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Herbal Safety

and Introductory

Phytochemistry

Richard Mandelbaum RH (AHG)

richardmandelbaum.com

arborvitaeny.com

Natural does not equal Safe!

Case study:

Piper methysticum (kava)

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Spectrum of Plant Activity

Spectrum of Plant Activity:

Food→Medicine→Poison

“The dosage makes

the medicine”

“The dosage makes

the poison”

Most adverse effects from herbs are not safety

issues per se, but fall under the categories of:

� Product quality / impurities

� Allergic or idiosyncratic and generally minor

reactions

� Misuse / overdose

� Predictable pharmacodynamic interactions

� Neglecting traditional contraindications

A well-trained herbalist using only highest

quality herb and products can minimize

all these risks

*

� Most serious adverse effects involve

� Branches / nuts falling on head

� Adulteration

� Microbial contamination

� Toxic metals

� Radioactivity

� Agricultural chemicals

� Other pollutants

� Pharmaceuticals

� Misidentification

� Wrong plant

� Wrong plant part

� Overdose

� Including standardized products

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Criteria for quality

of herbal medicines

� Positive identification

� Organic or ethically wildcrafted from a “clean” location

� Proper harvesting: correct time of year, correct part of

plant used

� Integrity of product: unadulterated

� Correct processing / preparation:

� Properly extracted

� Properly dried and/or stored (including shelf life)

� Freshly ground

� Whole plant extract (Standardization: myth vs. reality)

Adriane Fugh-Berman, Herb-drug interactions THE LANCET • Vol 355 •

January 8, 2000

Hemlock tea

Tsuga canadensis

I WILL MAKE YOU FEEL

FRESH AND

REVITALIZED AND GIVE

YOU A BOOST OF VITAMIN C TO BOOT.

Hemlock tea

Conium maculatum

I WILL KILL YOU DEAD

DEAD DEAD (AND I WILL

BE QUICK ABOUT IT

TOO).

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Dosage considerations

� Safety: therapeutic index

� Is the herb dosage-specific or dosage-flexible? (High dose herbs, Low dose herbs)

� Age (e.g. Clark’s Rule)

� Weight� Individual sensitivity� Individual absorption, metabolism, and excretion

� Reasons taking the herb: immediate effects vs. long term effects

� Economics- the price:dose ratio!

Other considerations in

formulating

� Synergies

� Incompatibilities

� Additive effects

� Final dosage per herb in formula:

therapeutic or subtherapeutic?

� Taste

� Financial realities

Using Herbs Safely

� Indications / Activity

� Contraindications

� Primary, secondary,

tertiary, etc. effects

� Toxicity; interactions

� Short term vs. long

term use

� Dosage

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Categories to Consider

Regarding Herbal Safety

� Poisonous plants: specific toxic constituents

� Phototoxicity

� Hypersensitivity, allergies, or idiosyncratic reactions

� Heroic remedies / purgatives

� Topical irritants, escharotics

� Special populations:

� Pregnancy and lactation

� Elderly and children

� Impaired absorption /

altered metabolism

“Isolation and experimentation with single constituents can provide information that can be adapted to a more holistic understanding of an herb’s action. Knowledge of individual constituents is also essential for developing quality control methods, extraction procedures, understanding of pharmacological activity and pharmacokinetics.”

-Andrew Pengelly

The Bottom of the Well:

The Elements

All of the rocky and metallic material we

stand on, the iron in our blood, the calcium

in our teeth, the carbon in our genes were

produced billions of years ago in the

interior of a red giant star. We are made of

star-stuff.

Carl Sagan

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Four elements constitute the vast majority of medicinal compounds

in plants (and all life on Earth):

� Carbon

� Nitrogen

� Oxygen

� Hydrogen

Also sulfur, phosphorus, ions and elements such as Ca, Mg, Fe, Cu, Se, Fl

Four elements, Hydrogen, carbon, oxygen and nitrogen, also provide an example of the astonishing togetherness of our universe. They make up the “organic” molecules that constitute living organisms on a planet, and the nuclei of these same elements interact to generate the light of its star. Then the organisms on the planet come to depend wholly on that starlight, as they must if life is to persist. So it is that all life on the Earth runs on sunlight.

