavulin, Nuclav). Extrapolated, based on similar properties: Beta-lactam antibiotics: Methicillin (Staphcillin); aztreonam (Azactam injection); carbapenem antibiotics: meropenem (Merrem I.V.); combination drug: imipenem and cilastatin (Primaxin I.M., Primaxin I.V.); cephalosporin antibiotics; penicillin antibiotics: ampicillin (Amficot, Omnipen, Principen, Totacillin); combination drug: ampicillin and sulbactam (Unisyn); bacampicillin (Spectrobid), carbenicillin (Geocillin), cloxacillin (Cloxapen), dicloxacillin (Dynapen, Dycill), mezlocillin (Mezlin), nafcillin (Unipen), oxacillin (Bactocill), penicillin G (Bicillin C-R, Bicillin L-A, Pfizerpen, Truxcillin), penicillin V (Beepen-VK, Betapen-VK, Ledercillin VK, Pen-Vee K, Robicillin VK, Suspen, Truxcillin VK, V-Cillin K, Veetids), piperacillin (Pipracil); combination drug: piperacillin and tazobactam (Zosyn); ticarcillin (Ticar); combination drug: ticarcillin and clavulanate (Timentin).

Beneficial or Supportive Interaction, Not Requiring Professional Management

Probability: 2. Probable
Evidence Base:

Preliminary

Effect and Mechanism of Action

A synergistic effect between amoxicillin (plus clavulanic acid) and coadministered ginseng results in increased antibacterial effect. The mechanism is likely caused by increased cellular immunity (Th1) induction by ginseng.

Research

A group of 75 patients with acute bronchitis received 875 mg amoxicillin and 12 mg clavulanic acid twice daily for 9 days. They were then randomized into two groups; one received additional ginseng (G115, 200 mg/day) and the other antibiotic only for the 9 days. On days 4 to 7 the ginseng group had significantly lower bacteria counts than the antibiotic-only group, although this became a nonsignificant trend after day 8. The authors of this pilot study suggested that ginseng may be a particularly useful adjunct in cases of acute bronchitis. ⁴³ (Arguably, however, most infectious disease experts would agree that antibiotic treatment of this condition is not necessary or indicated in patients who are not debilitated or immunosuppressed.)

Integrative Therapeutics, Clinical Concerns, and Adaptations

The effect of ginseng extracts in enhancing cell-mediated immunity, particularly natural killer (NK) cell activity, has been documented. The combination of natural compounds with beta-lactam antibiotics to deal with refractory conditions or bacterial resistance is also documented (e.g., see Green Tea monograph). The interaction identified by the previous study is more likely a specific instance of the general enhancement of immune responses by ginseng. Such an effect is probable in combination with a wide variety of antimicrobial agents, rather than as a specific interaction couplet between amoxicillin or beta-lactam agents, implying a broader clinical significance than suggested by the specific report.

Antineoplastic Chemotherapy and Radiotherapy

Bleomycin (Blenoxane), carboplatin (Paraplatin), cisplatin ( cis-diaminedichloroplatinum, CDDP; Platinol, Platinol-AQ), cytarabine (ara-C; Cytosar-U, DepoCyt, Tarabine PFS), dactinomycin (Actinomycin D, Cosmegen, Cosmegen Lyovac), daunorubicin (Cerubidine, DaunoXome), docetaxel (Taxotere), doxorubicin (Adriamycin, Rubex), etoposide (Eposin, Etopophos, Vepesid, VP-16), mitomycin (Mutamycin), oxaliplatin (Eloxatin), paclitaxel (Paxene, Taxol), paclitaxel, protein-bound (Abraxane), vinblastine (Alkaban-AQ,Velban, Velsar), vincristine (Leurocristine, Oncovin, Vincasar PFS), vinorelbine (Navelbine).

