Final Updates and Additions

for

HERB CONTRAINDICATIONS AND DRUG INTERACTIONS, 3^rd ed.

including extensive Appendices addressing

COMMON PROBLEMATIC CONDITIONS, MEDICationS AND NUTRITIONAL SUPPLEMENTS,

AND INFLUENCES ON pHASE i, ii & iii METABOLISM

with new Appendix on

botanicals AS COMPLEMENTARY ADJUNCTS WITH DRUGS

by Francis Brinker, N.D.

Copyright 2010

All rights reserved

Nothing from this document may be reproduced for sale or distribution in any form.

Last update July 13, 2010

Combining herbal use with medications should only be done after consultation with a knowledgeable physician. Preliminary research data on potentially beneficial combinations of herbals and drugs is provided to educate pharmacists and physicians and encourage further clinical research. Information provided in this book is not intended as recommending self treatment or to replace instructions provided by one’s own doctor or health care provider.

Introduction +

The content on this site is presented to supplement the information found in the third edition of the book. By this means the database can be enlarged, enhanced and updated without the user having to annually purchase a new printed edition largely containing information already provided in the previous edition or subscribing to an online updating service. The format for this site is consistent with that found in the book, so that herbs and appendix categories can be easily accessed by the same arrangement as in the printed text. The page numbers for the updates indicate where in the book the associated information can be found, while additions are identified as "NEW." The added reference citations begin with 1100. Citations for lower reference numbers are found in the book. Changes in scientific binomials and standardized common names used here are now based on the second edition of Herbs of Commerce (2000).

Since the information on this site presupposes familiarity with the content in the book, it must be understood in that context. The content on this site must be recognized as inadequate without access to what has been published in the 3^rd edition. However, abbreviated versions of prior referenced statements about the contraindications or the drug interactions are included at the beginning of an addition to identify the context of the addition. Listed below are important terms, abbreviations, and symbols used in the book and/or on this site, followed by a Table of those herbs and appendix sections to which additions have been made.

Regarding herbal contraindications, many bridge the empirical vs. speculative designations, with greater evidence provided by one or the other, though a combination of factors often contribute. The method of determining such designations is imprecise, and what is described as a speculative contraindication for self-prescribing by the general public (the method employed for this text and web site) may in some cases be more accurately described as a precaution for an expert prescriber educated in botanical medicine (as indicated in other texts primarily intended for professional use). Potential risks from contraindications or adverse interactions can be uncertain in regard to the actual degree of risk due to conflicting evidence. For this reason, in such cases the inclusion of contradictory data in a separate indented paragraph prefixed with the word, “However,” has been used as a means of emphasing the equivocal nature of the extant evidence for some controversial contraindications or interactions.

As stand-alone evidence of drug interactions with herbals, laboratory studies in vivo with animals in Category II. and/or with in vitro cell or tissue cultures in Category III. are insufficient to extrapolate the findings to humans with certainty. The reasons for this are many. For one, animals and their intestinal bacterial flora differ from humans in their abilities to digest, absorb, and/or metabolize the many different types of components found in any complex botanical preparation. Similar but distinct problems exists with in vitro laboratory studies utilizing cell organelles, cell cultures, tissues, or isolated organs. The systemic exposure of living tissues to complex solutions extracted from plants following intestinal absorption does not involve the same chemical content and proportions as is found in laboratory conditons where cells and tissues are exposed to the complete extract. Clinical case reports or case series appear to be of more real value in determining an herbal effect than extrapolating laboratory data to a clinical setting. In the absence or preferably in the context of controlled clinical studies, combining all types of preclinical evidence based on similar preparations facilitates a more complete and, hopefully, a more dependable assessment.

When herbal influence on drug pharmacokinetics is discussed, the term “bioavailability” is often used as a short-hand term to describe the total Area Under the concentration-time Curve (AUC). Though the total time that the drug concentration is monitored may vary from a few hours to a few days depending upon the study, this general term is applied to conveniently indicate when the overall average circulating serum level of the drug has been significantly altered.  Results reported here as "significant" are deemed so based on statistical significance demonstrated by a P value of < 0.05, at most. However, statistical significance in changes to biological markers does not guarantee a clinically significant effect when it comes to assessing therapeutic outcomes.

KEYS TO INTERPRETTING CONTENT IN THE BOOK AND AT THIS SITE

The following terms are used to describe the different means of determining botanical effects.

The categorization of I, II, III and IV is used to rank potential herb-drug interactions according to their probable pertinence based on the strongest degree of evidence available.

Where contradicting data exists for a particular item in any category, this is noted by an indentation, and the sentence will begin with the word, “However.”

I. human studies – published research done on healthy individuals

human clinical studies – published research from therapeutic trials on patients being treated for a condition

empirical – traditional knowledge or consensus based on experience from extensive use

human case reports – published individual responses to using herbal products

human case series – published responses from several patients using a preparation of the same herb

II. in animals (types listed) – laboratory tests using live animals (in vivo) and various modes of administering the herb or herbal component(s)

III. ex vivo –laboratory interaction finding on cells, tissue, or organs from animals or humans who were administered the herbal agent (as contrasted to in vivo when studies are done on the living organisms themselves)

in vitro –laboratory interaction finding with cell or tissue samples from animals or humans

speculative – using pharmacological evidence from in vitro research, animal studies, or human studies to infer probable or potential interactions or effects in humans

IV. [dubious interactions] shown in brackets with the drugs underlined rather than in bold type are based on preliminary findings, speculation, inaccurate information, and/or false assumptions that have been contradicted by established evidence.

Abbreviations for the various modes of administration are used as follows:

IM (intramuscular) – injected into a large skeletal muscle

IP (intraperitoneal) – injected into the peritoneal cavity

IV (intravenous) – injected into a vein

PO (per os) – by mouth; orally or through a feeding tube; b.i.d. = 2x/day, t.i.d. = 3x/day

SC (subcutaneous) – injected under the skin

ADDITIONAL INFORMATION BASED ON THE FOLLOWING IS AVAILABLE FOR THE LISTED HERBS AND APPENDICES:

+ denotes new contraindication(s) and/or interaction(s) not previously listed in the book for the herb

^ denotes new herb with contraindication(s) and/or interaction(s) in body of text or an entirely new appendix section

Ä denotes use of new standardized common name from second edition of Herbs of Commerce

If none of the above are present in the list below, elaborations have been made to information already included in the book.

An asterisk (*) in front of an herb’s scientific name denotes toxic effects from over-consumption of that herb or a major active component.

Where [CORRECTION:] appears before numbers or information in ALL CAPS, it denotes correction of an error found in the book.

HERBAL AGENTS – Contraindications and/or Drug Interactions

The following list are those herbs that are either new or for which updates or new information has been added.

Agar +

Agave ^

Alfalfa +

American ginseng +

Andrographis ^

Anise +

Apricot ^

Arjun ^

Arnica +

Artichoke +

Ashwagandha +

Asparagus +

Astragalus

Bacopa ^

Barberry +

Basil +

Beebalm ^

Beth root ^

Bilberry

Birch +

Bitter melon +

Bitter orange +

Black chokeberry ^

Black cohosh +

Black cumin ^

Black currant ^

Bladder kelp ^

Bladderwrack +

Blue cohosh +

Blue flag ^

Blue vervain ^

Bloodroot +

Boldo +

Borage +

Boswellia ^

Bromelain +

Burdock +

Butcher's broom ^

Butternut ^

Cajeput ^

Calendual +

California spikenard ^

Camphor bark +

Caraway ^

Cascara sagrada

Cassia cinnamon + Ä See Cassia

Cat’s claw +

Cayenne

Celandine +

Celery +

Chamomile, German + Ä See Chamomile

Chamomile, Roman Ä See Roman Chamomile

Chaste tree +

Chickweed ^

Chicory +

Chinese cucumber ^

Chinese skullcap ^ Ä

Cinchona +

Cinnamon +

Clove +

Cocoa +

Coffee

Comfrey +

Copaiba ^

Coptis ^

Cordyceps +

Corydalis ^

Cotton +

Couch grass Ä See Triticum.