George Wald

Co-Evolution, Dynamism and

Adaptation

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What determines a molecule’s pharmacological effect?

� Composition

� Size

� Bonding of atoms

� Stereochemistry (shape)

� Polarity

These attributes all interplay with each other

Isomers

� Molecules with the same constituents but

different connectivity / bonds

� Structure determines reactivity

� Chemical formula alone does not identify a

particular compound

� Example: fructose vs. glucose

Stereochemistry of Phytochemicals

Stereoisomerism is common in the monoterpenes

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Primary Metabolism:� Molecules and processes necessary for life� Respiration

� Photosynthesis

� Growth and development

� Energy

� Include:� Genetic material

� Proteins, carbohydrates, lipids

� Components of cell membranes

� Primarily carbohydrates, lipids, and amino acids; less likely to be potent medicinal compounds

Secondary Compounds

Secondary metabolism:

� Not required for the short-term survival of the organism

� Mostly considered “defensive” substances

� Over 100,000 compounds identified to-dateFunctions include:� Toxic to animals to deter eating (insects,

grazers)� Pigments to protect from solar radiation� Volatile oils to attract pollinators

� No doubt many other things unknown to us (Science when honest, is humble)

Constituents: Major Categories

Primary Constituents:

� Carbohydrates

� Lipids

� Amino acids

Secondary Constituents:

� Polyphenols

� Terpenoids and Steroids

� Alkaloids

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Types of Carbohydrates

� Monosaccharides – simplest sugars

� Disaccharides – composed of two monosaccharides

� Oligosaccharides – three to ten sugars

� Polysaccharides – much longer chains of sugars (up to several thousand)

Saccharides become less water-soluble as they get larger

Polysaccharides

� Cellulose

� Inulin (Arctium, Cichorium, Cynara)

� Pectin

� Starch (to store glucose)

� Gums and mucilage – for example agar,

carrageenan found in algae

� Some polysaccharides have therapeutic

effect on immune function (Echinacea,

medicinal mushrooms – beta glucans)

Lipids (fats)

Primarily nonpolar hydrocarbons; insoluble in water

Functions:� Energy reserves in plants (seeds tend to be high in lipid

content)

� Cell membranes

� Fat-soluble vitamins

Fatty acids are the building blocks� Saturated

� Unsaturated

� More biologically active

� Essential fatty acids – linoleic and linolenic acids

� Omega 3/6/9

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Amino acids

� Building blocks for proteins

� Proteins

� Comprise muscular tissue

� Transportation of molecules (hemoglobin)

� Enzymes carry out reactions in plants and animals

� Few medicinal proteins� Lectins – many toxic, some have anticancer effect

� Amanita toxins

� Cyclotides found in Viola and other plants –hemolytic, antimicrobial

Glycosides

� Widespread in plants

� Molecules bonded to one or more carbohydrate (sugar) molecules

� Glycosides are generally more bioavailable than the aglycone alone

� Many compounds isolated from plants actually existed in the plant as glycosides but are isolated as the aglycones – this can alter the biological activity

Phenolic compounds

� Refers to any molecule that contains an

aromatic ring with an alcohol on it

� Flavonoids

� Tannins

� Lignans

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Phenols: Anthocyanidins and Flavonoids

� Anthocyanidins are glycoside compounds

� Flavonoids can also occur without sugar bonds

� One of the earliest groups of secondary compounds to appear as land plants evolved from aquatic plants

� Primarily pigments that protect against ultraviolet radiation; most common plant pigments after chlorophyll and carotenoids

� Most of the medicinal effect is attributed to antioxidant activity, also anti-inflammatory, vasotonic

Phenols: Tannins

� Second group of secondary compounds to

appear (after flavonoids)

� Very common in wood, bark, and foliage

� Bitter, water soluble

� Can interfere with digestion by binding to

digestive enzymes

� Used for tanning leather: stabilize collagen

in animal skin

� Topical astringents

Coumarins

� Glycosides

� Widely distributed group

� Will form dicoumarins in certain plants if

they wilt in the presence of specific fungi

(Melilotus)