	Potential or Theoretical Beneficial or Supportive Interaction, with Professional Management
	Prevention or Reduction of Drug Adverse Effect

Probability: 4. Plausible
Evidence Base:

Preliminary

Effect and Mechanism of Action

Coadministered ginseng may potentially act as both a chemosensitizer and a protector against antineoplastic drug toxicities, particularly antitumor antibiotics and platinum compounds. Mechanisms may include multidrug resistance disabling, potentiation of cytotoxic activity with some drugs, protection of healthy cells, and enhancement of immune system activity during myelosuppression. These potential interactions have not been subject to Western clinical trials at this time, although they are supported by anecdotal clinical practice and preliminary pharmacological data.

Research

Experimental and animal data supporting the general use of ginseng extracts, particularly red ginseng, in association with antineoplastic agents are available. Most reports are in original Asian literature, which is only briefly summarized here.

Isolated triterpene (ginsenoside) fractions have been shown to reverse drug resistance to daunomycin, doxorubicin (Adriamycin), and vinblastine in resistant leukemia cell line P388/ADM, with Adriamycin sensitivity increasing the most. ³⁶ Inhibition of leukemic progenitor cells cultured from bone marrow of patients with acute myelogenous leukemia (AML) increased significantly when cytotoxic drugs (homoharringtonine, cytarabine, Adriamycin, etoposide) were coadministered with a complete saponin extract of Panax ginseng(20 µg/mL); a total of 17 of 72 drugs tested exhibited resistance reversal. ⁴⁴ A Chinese formula with ginseng as the main ingredient reduced the cardiotoxic effects of Adriamycin in rabbits compared with controls. ⁴⁵ Combination treatment with a sapogenin metabolite of ginseng (50 mg/kg) in mice orally administered with doxorubicin (3 mg/kg) significantly reduced germ cell injury and other parameters (e.g., serum LDH, CPK) to the level of control animals. ⁴⁶

The effects of extracts of both red and white ginseng were compared in the activity of mitomycin C in vitro against Ehrlich ascites sarcoma cells. The ginsenosides Rh2 and Rg3 promoted mitomycin uptake by the tumor cells, and when an in vivo comparison was performed in mouse Ehrlich ascites sarcoma and rat ascites hepatoma, the red ginseng extracts showed a stronger effect in combination with mitomycin than the white ginseng extract. ^47-49 Conducting in vitro studies with ginsenoside Rg(3), Kim et al. ³⁹ showed that inhibition of multidrug resistance was caused by competitive inhibition of binding with P-glycoprotein (P-gp), rather than by transcription effects on MDR1 gene or P-gp levels. Ginsenoside Rh2 from red ginseng demonstrated a synergistic effect with cisplatin in vitro and in vivo (when inoculated into mice) against growth of a cell line derived from a human ovarian adenocarcinoma. ⁵⁰ A cisplatin-resistant subline of human lung cancer cells was also shown to undergo resistance reversal in vitro when cisplatin was coadministered with IH-90 (intestinal metabolite of Rb1 and Rd). ^37,51

Shin et al. ⁵² used a rodent model to demonstrate that red ginseng polysaccharide had a synergistic effect with paclitaxel against the proliferation of implanted sarcoma and melanoma cancer cell lines. The extract also restored NK cell activity suppressed by the drug. Radioprotective effects of ginseng pretreatment have also been demonstrated in rodent models. ^53-59 Immunomodulation effects of ginseng have been shown to preserve bone marrow function and CD4 cell activity during exposure to chemotherapeutic agents. ⁶⁰ A small trial ( n= 42) with stage III gastric cancer patients found that CD3/CD4 cell activity was preserved, with positive effects on survival, when red ginseng was combined with postoperative adjuvant chemotherapy. ⁶¹

Integrative Therapeutics, Clinical Concerns, and Adaptations

Clinical research is needed to corroborate these interactions in vivo. Given the pleiotropic anticancer effects of ginseng extracts, multiple rationales exist for incorporation of the herb into integrative protocols in the oncology setting. The antifatigue and immunomodulating effects of ginseng are likely to add to its usefulness, particularly for later-stage cancers. Modern Chinese medicine has incorporated herbal and conventional treatments to a higher degree than current Western practice, with ginseng a primary ingredient in compound formulations designed to address specific clinical circumstances. ⁶² At present, further clinical data are required to substantiate the use of ginseng in this context; however, its value as an adjuvant in oncology is beginning to be recognized in the West. ¹²

Ethanol

	Impaired Drug Absorption and Bioavailability, Negligible Effect
	Prevention or Reduction of Drug Adverse Effect
	Beneficial or Supportive Interaction, Not Requiring Professional Management

Probability: 2. Probable
Evidence Base:

Preliminary

Effect and Mechanism of Action

Ginseng appears to increase the metabolic clearance of ethanol and lower blood alcohol level, possibly by delaying gastric emptying. The clinical significance of the interaction is low.