Cranberry ^

Cranesbill ^

Crucifers

Cumin ^

Dan shen

Dandelion +

Devil’s claw

Dill +

Dog rose ^

Dong quai +

Dulse +

Dyer’s broom +

Eastern red cedar ^

Eleuthero

Ephedra

Eucalyptus

European pennyroyal ^

European vervain ^

Evening primrose +

False unicorn root ^

Fennel +

Fenugreek +

Feverfew

Flax

Forsythia ^

Fragrant angelica ^

French maritime pine ^

Garlic +

Ginger +

Ginkgo

Ginseng + Ä See Asian ginseng

Goat’s rue ^

Goldenrod ^ Ä For Solidago virgaurea see European goldenrod.

Goldenseal +

Gotu kola +

Grapes ^

Grapefruit +

Guar gum +

Guarana

Guggul ^

Gurmar + Ä See Gymnema

Hawthorn +

Henna ^

Hops +

Horse chestnut +

Horseradish +

Horsetail +

Iboga +

Inmortal ^

Ipecac +

Jamaica dogwood +

Job’s tears ^

Jujube seeds ^

Kava +

Konjac

Kudzu +

Kutaki Ä

Lavender Ä See English lavender.

Lemongrass +

Licorice +

Life root

Lobelia +

Lomatium ^

Lycium ^

Maca ^

Maitake +

Makandi +

Mangosteen ^

Marijuana + See Cannabis.

Marshmallow +

Mate

Meadowsweet +

Milk thistle +

Muirapuama ^

Mustard

Myrrh +

Nard ^

Neem ^

Nutmeg +

Oat +

Ocotillo ^

Olive +

Orange ^

Oregon grape +

Osha ^

Papain

Passion flower +

Pennyroyal Ä See American pennyroyal.

Peppermint +

Periwinkle Ä See Lesser periwinkle.

Petasites +

Plantain Ä For Plantago lanceolata see English plantain.

Pleurisy root +

Poke ^

Pomegranate +

Prickly ash

Prickly pear

Psoralea ^

Psyllium

Puncture vine ^

Purslance ^

Quassia (Jamaican) ^

Quassia (Surinam) ^

Queen Ann’s lace Ä See Wild carrot

Raspberry +

Red clover +

Rehmania +

Reishi +

Rhatany ^

Rhodiola ^

Rhubarb, Chinese Ä See Chinese rhubarb

Royal sun agaricus ^

Sage +

Schizandra +

Scotch broom

Scouring rush ^

Sea buckthorn ^

Senna +

Sesame ^

Shepherd’s purse +

Shrub aloe ^

Small spikenard ^

Soy +

Spikenard ^

St. John’s wort +

Stevia ^

Stinging nettles +

Sweet annie ^

Sweet clover

Szechuan lovage ^

Szechuan pepper ^

Tea +

Tea tree ^

Thuja +

Thunder god vine ^

Thyme +

Tobacco +

Turkey tail +

Turmeric +

Tylophora ^

Uva ursi

Valerian +

Vetiver ^

Watercress +

Wheat ^

Wild cherry Ä See Black cherry

Wild lettuce +

Wild marjoram See Oregano

Wild yam +

Willow +

Wintergreen ^

Witch hazel +

Wormwood +

Yarrow +

Yellow dock ^

APPENDIX SECTIONS WITH NEW HERBALS, DATA OR SECTIONS ADDED:

Appendix A – Herbals To Be Used With Caution

A.2 Due To Potential Photosensitizing Effect

A.2.1 Carrot family

A.4 In Acute Inflammation of the Urinary Tract

A.4.1 Medicinal Plants Containing Urinary Irritants

A.4.2 Medicinal Plants Containing Soluble Oxalates

A.5 In Gastrointestinal Irritation

A.5.1 Herbals That Can Upset the GI Tract

A.6 In Hypothyroid Conditions or Euthyroid Goiter

A.6.2 Antigoitrogens

A. 7 Due to Potential Adverse Effects

A.7.1 Herbals With Toxic Potential

Appendix B – Herbal/Drug Interactions

B.1 Modifying Intestinal Absorption of Medicines [AND PHASE III METABOLISM]

B.1.1.b.i Selective Precipitation of Alkaloids and Minerals by Tannins

B.1.1.b.ii Precipitation by Non-tannin Phenols

B.1.1.f Slows and/or Decreases Active Intestinal Transport by hPepT1 and/or Others

B.1.2.c Enhanced retention of Drugs by Inhibiting MRP1 or MRP2 ^

B.1.3 No Influence on Drug Absorption in Humans ^

B.1.3.a No Effect on P-glycoprotein Efflux ^

B.2 Potentiating Cardiotonic Medicines

B.2.2.b Potentiation by Kaliuretics and/or Diuretics

B.3 Potentiating Sedative or Tranquilizing Medicines

B.3.1 Hypnotic and/or Anxiolytic Drug Enhancement

B.4 Modigying Blood Sugar in Insulin-Dependent Diabetics

B.4.1 Hypoglycemic Herbals

B.4.2 Antihyperglycemic Botanicals Enhancing Oral Hypoglycemic Drugs in Humans ^

B.5 Modifying the Effects of Anticoagulants

B.5.1.c Warfarin or Heparin Metabolism Inhibitors and/or Anticoagulant Adjuvants

B.5.1.d Platelet Aggregation Inhibitors

B.5.1.e Fibrin Formation Inhibitors or Fibrinolysis Promoters

B.7 Modifying Enzyme Activities in Metabolic Conversions

B.7.1.a Modulation by Phase I &/or Phase II Enzymes &/or Other Clearance Factors

B.7.1.b Influence on Pregnane X Receptor (PXR) ^

B.7.1.c Influence on Aryl hydrocarbon Receptor (AhR) ^

B.7.2.a Influence on CYP 1A2 Metabolic Conversion of Substrates

B.7.2.b Influence on CYP 2E1 Metabolic Conversion of Substrates

B.7.2.c Influence on CYP 3A4 Metabolic Conversion of Substrates

B.7.2.d Influence on CYP 2C9 Metabolic Conversion of Substrates ^

B.7.2.e Influence on CYP 2C19 Metabolic Conversion of Substrates ^

B.7.2.f Influence on CYP 2D6 Metabolic Conversion of Substrates ^

B.7.3.a Influence on Glutathione S-Transferase Activity or its Isozyme Levels

B.7.3.b Influence on Activity and/or Content of UDP-Glucuronosyltransferases [UGT]

B.7.3.c Influence on NADPH-Quinone Reductase [QR] (DT-Diaphorase) Activity and/or Content

B.7.3.d Influence on Epoxide Hydrolase (Epoxide Hydratase)[EH] Activity

B.7.4.a Aromatase (CYP19) Conversion of Testosterone to 17b-Estradiol

B.7.4.b 5a-Reductase Conversion of Testosterone to Dihydrotestosterone

B.7.4.d 11b-Hydroxysteroid Dehydrogenase type 2 Conversion of Cortisol to Cortisone

B.7.4.e 17b-Hydroxysteroid Dehydrogenase types 1, 3 or 5 Conversion of Androstenedione to Testosterone

B.7.4.f 17b-Hydroxysteroid Dehydrogenase type 2 Conversion of Testosterone to Androstenedione or Estradiol to Estrone ^

B.7.4.g 17b-Hydroxysteroid Dehydrogenase type 1 Conversion of Estrone to Estradiol ^

B.7.4.h 3b-Hydroxysteroid Dehydrogenase type 1 or 2 Conversion of DHEA to Androstenedione and/or Pregnenolone to Progesterone ^