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Coumarins in Melilotus

Melilotoside, a glycoside precursor of coumarin, is found in Sweet Clover

• Antiedemic• Venous & lymphatic

insufficiency• Decreases capillary

permeability• Only weakly

anticoagulant unless fermented / wilted

Dicoumarol

� Dicoumarol is strongly anti-

coagulant; hemorrhagic; formed by the fusion of two

coumarin units via fungal

activity

� Can form in badly dried

Sweet Clover

� Inhibits Vitamin K activation

� Warfarin (Coumadin) and

phenprocoumon include the

anticoagulant structure of

dicoumarol

Glucosinolates

� Can also be classified as type of glycoside (goitrogenic glycosides)

� Contain sulfur compounds; pungent

� Found primarily in Brassicaceae; highest concentration in seeds

� Deter insects; topical irritants, decongestants when ingested

� Depress thyroid function (interfere with uptake of iodine)

� Significant dietary anti-cancer effect

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Allium Compounds

Sulfur containing compounds derived from

amino acid cysteine:

� allicin – antimicrobial, antifungal, inhibits

platelet aggregation

� ajoene – also lowers blood lipid levels

� cepaene found in onions

Terpenes

� Largest group of secondary compounds

� Generally not water soluble

� Essential oils and pungent resins –

protect plants from insects

� Steroids and Steroidal precursors

� Carotenoids

� Wide range of medicinal activity

� Built from building blocks of five-carbon

isoprene units

Terpenes

�Monoterpenes – ten carbons

� Sesquiterpenes – fifteen carbons

� Diterpenes – twenty carbons

� Triterpenes – thirty carbons

�Many medicines and toxins

�Saponins

�Cardiac glycosides

� Tetraterpenes – forty carbons

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Alkaloids� Nitrogen containing organic compounds;

characterized by a nitrogen atom in a ring

� Mostly synthesized from amino acids

� Second largest group of secondary compounds –over 4000 identified

� Most diverse group – 10,000 different structures

� Physiologically active – many hallucinogens, toxins, stimulants

� Found in a fifth of all plants, mainly flowering herbs, usually specific to families; very common in Solanaceae, Fabaceae (some alkaloids occur in 40% of all plant families)

Alkaloids� Often alkaline (high pH) but not always

� Usually bitter

� Many are polar molecules that dissolve readily in water and into the bloodstream

� Many can mimic or block the action of neurotransmitters

� Often named for the plant they were first identified in, but can sometimes occur in other plants as well

� Functions:� Protect against predation

� Regulate growth

� Products of detoxification

Examples of Medicinal Alkaloids

� Atropine, scopalamine – Datura, Atropa, etc.

� Reserpine – from Rauwolfia serpentina –lowers blood pressure

� Vincristine – from Catharanthus roseus –anticancer activity

� Berberine – found in Berberis, Hydrastis, Coptis

� Morphine – first alkaloid to be isolated in 1805

� Nicotine (lobeline is closely related)

� Also: Ephedrine, Cocaine, Quinine

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Examples of Medicinal Alkaloids

� Purine alkaloids� Caffeine

� Theobromine

� Pyrrolizidine alkaloids� Saturated – non-toxic (Arnica, Echinacea,

Euphrasia)

� Unsaturated - can become hepatotoxic after enzymatic conversion in liver (Symphytum, Tussilago)

� Some poisonous alkaloids

� strychnine

� curare (synthetic derivatives also used in surgery)

Conium maculatum (poison

hemlock): coniine

Common phyto-constituents

resp. for adverse effects

� Pyrrolizidine alkaloids

� Other toxic alkaloids

� Cardiac glycosides

� Coumarin glycosides

� Oxalic acids / oxalates

� Tannins

� Contact irritants (urticaria / phototoxicity)

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Pyrrolizidine Alkaloids

� Boraginaceae: Symphytum, Borago, Pulmonaria

� Asteraceae: Senecio, Tussilago, Petasites, Eupatorium

Pyrrolizidine Alkaloids (PAs)