Research

A much-quoted but methodologically limited preclinical study used 14 healthy males in an open-label and uncontrolled design that compared blood alcohol levels 40 minutes after ingestion for alcohol given alone and for the same dose of alcohol combined with 3 g Panax ginseng. Blood alcohol levels were 32% to 51% lower when ginseng was coadministered. Full pharmacokinetic measurements were not made, with no data on maximum concentration (C ^max ) or area under curve (AUC). ⁶³

Animal experiments have confirmed the general finding that alcohol clearance is increased by ginseng coadministration. Pretreatment with ginseng in a rat model (200 mg/kg) reduced ethanol AUC by 21% compared with controls. ⁶⁴ Pretreatment with ginseng and ginsenosides reduced the onset of loss of the righting reflex in mice treated with ethanol, but did not affect ethanol-induced sleeping time in the animals. ⁶⁵ Presence of a pharmacodynamic element in the effect of the ginseng/alcohol combination is uncertain. In a rodent model, however, red ginseng extracts reduced ethanol's impairment of a behavioral task, and administration of neurotropic agents suggested that this effect may be mediated by an adrenergic pathway. ⁶⁶ Another rodent study found that an ethanol-induced decrease in brain weight in neonatal rats was reduced by administration of ginsenosides, suggesting a neuroprotective effect against alcohol damage. ⁶⁷

Integrative Therapeutics, Clinical Concerns, and Adaptations

The ramifications of pharmacokinetic lowering of ethanol blood levels by ginseng are arguably of less clinical significance than interest for recreational alcohol consumers. This interaction should be clinically distinguished from potential neuroprotective activities of the ginseng saponins that may partly underlie the beneficial effects of the herb on cognitive function. ^68,69

Narcotic Analgesics (Opiates) and Psychostimulants

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.

Phenelzine and Other Monoamine Oxidase (MAO-A) Inhibitors

Evidence: Phenelzine (Nardil).

Extrapolated, based on similar properties, as MAO-A inhibitors: Isocarboxazid (Marplan), moclobemide (Aurorix, Manerix), procarbazine (Matulane), tranylcypromine (Parnate).

Potential or Theoretical Adverse Interaction of Uncertain Severity

Probability: 5. Improbable
Evidence Base:

Inadequate

Effect and Mechanism of Action

Possible hypomania or hypermania and exacerbation of CNS adverse effects normally associated with phenelzine alone have been reported during ginseng coadministration. Report reliability is low, the mechanism unknown, and the existence of the interaction improbable.

Research

Some data from in vitro and animal studies suggest effects of ginseng modulation on CNS neurotransmitters, but the clinical implications of such data are unknown, and extrapolations to in vivo interactions with effects on the monoamine oxidase system are unwarranted at this time. Tsang et al. ⁷⁸ showed that ginseng extracts dose-dependently inhibited uptake of gamma-aminobutyric acid (GABA), glutamate, dopamine, norepinephrine, and serotonin in rat brain synaptosomes. Ginsenosides compete with agonists for binding to GABA-A and GABA-B receptors. ⁷⁹ Panax quinquefoliusextracts are also known to exert GABA-A modulating effects. ⁸⁰

Reports

The claimed interaction between phenelzine and ginseng is listed in both conventional sources, such as Stockley, ⁸¹ and in authoritative monographs on Panax ginseng,including WHO. ⁴ This interaction is also reiterated by innumerable secondary and derivative sources, apparently based on two case reports, discussed here in depth.