B.7.5 Herbal Monoamine Oxidase –A &/or –B Inhibitors

Appendix C – Herbals Contraindicated for Mothers and Children

C.1 During Pregnancy

C.1.1 Herbals That May Impact the Uterus or Fetal Development

Appendix D – Vitamin/Mineral/Drug Interactions

D.1 Drug and Mineral Interactions with Vitamin Supplements

D.1.5 Vitamin B₆ (Pyridoxine, Pyridoxamine, Pyridoxal) / Drug Interactions

D.1.5.a Vitamin B₆-Rich Herb and Vegetable Sources

D.1.7 Folic Acid / Drug Interactions

D.1.8 Vitamin C (Ascorbic Acid, Ascorbates) / Drug Interactions

D.1.10.a Vitamin E-Rich Plant Sources

D.2 Drug and Vitamin Interactions with Mineral Supplements

D.2.1 Calcium / Drug Interactions

D.2.1.a Calcium-Rich Herb and Vegetable Sources

D.2.2.a Copper-Rich Herb and Vegetable Sources

D.2.4 Iron (as Ferrous Sulfate) / Drug Interactions

D.2.4.a Iron-Rich Herb and Vegetable Sources

D.2.5.a Magnesium-Rich Herb and Vegetable Sources

D.2.6.a Manganese-Rich Herb and Vegetable Sources

D.2.7.a Potassium-Rich Herb and Vegetable Sources

Appendix E – Herbals as Complementary Adjuncts with Medicines ^

E.1. Potentially Beneficial Combinations of Herbals with Drugs [formerly Addendum]

E.2. Herbal Aids for Modifying Substance Abuse ^

E.3 Complementing Treatment of Inflammations ^

E.4. Enhancing Chemotherapy and Chemoprevention or Reducing the Adverse Effects ^

E.5. Herbals for Preventing and Healing Radiation Adverse Effects and/or Enhancing Radiotherapy or Photodynamic Therapy ^

E.6. Herbals and Anti-infectious Agents ^

References

1100. – 2708.

Introduction

There are many possible meanings of the word “herb.” Taken in its broadest medicinal sense, it commonly refers to all plants and/or plant parts. Traditionally, it has been applied to the above-ground part of non-woody plants, excluding their roots and/or rhizomes. The term is used in this text with this intended meaning, to describe the part of the plant used for many of the botanicals included herein. In the culinary arts an herb is distinguished from spices as referring primarily to aromatic leaves, in contrast to seeds, bark, or roots/rhizomes. In all of these cases, the word is intended to be understood as the whole part of the fresh or dried plant, characteristically including its fiber content.

For the purposes of understanding the title of this book in all of its ramifications, the concept of “herb” incorporates chemically complex derivatives of all plant parts. This extended application of the term is in consideration of the majority of studies using only derivatives of the medicinal parts of plants. These extractives include, for example, juices, teas, tinctures, volatile oils, and other fractions that are physically or chemically removed from the fresh or dried plant parts. These preparations are more properly referred to as botanicals or “herbals”, the terms now employed in the text. Since these commercial derivatives are commonly consumed, it is important to acknowledge the specific forms used in studies when this is adequately described in published research.

By extension, major active components of the plants have been used to help understand the pharmacology of the extracts and whole herbs. Discussion of isolated phytochemicals should not be taken to imply that the pharmacology of a commonly used extract or herb is identical to that of a single compound that these may contain. Rather, the activity of an isolated compound is simply one contributing factor to the overall effect derived from using the extract or herb. The same case can be made in regard to a subfraction or even commonly used extracts, when compared to the whole herb itself. At each level of growing complexity (from isolate to subfraction to extract to herb) the influence of the isolate in relation to the overall effect diminishes both in quality and quantity.

Nevertheless, it remains useful to consider specific pharmacological research regarding the activity of isolates, subfractions, and extracts, when considering the effects of the herb itself. For this reason, research data from all of these forms are used as evidence in this book to help document the probability of specific outcomes. This remains a useful approach as long as it is understood that direct application of the findings for a specific preparation apply only to that preparation and dose; other correlations necessarily fall short.

The term “bioequivalence” is a relative concept, in that certain extractives or derivatives of an herb have more or less similarity to one another, depending on each one’s unique phytochemical content and proportions. Bioequivalency certainly cannot be assumed to strictly corrlate with an initial amount of plant material from which many variable preparations can be made. Though the inherent variability in content and complexity of “similar” preparations may be unsettling for the scientific purist, it should be no more uncomfortable than considering the fact that each person who uses a herb or its extract is also genetically and biochemically unique in their own peculiar response to the remedy. It is knowledge of the general similarities regarding pathophysiology, pharmacology and therapeutic responses in conjunction with an understanding of the individual distinctions between both preparations used and patients using them that comprise the challenging art of medical practice. These are facts that must be acknowledged and addressed in each case, to optimize the safety and efficacy of the intervention. The same relative significance can be applied to different quantities consumed of the exact same preparation. While an accepted therapeutic dose and duration can be completely safe, increasing its consumption in amount and/or length of use beyond its acknowledged safe limitations can lead to undesirable adverse effects. Therefore, in addition to characterizing the form used in scientific studies it is important to describe the dosage used.

In some cases, animal and in vitro evidence can provide either contradictory or supporting evidence to help assess the likelihood of interaction report(s) involving botanicals and drugs or in establishing mechanistic evidence for contraindication rationales.As stand-alone evidence, laboratory studies with animals (in vivo) and/or with cell cultures (in vitro) are insufficient to extrapolate the findings to oral dosing in humans. The reasons for this are many. Animals differ from one another and from humans in their abilities to digest, absorb, and/or metabolize the many different types of components found in any complex botanical preparation. Animal studies often utilize exaggerated doses to produce an effect that is more readily observed or measure biochemically, but this exposure also may not correlate with typical human dosage. In many animal studies on botanicals the use of injections helps to maintain a consistent and reliable dosage, but systemic bioavailability of the complete phytochemical complex does not accurately represent the partial systemic exposure that follows digestion and absorption with oral dosing in humans.

Similar but distinct problems exists with laboratory studies utilizing cell cultures or isolated organs. The exposure of living tissues to complex solutions extracted from plants following intestinal absorption does not involve the same content and proportion as is found in laboratory conditons where cells and tissues are exposed to the complete extract. The pre- and postabsorption conversion of various phytochemicals in the extract, potentially involving both activation and/or deactivation from digestion and metabolism, does not occur to nearly the same extent in cell monocultures and the nonreactive in vitro glass environment. The concentration tested in vitro also often greatly exceed tissue exposure in vivo. These issues call into question many of the so-called “mechanisms of actions” that supply the basis for theoretical indications, contraindications and interactions on which many speculate. In the case of these in vitro laboratory studies, more may be learned about potential mechanisms by studying the contribution of isolated components found in the herbs and/or extracts, so long as the particular isolate has been shown to absorbed systemically and is bioavailable in the sustained concentrations as tested in the lab. The only direct application of herb or extract in vitro lab data might be their local use on superficial tissues, i.e, the skin or mucosa, or on associated microbial growth on these surfaces.

HERBAL AGENTS –

Contraindications and Drug Interactions

AGAR p. 27

^ Gelidium spp. thallus

Drug Interactions

III. + 1) May inhibit absorption of oral drugs such as aspirin, digitalis and other cardiac glycosides, antibiotics, and anticoagulants if administered concurrently (speculative)¹⁵⁰

AGAVE NEW

^ Agave americana plant, juice

Contraindications

1) Pregnancy (empirical)² due to its emmenagogue and abortifacient effects (empirical)⁷⁴

ALFALFA p. 27

Medicago sativa plant

Drug Interactions

I. + 2) A kidney transplant patient maintained on azathioprine and cyclosporin for 16 years suffered severe acute rejection after taking alfalfa and black cohosh (Cimicifuga racemosa) for 6 weeks, though serum cyclosporine levels were not altered. Anti-T-cell immunoglobulin and steroid helped control transplant rejection. Immunostimulation through T-cell activition by alfalfa’s l-canavanine is suspected as contributing to the kidney rejection (PO in human case report).¹⁵⁵³

II. 1) CORRECTION: increase rate of metabolism of ETHOXYCOUMARIN in the liver by increasing the activity of hepatic microsomal mixed-function oxidase reactions (PO in mice)¹⁰³