Symphytine, a diester

Necine rings are metabolized into toxic pyrroles in the liver cells

Necine rings

Lycopsamine, a monoester

Pyrrolizidine Alkaloids

� Some types are considerably more toxic than others

� Saturated PAs are non-toxic

� Unsaturated macrocyclicesters are especially toxic

� Most cases of human PA intoxication are due to crops contaminated w/high-PA weed species, e.g. Senecio vulgaris in wheat

� Some people receiving acute exposure develop VOD; many, but not all, recover

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PAs: Macrocyclic Esters

Macrocyclic esters (e.g., in Senecio species –

over 1500 spp. worldwide) are the most toxic

type of PAs

Senecionine Senecio jacobaea Senkirkine

Woolly bear caterpillars (Grammia

incorrupta) intentionally consume plants

high in PAs when they are infected with

endoparasites (tachinid flies), which in

turn increases their survival. Healthy

caterpillars do not consume these

plants.

Caterpillars and Pyrrolizidine

Alkaloids

“Consistent with theoretical prediction, excessive ingestion of these toxins reduces the survival of unparasitizedcaterpillars. Parasitized caterpillars are more likely than unparasitized caterpillars to specifically ingest large amounts of pyrrolizidine alkaloids.

“This case challenges the conventional view that self-medication behavior is restricted to animals with advanced cognitive abilities, such as primates, and empowers the science of self-medication by placing it in the domain of adaptive plasticity theory.“

Singer et al., Self-medication as adaptive plasticity: increased ingestion of plant toxins by parasitized caterpillars, PLoS One. 2009;4(3):e4796. doi:

10.1371/journal.pone.0004796 2009 Mar 10.

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Variability: Parts of the Plant

Symphytum

� Pyrrolizidine alkaloid content is higher

in young comfrey leaves than in mature ones

� Roots have higher levels than leaves

� Concentrations in leaves vary from

about 0.02 – 0.18%

� Concentrations in roots: ~ 0.25 – 0.29%

� Species also matters: S.officinale being

significantly lower in PA content than S. x uplandicum (Russian comfrey)

Hypericin Hyperforin

Variability & Standardization

� St. John’s Wort extracts were originally

standardized to hypericin content

� Later, hyperforin was correlated to

antidepressant activity

� Latest research shows flavonoids are

important synergists

Standardization: Myth vs. Reality

Marketing has taken precedence over both Tradition and Science

Claims are based on the presumed existence of a single “active ingredient”, which has been proven only in limited, specific cases.

There is no standard definition of standardization (see next slide)! Some manufacturers simply mix batches, others chemically manipulate the plant material.

When constituent levels are manipulated, there are important potential downsides to using standardized herbs such as potential increased risk of ADRs and interactions.

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NIH – Office of Dietary Supplements

“Standardization is a process that manufacturers may use to ensure batch-to-batch consistency of their products. In some cases, standardization involves identifying specific

chemicals (also known as markers) that can be used to manufacture a consistent product…

Dietary supplements are not required to be standardized in the United States. In fact, no legal or regulatory definition exists for standardization in the United States as it

applies to botanical dietary supplements. Because of this, the term "standardization" may mean many different things. Some manufacturers use the term standardization

incorrectly to refer to uniform manufacturing practices; following a recipe is not sufficient for a product to be called standardized. Therefore, the presence of the word

"standardized" on a supplement label does not necessarily indicate product quality.

Ideally, the chemical markers chosen for standardization would also be the constituents that are responsible for a botanical's effect in the body. In this way, each lot of the product would

have a consistent health effect. However, the components responsible for the effects of

most botanicals have not been identified or clearly defined. For example, the sennosides in the botanical senna are known to be responsible for the laxative effect of the

plant, but many compounds may be responsible for valerian's relaxing effect.”

Standardization: Myth vs. Reality

In the limited number of herbs for which there is adequate research to support measuring levels of certain marker compounds to ensure potency for example the silymarincontent of Milk Thistle or the fatty acid content of Saw Palmetto.

This can be done � without manipulating naturally occurring

levels of these compounds � without synthetic chemical solvents or

industrial processes � without altering the spectrum of whole plant

constituents

Bottom line: the most proven, reliable herbal remedies will derive from the highest quality, whole spectrum plant-based ingredients.