The first documented report was a brief mention in a 1985 editorial by the then-editors of the Journal of Clinical Psychopharmacology,Shader and Greenblatt. ⁸² The case involved a 64-year-old woman who took an undisclosed dose for an undisclosed period of the combination dietary supplement product “Natrol High” while taking phenelzine, 60 mg/day. She then experienced symptoms of “insomnia, headache, and tremulousness.” Unfortunately, the authors failed to include any medical details or to identify the ingredients of the Natrol product, which contains no Panax ginseng,but rather some Eleutherococcus senticosus(previously known as Siberian ginseng), in combination with several micronutrients (e.g., niacin, vitamin B ⁶ , thiamine) and other herbs, including ginger, mallow, licorice root, and winter berry. ⁸³

In 1988, Shader and Greenblatt ⁸⁴ speculated further on the topic, relating to a further episode with the same patient. ⁸⁴ Now 67 years old and taking 45 mg phenelzine per day, the patient had been prescribed a herbal tea formula and some “ginseng” capsules “for energy.” The ingredients of the prescription tea formula and capsules were not identified and the dose not disclosed. She experienced similar symptoms as in the previous episode, but this time associated with increased depression. After cessation of the tea formula and “ginseng” capsules, she “felt better.”

The only other report on phenelzine is a letter from Jones and Runikis ⁸⁵ in 1987 commenting on the case in the original Shader-Greenblatt editorial. They briefly describe a 42-year-old female patient taking 45 mg phenelzine per day, along with 0.5 mg triazolam at night and 1 mg lorazepam four times daily. The patient concurrently consumed an unspecified amount of “ginseng and bee pollen.” The species and form of ginseng, the dose, and other constituents of the product were not disclosed. During coadministration of the herbal products and phenelzine, the patient became “extremely active and optimistic,” her sleep was decreased, and she did not “feel tired.” She also was irritable and had tension headaches and “occasional vague hallucinations,” which she attributed to the phenelzine, and she therefore ceased both the drug and the herbs. Her depressive symptoms then began to return, so she restarted the phenelzine at 45 mg/day. This time she experienced no therapeutic benefit from the drug (without the “ginseng and bee pollen”), although she did experience headache with the phenelzine alone.

The persistent citation of these two cases as evidence of a phenelzine-ginseng interaction is remarkable, given that ginseng was not even involved in the first case and not identified as the herb involved in the second. No dose was given, and concurrent multi-ingredient supplements were used, as well as psychiatric comedications in the second case. In addition, the adverse effects described are consistent with well-known adverse effects of phenelzine alone, which in both cases was used at doses higher (60 mg/day, 45 mg/day) than usual for maintenance therapy of 15 mg/day. Also, the Jones and Runikis case report ⁸⁵ seems to imply that the supplements were responsible for improved therapeutic outcome of the MAO inhibitor therapy, as opposed to the authors’ interpretation of an adverse effect, because rechallenge by phenelzine alone without the herbal agents failed to have a beneficial effect on depression.

An unrelated but possibly relevant case report from Italian psychiatrists Gonzales-Seljo and others claimed that ginseng alone is associated with mania. In fact, the patient had been taking lithium carbonate, 1200 mg/day, and amitriptyline, 75 mg/day, for 6 years. She abruptly ceased this regimen, then started taking one “ginseng tablet” (brand, form, dose, and other ingredients unidentified). Ten days after the cessation of lithium and amitriptyline, she became “manic,” including being sleepless, irritable, aggressive, and hyperactive. The authors suggested this must have been caused by the “ginseng.” Abrupt withdrawal symptoms from both lithium and tricyclics are well known, and relapse into mania after lithium withdrawal has been documented in at least 14 studies. ⁸⁶

Clinical Implications and Adaptations

The suggested ginseng-phenelzine interaction is in the “speculative-overstated” category. At least one of the three case reports relates to eleuthero (previously Siberian ginseng); this basic error was documented by Treasure and also by Chen, who notes this is the case in several of the infamous “ginseng abuse syndrome” reports. ^87-89 In the other reports the herb is simply unidentified. Neither the reports nor the known pharmacology of the herb lend significant support to the existence of an adverse interaction.