III. + 3) The cytotoxic effect of gemcitabine, a standard drug for pancreatic cancer, on pancreatic cancer cells was inhibited in the presence of coumestrol and genistein even when used at 2.5 times higher concentration (in vitro)¹⁶⁸¹

ALOE p. 29

Aloe vera = Aloe barbadensis gel (not the dried sap)

Contraindications

+ 2) Allergic hypersensitivity to aloe preparations such as contact dermatitis (empirical).¹⁸⁹⁰

+ 3) Pregnancy without professional advice (speculative) due to uterine stimulant, abortifacient, and/or teratogenic effects (in vitro, PO in rat study).¹⁸⁹⁰

Drug Interactions

IV. + 1) Following extensive bleeding in the surgical removal of a large hemangioma, this effect was attributed in part to a possible interaction between sevoflurane and the consumption of 4 tablets per day for two weeks of Aloe vera (PO in human case report). It was not known whether the aloe tablets were a whole herb product or contained an extract, nor were the tablets analyzed for constituent or to detect potential adulterants. Sevoflurance inhibits COX activity and TXA₂, impairs platelets, and prolongs bleeding, while aloe was suspected of contributing by reducing prostaglandin synthesis.¹⁷⁸⁵ This speculation was based on a study of a water extract and successive fractions with n-hexane, benzene, ethyl acetate, chloroform, acetone, and 96% ethanol from Aloe vera dried gel. Only the water extract of the gel reduced PGE₂ production (in vitro).¹⁷⁸⁶

ALOES p. 29

*Aloe vera, Aloe ferox, or Aloe perryi dried leaf latex or sap (not the gel)

Contraindications

8) Do not take during intestinal obstruction due to stimulation of peristalsis by the anthroquinones (empirical).^4,6,150,401

Causes of obstruction include stenosis and atony.¹⁸⁹⁰

+ 13) Allergic hypersensitivity to aloe preparations such as contact dermatitis (empirical)¹⁸⁹⁰

+ 14) Do not take if there is known dehydration due to depletion of water and electrolytes (empirical).¹⁸⁹⁰

Drug Interactions

IV. + 1) Following extensive bleeding in the surgical removal of a large hemangioma, this effect was attributed in part to a possible interaction between sevoflurane and the consumption of 4 tablets per day for two weeks of Aloe vera (PO in human case report). It was not known whether the aloe tablets were a whole herb product or contained an extract, nor were the tablets analyzed for constituent or to detect potential adulterants. Sevoflurance inhibits COX activity and TXA₂, impairs platelets, and prolongs bleeding, while aloe was suspected of contributing by reducing prostaglandin synthesis.¹⁷⁸⁵ This speculation was based on a study of a water extract and successive fractions with n-hexane, benzene, ethyl acetate, chloroform, acetone, and 96% ethanol from Aloe vera dried gel. Only the water extract of the gel reduced PGE₂ production (in vitro).¹⁷⁸⁶

AMERICAN GINSENG p. 30

Panax quinquefolius root

Contraindications

1) Estrogenic activity, especially of alcoholic root extracts, may be present in large part due to zearalenone and its metabolites from Fusariam fungal contamination (in vitro).¹⁶⁹⁵ In addition estrogen-independent stimulation of human breast cancer cell proliferation with the alcoholic extract (in vitro)¹⁶⁶⁴ suggests that regular consumption of the root or its alcoholic extracts should be avoided in those with a history of breast cancer (speculative)

Drug Interactions

I. + 1) 3 grams or more of the powdered root given prior to a glucose challenge reduced blood sugar levels in seven type 2 diabetics whose condition was being treated with sulfonylureas or a combination of these and metformin (PO in human study).¹¹¹⁴

In 12 nondiabetic subjects 3 grams of the dried cultivated root tended to lower plasma glucose at 90 minutes during a 75-gram oral GTT, but the same dose of wild root raised blood sugar after 120 minutes (PO in human study).¹⁷¹³ From 3-9 grams of the ground root improved glucose tolerance following a 25 gram glucose challenge in 10 nondiabetics (PO in human study).¹⁶⁸⁵ However, different batches of the root from the same supplier that differed in ginsenoside ratios were not consistent in reducing blood sugar of normal subjects under the same experiemental conditions (PO in human study).¹⁵⁹⁶ Roots grown in Wisconsin have shown wide variability in total and individual ginsenoside content from those grown in Illinois.¹⁷¹⁴

A water extract of the root has been shown to significantly lower blood sugar, probably due to the activity of several glycans (IP in mice).¹⁵⁷⁴

An alcoholic extract of the berries at 150 mg/kg daily in diabetics also lowers fasting blood sugar and improves overall glucose tolerance while lowering body weight (IP in mice).¹⁷⁰⁴

+ 2) 2 grams of encapsulated powdered root for 3 weeks in healthy subjects significantly reduced blood levels and anticoagulant effect of warfarin (PO in human study). The peak INR decreased along with peak plasma warfarin, compared to placebo.¹⁶⁰⁰

II. + 1) Hot water extract at 400 mg/100 gm given 10 minutes prior to ethanol delayed the effects of ethanol on the righting reflex and reduced its plasma levels, probably due to the additive effect of slowing of gastric emptying by alcohol and American ginseng extract or ginsenosides (PO in mice)¹¹¹⁷

+ 2) The saponin fraction enhanced phenylephrine vasoconstrictor effect (in vitro)¹⁵⁵⁰

III. 1) Standardized extract synergistically increased suppression of estrogen-dependent cancerous breast cells when combined with tamoxifen, cytoxan, doxorubicin, taxol and methotrexate (in vitro).⁹⁸¹

Tumor inhibition may be due in part to the antiangiogenic activity of its predominant ginsenoside Rb1, the opposite effect associated with Rg1 (in vitro, SC in mice)¹⁶⁸⁶ However, an alcoholic extract stimulated growth in the MCF-7 human breast cancer cell line (in vitro), though it showed no estrogenic activity in failing to induce transactivation of alpha- or beta-estrogen receptors (in vitro) or increase uterine weight after 4 days (PO in mice).¹⁶⁶⁴

In 3 digoxin immunoassays, an aqueous American ginseng extract increased the digoxin measurement results for the fluorescence polarization immunoassay (in vitro). Using the microparticle enzyme immunoassay, this extract significantly lowered the serum digoxin measurement (in vitro). No effect was found on the measurement done by Tina-quant (in vitro).¹⁹⁹⁵

AMERICAN PENNYROYAl [formerly PENNYROYAL] p. 159

Ä *Hedeoma pulegioides plant

ANDROGRAPHIS NEW

^ Andrographis paniculata plant

Contraindications

1) Pregnancy due to its abortifacient effects (empirical),¹⁵⁰ antifertility effect in females at high doses (in mice),⁷⁷⁷ and fetal damage (in animals)¹⁸⁹⁰

2) Gastric hyperacidity such as duodenal ulcers and esophageal reflux (empirical).¹⁸⁹⁰

Drug Interactions

III. 1) Avoid long-term use with immunosuppressive drugs (speculative)¹⁸⁹⁰ due to the activation of immunocompetent cells by its extract and component andrographolide (in vitro).¹⁹⁶⁷

2) Caution should be used when taking with antiplatelet or anticoagulant medications (speculative),¹⁸⁹⁰ since it inhibits platelet aggregation after consumption by cardiovascular disease patients (ex vivo).^404,1890

ANISE p. 31

Pimpinella anisum seed/fruit

Contraindications

+ 3) CNS toxicity following consumption the tea, especially in nursing mothers and/or their breast fed infants (PO in human case reports)¹¹⁴¹

+ 4) Pregnancy (speculative)¹⁵⁰ probably due to its estrogenic effects of its essential oil component anethole¹⁴ and the antagonism of testosterone and progesterone by anise seed oil (injected in rats)¹³¹²

APRICOT NEW

^ Prunus armeniaca seed

(Ch. xing ren)

Contraindications

1) Self prescribing due to potential for adverse effects from cyanogenic glycosides (speculative)¹⁵⁰

