Herbal Safety

and Introductory
Phytochemistry

Richard Mandelbaum RH (AHG)

richardmandelbaum.com
arborvitaeny.com

Natural does not equal Safe!

Case study:
Piper methysticum (kava)

1
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

2
 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 Hemlock tea

Tsuga canadensis Conium maculatum
I WILL MAKE YOU FEEL I WILL KILL YOU DEAD
FRESH AND DEAD DEAD (AND I WILL
REVITALIZED AND GIVE BE QUICK ABOUT IT
YOU A BOOST OF TOO).
VITAMIN C TO BOOT.

3
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

4
 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

5
 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

6
 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

7
 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-date
Functions 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

8
 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

9
 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

10
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)

11
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

12
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

13
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

14
 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)

15
Pyrrolizidine Alkaloids

Boraginaceae: Symphytum, Borago, Pulmonaria

Asteraceae: Senecio, Tussilago, Petasites,
Eupatorium

Pyrrolizidine Alkaloids (PAs)

Necine rings

Lycopsamine, a monoester

Necine rings are

metabolized into
toxic pyrroles in Symphytine, a diester
the liver cells

Pyrrolizidine Alkaloids
Some types are considerably
more toxic than others
Saturated PAs are non-toxic
Unsaturated macrocyclic
esters 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

16
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 unparasitized
caterpillars. 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.

17
Variability: Parts of the Plant

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)
Symphytum

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

Hypericin Hyperforin

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.

18
 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 silymarin
content 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

19
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.

20
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: Pharmacokinetic:
what a drug (or what the body
herb) does to the does to a drug (or
body herb)

Plus: beneficial interactions – decreasing

risk of ADRs or increasing efficacy

21
 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

22
 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.

23
 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.

24
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

25
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

…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.

Emergency Department Visits for

Adverse Events Related to Dietary Supplements
N Engl J Med 2015; 373:1531-1540, October 15, 2015

26
-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!

27
Primum non nocere

Thank you

richardmandelbaum.com
arborvitaeny.com

28