The declining use of phenelzine as a therapeutic intervention for depression (largely because of the lethal nature of interactions of this class of drugs with such common agents as dextromethorphan in OTC cough syrup) suggests that future routine pharmacosurveillance reports are unlikely to be forthcoming or to generate further clarification. The persistent tendency for secondary sources to repeat uncritically the interaction merits the full discussion here, but the clinical significance can be regarded as negligible. However, prudence still suggests great care be exercised when combining classic MAO inhibitors with botanicals or drugs known to interact in any significant way with neurotransmitter function.

Vaccine Immunotherapies

Potential or Theoretical Beneficial or Supportive Interaction, with Professional Management

Probability: 2. Probable
Evidence Base:

Preliminary

Effect and Mechanism of Action

Ginseng extracts may increase the effectiveness of some vaccine therapies. This synergy has been observed both directly, when vaccines are prepared with the addition of parenteral ginseng saponin ingredients, and indirectly with oral pretreatment with ginseng before vaccination. The mechanism of the increased antibody response may be improved immunogenicity from enhanced antigen-presenting cell (APC) activity. The clinical significance remains to be established.

Research

Scaglione et al. ⁹⁰ followed 227 patients attending a primary care practice who were scheduled to receive a polyvalent influenza vaccine. They were divided into two groups; one received G115, 100 mg ginseng per day, and the other placebo for 12 weeks. The vaccine was administered on week 4. There was a statistically greater incidence of subsequent influenza in the placebo group. At week 8, antibody titers and NK cell activity were much ( p< 0.0001) higher in the verum group.

In the veterinary setting, Rivera et al. ⁹¹ examined the effects of adding a ginsenoside preparation into a conventional porcine parvovirus (PPV) vaccine in a guinea pig model. They also injected ginseng and vaccine at separate sites, as well as providing ginseng pretreatment, followed by immunization. An aluminum hydroxide vaccine co-ingredient was also tested with and without ginsenosides. The Al(OH) ³ with ginseng mixture vaccine produced a 20-fold increase in immunoglobulin G (IgG) response to the PPV antigen, a synergistic effect greater than adding either Al(OH) ³ or ginsenosides alone. Rivera et al. ⁹² also conducted in vivo investigations with pigs and the commercial PPV vaccine, adjuvated with Al(OH) ³ , supplemented with ginseng versus vaccine alone. Vaccines with ginseng resulted in higher immunogenicity (higher IgG values by ELISA) than without ginseng. The authors suggest that ginseng may be a useful adjuvant for improving the potency and immunogenicity of commercial vaccine preparations.

Integrative Therapeutics, Clinical Concerns, and Adaptations

Ginseng saponins have well-established immunomodulatory effects. It appears likely that vaccine immunogenicity can be significantly enhanced by ginseng pretreatment and, more interestingly, perhaps by adding ginsenosides as a co-adjuvant to the vaccine mixture itself. The clinical benefits of using immunomodulating herbs for populations at risk of infection, whether alone or combined with conventional therapies, is an established practice among practitioners of botanical and natural medicine. Wider adoption of such integrative strategies may be predicated on currently emerging research data.

The increasing interest in vaccines in oncological settings may provide such a stimulus, and a recent study of relevance to the ginseng-vaccine interaction issue has come from this field. The priming of cell cultures with specific ginseng saponin metabolites (M1and M4 being bacterial hydrolysis products of ginsenosides) has been shown to increase the ability of dendritic cells to induce differentiation of T cells (i.e., to enhance Th1 responses), and ginseng may be a useful adjuvant in the emerging dendritic cell cancer vaccine field. ⁹³ However, future research is needed to clarify the full potential of ginseng in vaccine immunotherapies.

Evidence: Phenprocoumon (Jarsin, Marcumar), warfarin (Coumadin, Marevan, Warfilone).

Extrapolated, based on similar properties: Anisindione (Miradon), dicumarol, ethyl biscoumacetate (Tromexan), nicoumalone (acenocoumarol; Acitrom, Sintrom), phenindione (Dindevan).

Potential or Theoretical Adverse Interaction of Uncertain Severity

Probability: 5. Improbable
Evidence Base:

Mixed

Effect and Mechanism of Action

The mechanism of this suggested interaction, based on a single case report of INR reduction in a patient previously stable on warfarin, is unknown. The proposed interaction seems improbable or idiosyncratic.