2) Children due to increased vulnerability to toxic and lethal effects from cyanogenic glycosides (empirical)¹⁵⁰

Drug Interactions

II. + 1) The absorption of sulfasalazine was increased 2- to 4-fold when taken with apricot extract (PO in rats).²²⁸⁷

ARJUN NEW

^ Terminalia arjuna bark

(Manipuri: Maiyokpha; Tamil: Marutu; Malayalam: Nirmarutu; Kannada: Nirmatti)

Drug Interactions

I. 1) An extract given at 500 mg 3 times/day for 2 weeks improved symptoms of patients with Class IV refractory chronic congestive heart failure compared to placebo, when given in a crossover design to 12 patients taking digoxin, along with the diuretic drugs furosemide, and spironolactone (PO in human clinical study). In addition, vasodilator prescriptions included 8 for enalapril, 3 for captopril, 1 for nifedipine, and 3 for isosorbide dinatrate. Antiarrhythmic medication amiodarone was used by 2 patients, while all were administered potassium supplements. In an open continuation of the trial for a mean of 24 months signs and symptoms continued improving for 2-3 months and were maintained throughout the study, while diuretic dosages were reduced for all and other doses were kept flexible. After 4 months 9 patients were at Class II and 3 at class III.²⁶⁶¹

ARNICA p. 31

Arnica montana flowers

Contraindications

+ 6) Internally by nursing mothers and not applied topically to the nipple, due to potential toxicity to the infant (empirical).¹⁸⁹⁰

ARTICHOKE p. 32

Cynara solymus leaves

Contraindications

1) Allergic hypersensitivity to artichoke or other Asteracea [Compositae] family plants (empirical),^{6,17,401,777,1890}

though the likelihood of globe artichoke preparations producing an allergic response is very low (empirical).¹⁸⁹⁰

A man and a woman who handled artichokes in their occupations suffered seasonal allergic eruptions and urticaria, respectively, and tested positive to patch or skin prick tests, especially to the stem, leaves, and their fuzz (TP in human case reports).^1974,1975

2) Bile duct obstruction, due to its cholagogue effect (empirical)^{6,17,401,777,1890}

and its choleretic activity as shown with a single 1.9 gram dose of its 4.5-5:1 strength extract (PO in human study).¹²⁷⁰

Drug Interactions

III. 1) It may enhance cholesterol-lowering agents, due to additive effects (speculative).⁷⁷⁷

Tablets with 450 mg of a 25-35:1 aqueous extract reduced total cholesterol, LDL cholesterol, and LDL/HDL ratio (PO in human clinical study).¹²⁷¹

ASHWAGANDHA p. 33

Withania somnifera root

Drug Interactions

II. + 2) After 10 days of using 100 mg/kg of a commercial root extract, tolerance to morphine analgesia was inhibited, and morphine dependence was blocked (PO in mice study), suggesting that it could be of use in opiate addiction¹²⁷⁷

+ 3) Leucopenia induced by cyclophosphamide was significantly reduced by ashwagandha methanolic extract (IP in mice). So, the intended cytotoxic activity of this chemotherapeutic agent and its efficacy in treating cancer may be diminished (speculative).¹⁵⁸³

However, when 4/5 of the total ashwagandha root extract was combined with 1/5 Tinospora cordifolia stem extract or the alkaloid-free polar ashwagandha extract was given in cyclophosphamide-treated ascitic sarcoma, not only did the extracts provide myelo- and immuno-protective activity, but the drug’s antitumor activty was not altered when compared to cyclophosphamide given alone (PO in mice).²²¹⁷

Also, 20 mg daily for 5 days of the methanolic extract was shown to reduce bladder damage caused by cyclophosphamide metabolites, one of the leading causes of adverse effects from this drug (IP in mice). Rather than severe inflammation and hemorrhage 4-48 hours after the drug, when given the extract the bladder morphology was normal, the elevated serum and urine protein levels were normalized, while the lowered liver and bladder glutathione levels were enhanced.¹²⁷⁹

However, the discontinuity effects caused by cyclophosphamide on the GI mucous membrane with bleeding spots in the lower esophagus and upper stomach were not affected by ashwagandha extract, suggesting the extract’s inability to protect against general cyclophosphamide cytotoxicity (PO in mice).¹²⁷⁸

100 mg/kg root extract given for 15 days with cyclophosphamide, azathioprin and prednisolone prevented the myelosuppressive activity of these drugs by increasing the hemoglobin, red blood cell and platelet counts for all three groups, and the white blood cell count for the cyclophosphamide and prednisolone groups (PO in mice). The response was different for azathioprin and prednisolone than with cyclophosphamide in that it reflected more of a direct response of the immune system to ashwagandha, rather than indirect modulation or interference with the drug’s immunosuppressive action.¹²⁷⁸

+ 4) Pretreatment with 100 mg/kg extract enhanced the antiepileptic effects of diazepam and clonazepam when convulsions were induced by lithium-pilocarpine model (PO in rats)¹²⁹⁰

+ 5) Adverse effects such as orofacial dyskinesia and poor memory retention induced by reserpine and associated with brain lipid peroxidation have been reversed dose-dependently by chronic use of ashwagandha root extract (PO in rats).¹⁸⁵⁵

+ 6) Increased levels of pertussis antibodies were detected after 100 mg/kg of a water extract was given daily for 15 days after receiving a Diphtheria, Pertussis, Tetanus [DPT] vaccine (PO in mice). When immunized animals were challenged on day 14 with intracerebral pertussis, morbidity and mortality were reduced in those that had been treated with the extract.²⁰⁰⁶

+ 7) A decrease in benzo(a)pyrene-induced lung tumor markers AHH, GGT, and LDH in the serum and lungs by paclitaxel was further decreased when ashwaganha ethanol extract 400 mg/kg once weekly for 4 weeks was added to paclitaxel treatment (PO in mice). Likewise, a further reduction of lung glycoprotein markers was also noted with the combination, compared with use of paclitaxel alone.²²¹⁸

+ 8) Catalepsy induced by haloperidol was reduced dose-dependently when an ashwagandha water extract was given 30 minutes prior to haloperidol in the acute study and for 6 days prior in the chronic study (PO in mice). The reduction in catalepsy was correlated with superoxide dismutase levels in the brain, indicating that the antioxidant activity of the extract could have contributed to its effect.²²⁹⁵

9) In 3 digoxin immunoassays, 3 liquid hydroalcoholic extracts were fed to animals, and the serum was tested and produced significant false positive apparent digoxin concentrations (PO in mice). These results were confirmed for digoxin with fluorescence polarization immunoassay but not for carbamazepine, phenytoin, phenobarbital, valproic acid, procainamide, N-acetyl procainamide, theophylline, gentamicin, tobramycin, acetaminophen, or salicylate (in vitro).²⁶⁶⁵ A 60-65% ethanolic ashwagandha extract increased the digoxin measurement results for the fluorescence polarization immunoassay (in vitro). Using the microparticle enzyme immunoassay, this extract significantly lowered the serum digoxin measurement (in vitro). No effect was found on the measurement done by Tina-quant (in vitro).¹⁹⁹⁵

asian GINSENG [Formerly GINSENG.] p. 107

Panax ginseng root

Contraindications

1) High blood pressure (empirical, human case report)^{150,361,404,777}

However, 200 mg of a ginseng extract standardized to 4% ginsensosides reduced diastolic blood pressure 2 hours after ingestion.¹²⁹⁸

2) Acute asthma (empirical)^404,777,1308

or other inflammation (empirical)¹³⁰⁸

3) Acute infections^404,777

accompanied by fever (empirical)¹³⁰⁸

4) Excessive menstruation or nose bleeds (empirical)⁷⁷⁷

due to platelet aggregation inhibition by ginsenoside Rg₁ (in vitro)¹¹⁹⁶ and ginseng lipophilic fraction (in vitro, ex vivo), and prolonged time of fibrinogen conversion to fibrin (ex vivo) following a 25 mg dose of the lipophilic fraction (PO in rats)¹¹⁹⁴