“Analyzing a medicinal plant

for its constituents is certainly

of theoretical interest, but for

practical purposes it is more

likely to cause confusion. The action of any medicinal

plant, including chamomile, is complex. It is the sum of

all the constituents the produces the medicinal action.”

- Rudolf Weiss

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Common actions of herbs that

can result in adverse effects

Bulk laxatives

Stimulant laxatives

Diuretics

Emetics and purgatives

Emmenagogues

GI irritants: can include saponins, alkaloids,

tannins, essential oils

Nervous system stimulants

Photosensitizing herbs

Criteria to assess information re: safety

� Traditional knowledge

� Well designed and conducted clinical

trials

� Actual well documented case reports

� misidentification of herb?

� adulteration of product?

� other factors including drugs taken into

account?

� dosage and preparation well established?

� Extrapolation from animal studies

� Extrapolation from chemical analysis

� Folk knowledge

� Anecdote and subjective opinion

Herbs during Pregnancy

Pregnancy is a time to focus on

the Food end of the spectrum

and only the gentlest of

remedies at the lowest

effective dose.

Any use of stronger herbal

remedies must be done

under the supervision of a

qualified midwife or

herbalist.

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Categories of Herbs to

Avoid during Pregnancy

� Herbs that cause uterine contractions or induce

bleeding: emmenagogues, abortefacients

� Teratogenic / mutagenic herbs

� Herbs with pronounced hormonal impact

� Strong stimulants or depressants/sedatives

� Herbs toxic to mother therefore indirectly

harmful to fetus

� Some culinary herbs are safe during

pregnancy in typical food quantities but may

not be safe as concentrated remedies

Herbs to Avoid during

Lactation

� Toxic herbs known to pass constituents

into breast milk

� Other potentially toxic herbs for which

there is not enough information

(traditionally or scientifically)

� Age of the child matters!

Herb-Drug Interactions

Pharmacodynamic:

what a drug (or

herb) does to the

body

Pharmacokinetic:

what the body

does to a drug (or

herb)

Plus: beneficial interactions – decreasing

risk of ADRs or increasing efficacy

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Pharmacodynamic interactions

Involving pharmacological action –

predictable based on the herb’s and

drug’s known and established therapeutic

and physiological effects.

� Additive effect, or

� Antagonistic /

opposing effect

Pharmacokinetic interactions

Altering absorption, metabolism, or excretion – harder

to predict; need solid science to inform us.

� Decreasing bioavailability (increasing

elimination)

� mucilages

� laxatives

� tannins, resins

� Hypericum – induces CYP450 pathway in liver

� Increasing bioavailability (decreasing elimination)

� pungent, spicy herbs and foods

� other herbs/foods that impede liver CYP metabolic pathways such as grapefruit

Considerations Regarding

Interactions

What is the potential harm from too a high or too low

blood level of the drug in question?

� Herbs with profound effect on liver, GI tract, or kidneys more

likely to affect bioavailability

� Use more caution with drugs and herbs that have a narrow therapeutic index or known propensity to provoke ADRs

� Drug-drug interactions far more problematic and common

� When in doubt, consult experts and proceed with caution!

� Use fewer and milder herbs

� Use lower doses and build up gradually

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Setting the Context:

Herbal remedies are overwhelmingly safe

"...side effects or toxic reactions associated

with herbal medicines in any form are rare.

In fact, of all classes of substances

reported to cause toxicities of sufficient

magnitude to be reported in the United

States, plants are the least problematic.“

-Norman Farnsworth, Director of the World

Health Organization Collaborating Centre for

Traditional Medicine and Research Professor

of Pharmacognosy, University of Chicago at

Illinois,

Causes of Death – U.S. 2007

Cause No. of Deaths

Heart disease 616,067

Malignant neoplasm 562,875

Cerebrovascular disease 135,952

Chronic lower respiratory tract disease 127,924

Unintentional injuries 123,706

Fatal ADRs in hospitals (no error) 106,000 (76,000 to 137,000 – JAMA 1997)

Alzheimer disease 74,632

Diabetes mellitus 71.,382

Medical errors 69,000 (40,000-98,000/yr – CDC 1999)

Influenza and pneumonia 52,717

Nephritis, nephrotic syndrome, etc. 46,448

Septicemia 34,828

Other 499,283 (1990 data for this category)

Dietary supplements (all) 5 (CDC, FDA; US National Poison Data System –

zero for 2008, 2010

Source: National Vital Statistics System, National Center for Health Statistics, CDC.