Research

Zhu et al. ⁹⁴ investigated the potential warfarin-ginseng interaction in a rodent model. They examined pharmacokinetic and pharmacodynamic parameters in both single-dose and steady-state warfarin dosing regimens using plasma warfarin AUC and prothrombin time (PT) measurements. No significant effects were found on either single or multiple warfarin doses, either in terms of warfarin AUC or PTs. An open-label human study, using a randomized crossover design in 12 healthy subjects who had 7 days of pretreatment with high-dose ginseng (3.0 g/day, equivalent ∼ 45.0 mg ginsenosides/day), found no effect of ginseng coadministration on S-warfarin or R-warfarin enantiomer clearance and no significant effect on platelet aggregation or INR. ⁹⁵ By contrast, an in vitro study using human platelet aggregation assay resulted in significant reduction of thrombin- and collagen-induced aggregation in response to a red ginseng extract. ⁹⁶ The human data contrast with the available animal studies. In rodent models, ginseng administration led to a significant increase in PT and partial thromboplastin time (PTT) of rats treated with various anticoagulants. ^96,97

A recent clinical study used the related species P. quinquefolius(American ginseng) to examine potential interactions with warfarin. The study gave 12 healthy volunteers warfarin for 3 days at 5 mg/day, followed by 4 weeks of American ginseng (1.0 g twice daily), with a repeat 3 days of warfarin during the fourth week. Parameters measured were peak warfarin and peak INR, as well as INR AUC and warfarin AUC. Compared to controls, there were modest reductions in INR (except in one patient who showed an INR increase, as well as small but significant reductions in warfarin AUC and peak plasma levels). ⁹⁸ However, the variability of the results was very high, and there was no pharmacokinetic phenotyping of the healthy volunteers. Cytochrome P450 2C9 polymorphisms are known to be a critical factor associated with warfarin response variability. The ethnic composition of the study group suggested possible CYP450 2C9 phenotype variations as an explanation for the wide variability of the data, which were not controlled for by the investigators. ^99-102 The investigators’ comment that their study was conducted to clarify the matter of the Janetzky case report ¹⁰³ (see next) seems curious given the investigators choice of P. quinquefoliusrather than P. ginseng,which was the subject of the warfarin-ginseng case report.

Reports

The case report on which this potential interaction was based concerned a 47-year-old male with a history of hypertension, thrombosis, angina, and osteoarthritis. He was stabilized on warfarin at 5.0 mg/day and an INR of 3.0 to 4.0 for 9 months before commencing a ginseng preparation (Pharmaton 100-mg capsules, unspecified number, three times daily) for 4 weeks. He was comedicated with diltiazem at 30 mg three times daily, nitroglycerin as needed, and salsalate at 500 mg three times daily. After 4 weeks of ginseng coadministration, his INR was found to be 1.5. Two weeks after cessation of the herbal product, the INR returned to 3.3. The patient denied other changes to his dietary regimen, herb intake, or drug protocols. He did not experience a thrombotic episode during the period of reduced INR, but because of his history, a rechallenge was not performed. The authors noted that ginseng appeared to be associated with the INR change, but that the mechanism was not obvious. ¹⁰³

A similar report from Rosado ¹⁰⁴ involved a prosthetic aortic valve patient who failed to maintain his INR while taking warfarin and was admitted to a hospital with an acute myocardial infarction and diabetic ketoacidosis. The author suggested that self-treatment with an unconfirmed “ginseng” commercial product for an unspecified period was likely the cause of his INR decrease.

Both these reports remain as isolated examples, and given the poor level of documentation, they cannot be taken as reliable support for the interaction.