However, 10 adults taking a proprietary Asian ginseng product at the manufacturer’s recommended dose for 2 weeks had no increase in coagulation time in ADP and epinephrine assays of intrinsic and extrinsic platelet function, respectively (ex vivo), but the product was not analyzed for its phytochemical content.²²⁶²

+ 5) Headaches, palpitations or strong pulse, or insomnia since ginseng can cause these in some people (empirical)¹³⁰⁸

+ 6) Anxiety, nervousness or emotional imbalance due to its enhancement of the sympathetic nervous system (speculative),¹³⁰⁸ or in those with clinical affective disorders such as major depression who may experience a manic state (PO in human case report)^27,560,1461

+ 7) Pregnancy due to possible estrogenic effects (speculative)¹³⁰⁸

Estrogenic activity, especially of alcoholic extracts, may be present in large part due to zearalenone and its metabolites from Fusariam fungal contamination (in vitro).¹⁶⁹⁵

One study of 88 pregnant women suggested an increase risk of adverse fetal outcome (PO in human study).¹⁵⁰⁹

Ginsenoside Rb₁ at concentrations of 30-50 mcg/ml increased teratogenic effects in whole rat embryos (in vitro),¹⁴⁸⁵ results with uncertain implications for women taking the whole root or complex extracts in typical doses.

+ 8) Brittle type 1 diabetes (speculative)⁸⁹³ because of the hypoglycemic effect in diabetic patients (PO in human clinical study),¹⁰⁹ probably due to the glycans of ginseng roots known as panaxans (IP in mice)^567-569 and/or ginsenoside Rb₂ that lowered blood sugar in diabetics (IP in rats).⁷²

However, the anti-hyperglycemic activity was not confirmed as a hypoglycemic effect, since doses ranging from 1 to 9 grams of powdered root in a randomized, multiple-crossover design did not significantly affect plasma glucose or insulin following an oral glucose tolerance test (PO in human study). Rather, the 2-hour plasma glucose was significantly higher in pooled results.¹⁶¹² Also, effects in 12 nondiabetic subjects on 75-gram oral glucose tolerance test responses to 3 grams of dried root varied according the type of ginseng. The dried whole root was found to raise plasma glucose, whereas Asian-red ginseng steam-treated root had no effect (PO in human study).¹⁷¹³ Compound K, the main gut bacterial metabolite of protopanaxadiols, enhances glucose transport rate, while the major protopanaxatriol Rg1 inhibits glucose transport across intestinal cells (in vitro) These act by modulating the sodium/glucose cotransporter 1 gene expression (in vitro).²⁰⁴³

An alcoholic extract of the berries at 150 mg/kg daily in diabetics also lowers fasting blood sugar and improves overall glucose tolerance while lowering body weight and plasma cholesterol levels (IP in mice). The antihyperglycemic activity, but not the anti-obesity effect, is due in large part to ginsenoside Re.¹⁷⁰⁵

+ 9) Use at least one week, and definitely in the 24 hours, prior to surgery due to short term potential for hypoglycemia and long term potential for decreased coagulation leading to hemorrhage (speculative).^1309,1310 The hypoglycemic effect appears to be due to the glycans of ginseng roots known as panaxans (IP in mice).^567-569 Diminished coagulation may be attributed to panaxynol, ginseng lipophilic fraction, and some ginsenosides’s antiplatelet activity (in vitro^{410,565,1194, 1196} and lipophilic fraction ex vivo¹¹⁹⁴), and prolonging time of fibrinogen conversion to fibrin by ginsenoside Ro (in vitro)⁵⁶⁵ and ginseng lipophilic fraction (ex vivo) following a 25 mg dose of the lipophilic fraction (PO in rats),¹¹⁹⁴ and the potent platelet activating factor antagonism of several ginsenosides (in vitro).⁷¹⁸

However, 10 adults taking a proprietary Asian ginseng product at the manufacturer’s recommended dose for 2 weeks had no increase in coagulation time in ADP and epinephrine assays of intrinsic and extrinsic platelet function, respectively (ex vivo), but the product was not analyzed for its phytochemical content.²²⁶²

Drug Interactions

I. 1) Caffeine with large amounts of “ginseng” led to hypertension, nervousness, diarrhea, skin eruptions and insomnia in 14 subjects (PO in human case series).¹⁰⁸

Caffeine metabolism by CYP 1A2 was not affected when 1.5 gm of ginseng standardized to 5% ginsensosides was consumed daily for 4 weeks. CYP 2D6, 2E1, and 3A4 were also unaffected (PO in human study).¹³²⁸

3) Phenelzine produced manic-like symptoms with the use of ginseng (human case reports).^26,27

However, the “Natrol High” product that supposedly contained Asian ginseng in one report²⁶ actually contained the generically- and phytochemically-distinct eleuthero or “Siberian ginseng” (Eleutherococcus senticosus) as part of a combination product. Positive identification of ginseng and its causality in the other report was not established. This interaction was still assessed as possible due to the evidence in latter report, while the former was described as unevaluable based upon its inadequate data.¹²³⁹

+ 5) When 5.4 gm of red Korean ginseng were taken daily with zidovudine by HIV-1 infected patients for 4-6 years, it effectively maintained their CD4+ T cell counts and delayed development of resistance mutations to zidovudine (PO in human clinical study).¹³³⁵ In addition to zidovudine, red ginseng use with nucleoside reverse transcriptase inhibitor (NRTI) didanosine lowered resistance mutations, but not for lamivudine, and no multinucleoside drug resistance mutations were detected (PO in human clinical study).¹³³⁶

+ 6) Following surgical removal of stage III gastric cancer in 42 patients, 4.5 grams daily of red ginseng powder doubled 5-year and overall survival rates and improved CD3 and CD4 levels compared to placebo, while patients were also given chemotherapy with 5-fluorouracil and cisplatin (PO in human clinical study).¹³⁸²

+ 7) 200 mg daily of the standardized extract G 115 given 4 weeks prior and 8 weeks after a polyvalent influenza vaccine resulted in significantly fewer cases of influenza and the common cold during the 8 weeks following vaccination than in the group receiving placebo. The antibody titers and natural killer cell activity were also much higher in those receiving the extract, along with no significant differences in adverse effects (PO in human clinical study).⁴⁰⁸

+ 8) 200 mg/day of uncharacterized "ginseng" for 18 days inhibited metabolism of CYP 3A4 substrate nifedipine, as indicated by increased peak plasma concentration of 29% (PO in humans).¹⁷²⁸

However, daily doses for 28 days of 1.5 gm Asian ginseng standardized to 5% ginsenosides failed to alter the metabolism of CYP 3A4 substrate midazolam in humans (PO in human study).¹³²⁸ Likewise, 200 mg/day for 14 days of ginseng extract standardized to 4% ginsenosides failed to alter cortisol metabolism in 20 subjects (PO in human study).¹⁸¹¹

+ 9) A woman treated for major depression with clomipramine and haloperidol became manic with the use of 300 mg/day of a ginseng root extract (PO in human case report).¹⁴⁶¹

Clomipramine is a substrates for CYP 2D6, while haloperidol is a substrate for CYP 3A4. A daily dose of 1.5 grams of an Asian ginseng product standardized to 5% ginsenosides inhibited metabolism of the substrate debrisoquin CYP 2D6 by 7% and an uncharacteried product inhibited CYP 3A4 as shown by increasing the peak plasma concentration of substrate nifedipine by 29% (PO in human studies),^1728,1808 though standardized ginseng extracts with other 3A4 substrates showed no altered bioavailability (PO in human studies).^1328,1811

10) [Previously III.2.] Warfarin anticoagulant activity was reduced as the INR fell from 3.1 to 1.4 following several weeks of taking ginseng extract G 115 capsules 3 times daily (PO in speculative human case report). Two weeks after the extract was discontinued, the INR returned to 3.3.¹¹⁰