Produced by: Office of Statistics and Programming, National Center for Injury Prevention and Control, CDC.

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Actual Causes of Death United States

1990 and 2000

Cause Est # of Deaths(%) – 1990 Est # of Death (%) – 2000

Tobacco 400,000 (19%) 435,000 (18.1)

Diet/Physical 300,000 (14%) 365,000 (15.2) – corrected

Inactivity

Iatrogenic 175,000 (approx 7.5)

Alcohol 100,000 (5%) 85,000 (3.5)

Microbial Agents 90,000 (4%) 75,000 (3.1)

Toxic Agents 60,000 (3%) 55,000 (2.3)

Motor Vehicles 25,000 (1%) 43,000 (1.8)

Firearms 35,000 (1%) 29,000 (1.2)

Sexual Behavior 30,000 (1%) 20,000 (0.8)

Illicit Use of Drugs 20,000 (<1%) 17,000 (0.7)

Dietary Supplements 5 (approx 0.0005)

TOTAL 1,060,000 (50%) 1,159,000 (48.2)

Source: Mokdad, Marks, Stroup, Gerbeding, Actual Causes of Death in the United States, 2000; Journal of the American Medical Association, 291:1238-1245, 2004.

Medical error—the third leading cause of death in the US, BMJ 2016; 353, 03 May 2016

We calculated a mean rate of death from medical

error of 251 454 a year using the studies

reported since the 1999 IOM report and

extrapolating to the total number of US hospital

admissions in 2013. We believe this understates the true incidence of death due

to medical error because the studies cited rely

on errors extractable in documented health

records and include only inpatient deaths.

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Reporting Adverse Effects

Dietary Supplement and Nonprescription

Drug Consumer Protection Act - 2007

� Mandatory for manufacturers for “serious”

AE

� Voluntary for others (practitioners, public)

� http://www.fda.gov/Safety/ReportaProblem

/default.htm

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Reporting Adverse Effects

Serious AE:

Death; a life-threatening experience;

inpatient hospitalization; significant or

persistent disability; congenital anomaly or

birth defect, or requires, based on

reasonable medical judgment, medical or

surgical intervention to prevent above

Adverse Effects - Data

� AE reports from Dietary Supplements are

rapidly rising (increased incidence or

increased reporting?)

� 2008-2011: 6307 AERs from D.S.; in

general less than 10% are herbs

� Causal relationship established on only

3% of these cases

� 2008-2010: 1.8 million AERs from drugs

Emergency Department Visits for Adverse Events Related to Dietary Supplements

N Engl J Med 2015; 373:1531-1540, October 15, 2015

…We estimate that more than 23,000 emergency department visits annually in the United States from 2004 through 2013 were for adverse events associated with dietary

supplements. Such visits commonly involved cardiovascular adverse effects from weight-loss or energy herbal products among young

adults, unsupervised ingestion of micronutrients by children, and swallowing problems associated with micronutrients

among older adults.

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-21% of adverse events resulting in ER visits were

unsupervised children accessing DS-40% were swallowing problems (mostly elderly)

-Followed by energy, weight loss, sexual enhancement

� The most toxic plants are not used in modern

herbal practice

� Even if seriously under-reported, all data indicate

that adverse effect rate is vastly lower than

pharmaceutical adverse effect rate

� Complex of constituents in plants often buffer or

alter toxic effects of certain single constituents

� “Nocebo” effect may account for up to 19% of all

adverse effects

� Product quality and overdose are the cause of

most problems.

When in doubt play it safe, do not work

beyond your knowledge base,

consult reliable references, and

consult qualified practitioners!

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Primum non nocere

Thank you

richardmandelbaum.com

arborvitaeny.com