Clinical Implications and Adaptations

The weight of the currently available research data suggests that the reported ginseng-warfarin interaction is not a clinically significant problem. Further studies of more effective design should be conducted to examine possible differences between American and Asian ginseng species on hemostatic parameters and possible interactions with clinical anticoagulation. Because Coumadin interacts with a wide variety of substances, sometimes unpredictably, it is prudent to measure the INR at least twice weekly in the weeks after starting or stopping any another therapy, including other drugs, nutraceuticals, and botanicals. Only in recent years have the significant interactions of Coumadin with acetaminophen and cranberry juice been recognized, despite both these having been coadministered with Coumadin for many years before recognition of the interaction.

theoretical, speculative, and preliminary interactions research, including overstated interactions claims

Furosemide and Related Loop Diuretics

Bumetanide (Bumex), ethacrynic acid (Edecrin), furosemide (Lasix), torsemide (Demadex).

A frequently cited letter in JAMAsuggested that the development of refractory response to diuretic therapy in a 63-year-old man with membranous glomerulonephritis on a regimen that included cyclosporine and furosemide was caused by “germanium” content of a “ginseng” preparation. ¹⁰⁵ The ginseng species, dose, and duration of administration were not identified (nor were the other “daily nutritional supplements”). The basis for the authors’ supposition that the ginseng product contained germanium is therefore unclear; regardless, the “interaction” was attributed to germanium toxicity, not “ginseng,” and therefore describing it a “ginseng interaction” is incorrect by the author's own account. Without any corroboratory data, this interaction report is unevaluable and unsupported.

Oral Hypoglycemic Agents and Insulin

Buformin (Andromaco Gliporal, Buformina), chlorpropamide (Diabinese), glimepiride (Amaryl), glipizide (Glucotrol; Glucotrol XL), glyburide (glibenclamide; Diabeta, Glynase, Glynase Prestab, Micronase, Pres Tab), insulin (animal-source insulin: Iletin; human analog insulin: Humanlog; human insulin: Humulin, Novolin, NovoRapid, Oralin); metformin (Dianben, Glucophage, Glucophage XR); combination drugs: glipizide and metformin (Metaglip), glyburide and metformin (Glucovance); phenformin (Debeone, Fenformin), tolazamide (Tolinase), tolbutamide (Orinase, Tol-Tab).

Several secondary sources claim that there is a potential adverse interaction between ginseng and antidiabetic drugs. This appears to be a typical speculative “reverse extrapolation” based on the established property of American ginseng (P. quinquefolius)to induce postprandial glucose level lowering in animal and human studies. ^106,107 The use of other ginseng species, including P. ginseng, as adjuvants for glycemic control is not currently indicated by the available data, which are confined to parenteral administration in rodent models of polysaccharide compounds, “panaxans,” rather than ginsenosides. ^108,109

Clinical application of ginseng-related herbs in diabetes has been well reviewed by Sievenpiper et al. ^110-113 Relevant issues concerning commercial product variability, dose, and ginsenoside composition are raised in the context of safety and efficacy of these agents as potential antihyperglycemics. However, speculative assertions of adverse interactions are unwarranted by the data and represent a poorly informed clinical appreciation of the general clinical context of using herbal adjuvants in glycemic control.