Nonetheless, in a diabetic man with aortic valve prosthesis, a thrombus interfered with the artificial leaflets valve in conjunction with a reduction of INR to 1.4 in spite of increasing warfarin dosage, following use of an undisclosed commercial ginseng product used at an unreported dose for an indefinite time (PO in human case report).¹⁹⁸⁶

However, a study of 25 ischemic stroke patients given warfarin with or without 1.5 grams/day of an 11:1 aqueous ginseng extract for 2 weeks did not result in any differences in INR or prothrombin time between the two groups (PO in human clinical study).²³²⁶ When 1 gram solid Korean red ginseng aqueous extract daily was given for 6 weeks to patients using warfarin, there were no significant changes in INR after 3 or 6 weeks, compared to placebo (PO in human clinical trial).²⁶²⁵ Furthermore, an open-label 3-way crossover randomized trial with 12 healthy subjects found that ginseng extract daily providing 53.6 mg ginsenosides derived from 3 grams of the root given 7 days before and after a single warfarin dose does not affect warfarin clearance, INR, or platelet aggregation (PO in human study).¹⁵⁷⁸ In this study the apparent clearance was increased by 14%, but this seems unlikely to have clinical significance (speculative).²⁰¹⁶

+ 11) A randomized, double-blind, crossover trial using Korean ginseng rootlets in capsules at doses of 2 grams 3 times daily before meals for 12 weeks in 19 patients with well-controlled diabetes type 2 treated with diet plus hypoglycemic drugs alone or in combination in 14, including sulfonylurea in 10, metformin in 9, rosiglitazone in 2, and acarbose in 1; this resulted in reduction in oral glucose tolerance test indices by 8-11% and plasma insulin by 33-38% (PO in human clinical study). It also increased insulin sensitivity indices by 33% compared to placebo. The rootlets had total ginsenoside concentration of 1.92% with content of protopanaxadiols Rb1 0.48%, Rc 0.29%, and Rb2 0.25%, along with protopanaxatriols Rg1 0.51% and Rf 0.23%.²⁰⁴²

Ginseng extract’s anti-hyperglycemic effect was shown in non-insulin-dependent diabetic patients when 200 mg daily was given orally for 8 weeks (PO in human clinical study).¹⁰⁹ Ginseng extract G115 at single doses of 200 mg and 400 mg reduced fasting blood glucose levels in 30 healthy young adults after 60, 90 and 120 minutes (PO in human study).²¹⁵³

However, the anti-hyperglycemic activity was not confirmed as a hypoglycemic effect in healthy subjects, since doses ranging from 1 to 9 grams of powdered root in a randomized, multiple-crossover design did not significantly affect plasma glucose or insulin following an oral glucose tolerance test (PO in human study). Rather, the 2-hour plasma glucose was significantly higher in pooled results.¹⁶¹² When given with a 25-gram glucose drink to 27 healthy subjects, 200 mg of G115 actually raised blood sugar levels after 1 hour but had no effect after 2 hours, compared to controls (PO in human study).²¹⁵³ Also, effects on 75-gram oral glucose tolerance test responses in 12 nondiabetic subjects given 3 grams of dried root varied according the type of ginseng. The dried whole root was found to raise plasma glucose, whereas Asian-red ginseng steam-treated root had no effect (PO in human study).¹⁷¹³ Compound K, the main gut bacterial metabolite of protopanaxadiols, enhances glucose transport rate, while the major protopanaxatriol Rg1 inhibits glucose transport across intestinal cells (in vitro) These act by modulating the sodium/glucose cotransporter 1 gene expression (in vitro).²⁰⁴³

II. + 3) Extract G115 increased intestinal clearance of the active metabolite albendazole sulfoxide (IV in rats)¹⁷¹¹

+ 4) An acidic polysaccharide fraction of red ginseng, derived from the marc following 85% ethanol extraction, combined with paclitaxel increased life span with transplanted sarcoma 180 by 29-43% at 25 mg/kg and reduced B16 melanoma tumor weight by 76% at 100 mg/kg, compared to the results from using paclitaxel alone (IP in mice)¹⁷²¹

+ 5) The use of the 5 grams/day of the root as a decoction for 30 days along with doxorubicin (adriamycin) given by intraperitoneal injection over a 2-week period reduced the physical and biochemical signs of heart failure associated with the drug (PO in rats).²²⁵⁷

III. + 1) Insulin dosage may need adjusting (speculative) because of ginseng extract’s hypoglycemic effect in diabetic patients (PO in human clinical study).¹⁰⁹

Effects in 12 nondiabetic subjects on 75-gram oral glucose tolerance test responses to 3 grams of dried root varied according the type of ginseng and the protopanaxadiol to protopanaxatriol ratio. The dried whole root was found to raise plasma glucose, whereas Asian-red ginseng steam-treated root had no effect (PO in human study). The Asian-red protopanaxadiol content and ratio were greater.¹⁷¹³

A randomized study found that while 6 grams Korean red ginseng root body and water extract were ineffective in reducing glycemia from a 50-gram glucose tolerance test, the rootlets were effective (PO in human study). A dose of 2 grams of rootlets was found to be equally effective, and the ginsenoside Rb1 was identified as the sole predictor of effects on postprandial glucose.¹⁹⁷⁷

However, another study with 27 young healthy subjects showed that the extract G115 at single 200 mg doses lowered fasting blood sugar from 60-120 minutes compared to placebo, but when given with a drink containing 25 grams of glucose it raised blood glucose levels more than when glucose was given alone (PO in human study).²⁰¹⁸

An ethanolic extract of ginseng berries that differed in ginsenoside proportions had an even greater anti-hyperglycemic and anti-obesity effects than the root extract (IP in mice).¹⁵⁹⁷ The alcoholic extract of the berries at 150 mg/kg daily in diabetics also lowers fasting blood sugar and improves overall glucose tolerance while lowering body weight and plasma cholesterol levels (IP in mice). The antihyperglycemic activity, but not the anti-obesity effect, is due in large part to ginsenoside Re.¹⁷⁰⁵

2) [See IV. 2)]

+ The synergistic cytotoxic effect of the chemotherapy drug mitomycin C combined with ginseng component panaxytriol was shown on gastric carcinoma MK-1 cells (in vitro).¹⁷¹²

3) [Formerly IV. 1)] Using 5 digoxin immunoassays on 2 liquid Asian ginseng extracts and 1 capsule, one liquid increased the digoxin concentration results only for the fluorescence polarization immunoassay (in vitro, ex vivo with rats, ex vivo with humans). Using the microparticle enzyme immunoassay, the liquid extract significantly lowered the serum digoxin measurement (ex vivo with humans).^1352,1995

IV. 1) [See III. 3]

ASPARAGUS p. 34

Asparagus racemosus root

Drug Interactions

II. + 1) Increased levels of pertussis antibodies were detected after 100 mg/kg of a water extract was given daily for 15 days after receiving a Diphtheria, Pertussis, Tetanus [DPT] vaccine (PO in mice). When immunized animals were challenged on day 14 with intracerebral pertussis, morbidity and mortality were reduced in those that had been treated with the extract.²⁰⁰⁶

ASTRAGALUS p. 34

Astragalus membranaceus root

Contraindications

+ 2) Allergic hypersensitiviy or autoimmune conditions, since they may be aggravated due to immunostimulating polysaccharides (speculative).⁴⁰⁹

+ 3) Following organ transplantation due to immunostimulating polysaccharides (speculative).⁴⁰⁹

Drug Interactions

I. 1) The effects of recombinant interferon-a1 were therapeutically enhanced with an astragalus preparation that improved the outcome in chronic viral cervicitis associated with human papillomavirus type 16 and herpes simplex virus type 2 (human clinical study).²³⁵⁹