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88.Chen KJ. The effect and abuse syndrome of ginseng. J Tradit Chin Med 1981;1:69-72.View Abstract
89.Treasure JE. MEDLINE and the mainstream manufacture of misinformation. J Am Herbalists Guild 2006;6:50-56.
90.Scaglione F, Cattaneo G, Alessandria M, Cogo R. Efficacy and safety of the standardised Ginseng extract G115 for potentiating vaccination against the influenza syndrome and protection against the common cold [corrected]. Drugs Exp Clin Res 1996;22:65-72.View Abstract
91.Rivera E, Daggfeldt A, Hu S. Ginseng extract in aluminum hydroxide adjuvanted vaccines improves the antibody response of pigs to porcine parvovirus and Erysipelothrix rhusiopathiae. Vet Immunol Immunopathol 2003;91:19-27.
92.Rivera E, Hu S, Concha C. Ginseng and aluminum hydroxide act synergistically as vaccine adjuvants. Vaccine 2003;21:1149-1157.
93.Takei M, Tachikawa E, Hasegawa H, Lee J-J. Dendritic cells maturation promoted by M1 and M4, end products of steroidal ginseng saponins metabolized in digestive tracts, drive a potent Th1 polarization. Biochem Pharmacol 2004;68:441-452.View Abstract
94.Zhu M, Chan KW, Ng LS et al. Possible influences of ginseng on the pharmacokinetics and pharmacodynamics of warfarin in rats. J Pharm Pharmacol 1999;51:175-180.View Abstract
95.Jiang X, Williams KM, Liauw WS et al. Effect of St John’s wort and ginseng on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects. Br J Clin Pharmacol 2004;57:592-599.
96.Yun YP, Do JH, Ko SR et al. Effects of Korean red ginseng and its mixed prescription on the high molecular weight dextran-induced blood stasis in rats and human platelet aggregation. J Ethnopharmacol 2001;77:259-264.View Abstract
97.Park HJ, Rhee MH, Park KM et al. Effect of non-saponin fraction from Panax ginseng on cGMP and thromboxane A₂ in human platelet aggregation. J Ethnopharmacol 1995;49:157-162.View Abstract
98.Yuan CS, Wei G, Dey L et al. Brief communication: American ginseng reduces warfarin’s effect in healthy patients: a randomized, controlled trial. Ann Intern Med 2004;141:23-27.
99.Redman AR, Dickmann LJ, Kidd RS et al. CYP2C9 genetic polymorphisms and warfarin. Clin Appl Thromb Hemost 2004;10:149-154.
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101.Kamali F, Khan TI, King BP et al. Contribution of age, body size, and CYP2C9 genotype to anticoagulant response to warfarin. Clin Pharmacol Ther 2004;75:204-212.
102.Scordo MG, Pengo V, Spina E et al. Influence of CYP2C9 and CYP2C19 genetic polymorphisms on warfarin maintenance dose and metabolic clearance. Clin Pharmacol Ther 2002;72:702-710.
103.Janetzky K, Morreale AP. Probable interaction between warfarin and ginseng. Am J Health Syst Pharm 1997;54:692-693.
104.Rosado MF. Thrombosis of a prosthetic aortic valve disclosing a hazardous interaction between warfarin and a commercial ginseng product. Cardiology 2003;99:111.
105.Becker BN, Greene J, Evanson J et al. Ginseng-induced diuretic resistance. JAMA 1996;276:606-607.View Abstract
106.Xie JT, Wu JA, Mehendale S et al. Anti-hyperglycemic effect of the polysaccharides fraction from American ginseng berry extract in ob/ob mice. Phytomedicine 2004;11:182-187.View Abstract
107.Xie JT, Mehendale SR, Wang A et al. American ginseng leaf: ginsenoside analysis and hypoglycemic activity. Pharmacol Res 2004;49:113-117.View Abstract
108.Oshima Y, Konno C, Hikino H. Isolation and hypoglycemic activity of panaxans I, J, K and L, glycans of Panax ginseng roots. J Ethnopharmacol 1985;14:255-259.View Abstract
109.Konno C, Murakami M, Oshima Y, Hikino H. Isolation and hypoglycemic activity of panaxans Q, R, S, T and U, glycans of Panax ginseng roots. J Ethnopharmacol 1985;14:69-74.View Abstract
110.Sievenpiper JL, Arnason JT, Leiter LA, Vuksan V. Variable effects of American ginseng: a batch of American ginseng (Panax quinquefolius L.) with a depressed ginsenoside profile does not affect postprandial glycemia. Eur J Clin Nutr 2003;57:243-248.View Abstract
111.Sievenpiper JL, Arnason JT, Vidgen E et al. A systematic quantitative analysis of the literature of the high variability in ginseng (Panax spp.): should ginseng be trusted in diabetes? Diabetes Care 2004;27:839-840.View Abstract
112.Sievenpiper JL, Arnason JT, Leiter LA, Vuksan V. Decreasing, null and increasing effects of eight popular types of ginseng on acute postprandial glycemic indices in healthy humans: the role of ginsenosides. J Am Coll Nutr 2004;23:248-258.View Abstract
113.Sievenpiper JL, Arnason JT, Leiter LA, Vuksan V. Null and opposing effects of Asian ginseng (Panax ginseng C.A. Meyer) on acute glycemia: results of two acute dose escalation studies. J Am Coll Nutr 2003;22:524-532.View Abstract

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