+ 2) A meta-analysis compiled 34 randomized trials that combined astragalus herbal formulas with chemotherapy regimens based on cisplatin for non-small-cell lung cancer in 2,815 patients. The data showed that chemotherapy plus oral astragalus formulas such as Jin Fu Kang, or Ai Di Zhu She Ye injections containing astragalus used 8 studies, improved outcomes versus chemotherapy alone (PO or IV in human clinical studies). Seven studies (529 patients) showed reduced risk of death after 6 months, twelve (940 patients) after 12 months, nine (768 patients) after 24 months, and six (556 patients) after 36 months. One of the studies reducing this risk from 12-36 months used astragalus alone, rather than in a formula. Tumor response rate favored the combination with herbs in 29 of 30 studies reporting this data, including two with astragalus alone. Karnofsky performance status was stabilized or improved in one study with astragalus alone, two studies with Jin Fu Kang, four studies with Ai Di Zhu She Ye, and five studies with other astragalus formulas, totaling 1,095 patients.¹⁸⁵¹ Astragalus decoction enhanced immune function by increasing proliferation of spleen cells, increasing B cell IgG production, enhanced induction of cytoxic T cells, and increased macrophage cytokine production of IL-6 and TNF (in vitro).¹⁸⁵²

II. 2) The hydroalcoholic extract induced Th cells and enhanced antibody response following use of cyclophosphamide (IP in mice).⁵⁹⁹

A partially purified fraction completely reversed immunosuppression induced by cyclophosphamide (IV in rats).¹⁵⁰⁴

Another fraction of the water extract of the roots was shown after 6 days to increase proliferation of colony-forming unit-fibroblast proliferation and improve bone marrow stromal cell survival, its production of IL-6, and expression of mRNA and bcl-2 protein, which helps promote blood cell formation after cyclophosphamide myelosuppression (IP in mice).²²¹²

So, if cyclophosphamide is being used for treatment of lymphomas or leukemias or to prevent graft rejection, concurrent use of astragalus could have an undesirable antagonistic effect to the immunosuppression.

BACOPA new

^ Bacopa monniera = Herpestis monniera whole plant

(Brahmi; Ind.: Brahmi Patra)

Drug Interactions

II. 1) Both cold aqueous infusion and 95% alcoholic extract potentiated sleep induced by pentobarbital, though the water extract was much more active (IP in rats)¹²⁹¹

2) Dried alcoholic extract at 40 mg/kg prevented increased lipid peroxidation and decreased antioxidant enzymes in liver caused by morphine when the two were given concurrently (PO in rats).¹⁶⁶¹ In addition, prior exposure of intestinal ileum to the alcoholic extract before exposure to morphine reduced the subsequent naloxone-induced contraction of the ileal tissue (in vitro), suggesting a possible use in reducing morphine withdrawal symptoms.¹⁶⁶²

3) After using phenytoin for 7 days cognitive deficit demonstrated in a passive avoidance task was reversed by 40 mg/kg dried alcoholic extract given concurrently for the next 7 days (PO in mice), suggesting possible use to prevent this adverse drug effect. Acquisition and retention of memory were also improved, and phenytoin's anticonvulsant activity was not affected.¹⁶⁶³

BARBERRY p. 35

*Berberis vulgaris root bark

Contraindications

+ 9) Do not use in nursing mothers without professional advice (speculative), since berberine is passed through the breast milk to the infant¹⁸⁹⁰ and displacement by berberine of bilirubin from serum albumen which may lead to kernicterus (IP in rats).¹⁰⁹²

Drug Interactions

I. + 3) Berberine 1.2 grams daily, given as tablets to 79 congestive heart failure patients on ACE inhibitors along with digoxin in 76, nitrates in 71, and diuretics / spironolactone in 77, significantly increased left ventricular ejection fraction and exercise capacity, improved dyspnea-fatigue index, and reduced frequency of ventricular premature complexes compared with 77 patients using only comparable conventional medications. The mortality of the berberine group decreased significantly as well, and there were no apparent side effects (PO in human clinical study).¹⁴⁵⁷ In 56 congestive heart failure patients on loop diuretics and ACE inhibitors, including 51 using digoxin and 46 on nitrates, the significant increases in left ventricular ejection fraction and decreases in ventricular premature beats from baseline from 1.2 grams of berberine daily was also significant better when plasma berberine concentrations were higher versus lower than 0.11 mg/L (PO in human clinical study).²⁶³⁹

+ 4) Berberine at 0.6 grams daily for 3 months increased previously stabilized cyclosporin A trough blood concentrations by 90% in 52 renal transplant patients, and when given for 12 days to 6 transplant patients increased the cyclosporine bioavailability by 35% (PO in human clinical study), likely by inhibition of CYP 3A4 (speculative).²²⁸¹

+ 5) The combination of 500 mg berberine 3 times daily for 3 months in 43 patients with poorly-controlled type 2 diabetes together with one or more of their regular oral hypoglycemic medications including sulfonylureas in 28, metformin in 20 acarbose in 15, and/or insulin in 10 resulted in lower fasting and postprandial blood sugar from week 1 through week 12 (PO in human clinical study). Fasting plasma insulin was also lowered by 28% and an index of insulin resistance by 45% of those on medications, while total cholesterol and LDL were likewise reduced. In 31 newly diagnosed type 2 diabetics to whom 15 were given the same dose of berberine and 16 used 500 mg metformin 3 times daily, berberine’s hypoglycemic effect was similar to that of metformin on fasting and postprandial blood glucose, as well as reducing glycosylated hemoglobin and plasma triglycerides (PO in human clinical study). Transient gastrointestinal adverse effects were experienced by 35% of the patients, or 20 in total.²³¹⁵

II. 1) The antitumor constituent berbamine (20 mg/kg once daily for 7 days) significantly enhanced antitumor activity of cyclophosphamide against Walker tumor (IP in rats).³⁹⁸

When the alkaloid component berberine was given once or twice at doses of 50, 100, or 200 mg/kg before cyclophosphamide injection, it significantly reduced the chemotherapy adverse effect of bladder hemorrhage in a dose-dependent manner (IP in rats).²⁵⁷⁰

2) Berberine administered prior to pentobarbital increased the induced sleeping time (IP in mice)¹⁰³²

A single 4 mg/kg dose of berberine prolonged pentobarbital sleeping time and increased strychnine toxicity (PO in rats)¹²¹⁵

+ 3) Pre-treatment with 4 mg/kg berberine prevented a rise in serum levels of liver enzymes from excessive acetaminophen, suggesting protection from its toxic effects (PO in rats). Use of this dose three times every six hours following a toxic dose of acetominophen reduced liver damage.¹²¹⁵

+ 4) Berberine at 100 mg/kg enhanced the anxiolytic effects of buspirone and ritanserin but did not interact with diazepine (PO in mice).²⁶⁶⁸

III. 3) Berberine increased efflux of rhodamine 123 and paclitaxel by inducing P-glycoprotein and thereby reducing the retention and concentration of these drugs in human hepatoma and digestive tract cancer cells, respectively (in vitro)^1045,1046

+ 4) Studies in human liver-derived cells with berberine was found to have an additive effect with lovastatin by increasing LDL receptor mRNA expression (in vitro). This statin did not reduce this effect of berberine, indicating a different mechanism of action (in vitro). In 63 high-cholesterol subjects taking 1.0 grams berberine HCl daily for 3 months, serum cholesterol was reduced 18%, LDL cholestreol 20%, and triglycerides 28%, compared to those using placebo (PO in human study). In the 32 who were taking no other medication or herbs, cholesterol was reduced 29%, LDL cholesterol 25%, and triglycerides 35%. HDL cholesterol was unaffected, and berberine was well tolerated. Berberine was found to have a dose-dependent cholesterol-lowering effect (in hamsters).¹⁶⁵⁶

+ 5) Do not combine with phenylbutazone or other drugs that displace protein binding of bilirubin (speculative),¹⁸⁹⁰ since displacement by berberine of bilirubin from serum albumen which can lead to kernicterus (IP in rats).¹⁰⁹²

BASIL p. 37

Ocimum basilicum plant

Drug Interactions

III. + 1) Alkaline aqueous extracts of basil were shown to potentiate insulin activity in glucose metabolism (in vitro).¹⁴⁶⁴

BEEBALM NEW

^ Monarda spp. plant