Pakistan J. Med. Res.

Vol. 43 No.4, 2004

Safety of medicinal plants


Inamul Haq
Ex-Drug Controller, Ministry of Health, Government of Pakistan, Islamabad

SUMMARY

The last decade has witnessed a great revival of interest in the use of herbal medicines both in the developed as
well as developing countries. Almost 50% of the medicines we use today are derived straight from plants and
25% of the prescription drugs have their genesis of tropical plants*. According to WHO, 80% of the world
population rely chiefly on plant based traditional medicines specially for their primary health care needs. The
common belief based on tradition, that medicinal plants being "natural" or near to nature are always safe, is not
held to be true lately. The advancement of technology has enabled the scientists to detect minute amounts of
carcinogenic and toxic chemicals in these herbs and recognize or evaluate potentially hazardous effects of some
of the herbs used in traditional medicines since centuries. This article aims to highlight the side effects and
adverse reactions/ interactions of few most commonly used herbs considered to be safe since centuries with an
advise to the physicians and pharmacists to consider the health hazards associated with the use of such drugs
while taking the history of the patients.

INTRODUCTION

hough medicinal plants have been used since
antiquity for the prevention and treatment of
various ailments, lately there has been a great resurgence
in the use of herbal remedies specially during the last
decade and a half. At the turn of the century,
approximately 170 herbal drugs were officially
recognized in the U.S.P and N.F.
1
The Director of WHO
Traditional Medicine reported in 1993 that 80% of the
world population rely chiefly on traditional medicine,
mainly plant based, specially for their primary health care
needs.
2
International Scenario.

America
In America, the annual market value of
phytomedicine was reported to be $ 1.5 billion in 1994
which has grown enormously over the years. It is
estimated that in 1997, Americans spent $ 3.2 billion on
herbal medicines like Gingko biloba for memory
problems and Achinacea for colds and flue in spite of the
fact that herbal medicines are inadequately regulated by
the FDA.
3
According to FDA survey, 16 million
Americans are using medicinal herbs actively.4 Herbal
medicines continue to be a major market in US
pharmacies and constitute a multi billion dollar industry
selling approximately 1500 botanicals and dietary
supplements or ethnic traditional medicine.
5


Europe
Europe is reported to has the highest turnover in
herbal medicines with a retail sales volume of $ 6 billion
per annum.
8


United Kingdom
In UK, around 5500 herbal products were
available in 1980 on the pharmacies or on the general
sales list out of which 1000 products derived from 550
herbs were estimated to be marketed with product licenses.
9

The sales of herbal medicines in the U.K increased by 25%
between 1990-1995 over the last years.
9a

*Phytochemistry & Pharmacology of Ficus bengalensis.
J.Trop.Med.Plants Vol.3. No.1
June 2002).

Germany:
The Geffi1an herbal medicines market was
worth $ 1.7 billion in 1989
10
equal to 10% of the total
pharmaceutical market which surpassed $ 2.0 billion by
1998. Over 70% of German Physicians either prescribes
medicinal herbs or refer their patients to traditional
practitioners.
10a
The cost of about 40% of the herbal
remedies prescribed by the German Physicians are
covered by the health care system.
10


China
In China, the total production of herbal
medicines was $ 2.3 billion in 1995 showing an increase
of 212.6% compared with 1990. Herbal medicines
represented 33.1% of the total drug market in 1995.
Botanicals are used for the primary health care needs of
40% of China's urban patients and over 90% of its rural
patients.
6

T
Review Article
Inamul Haq
Japan
In Japan, sales of herbal medicine products are
estimated to be $ 2.1 billion per year constituting about
4.0 % of the total market for pharmaceutical products. In
Tokyo, 49% population had used herbal medicine in 1990
according to a survey. Per capita consumption of herbal
medicines is reported to be the highest in Japan.
7


Table-1 shows the Worldwide Phytomedicine Market, 1994
(Per Dr. Grunwald. Phytopharm. Phytotherapeutics market)

Country Million US $ @ Retail
European Union 6,000
Rest of Europe 500
Asia 2,300
Japan 2,100
North America 1,500
Total 12,400
Source: Brevoort, P. "The current Medical & Dietary Uses of
Botanicals: A market perspective" in July 1996 USP Open Conference
on Botanicals for Medical & Dietary Uses: Standards &
Information Issues. Proceedings of the Conference.
United States Pharmacopoeal Convention Inc.

Malaysia
In Malaysia, the market for traditional medicine
is estimated to be M $ 1.0 billion to M $ 2.0 billion
annually, which is larger than the market for modern
medicine.
11


Ghana
In Ghana, 70% population rely on herbal
medicines where the Practitioner: Patient ratio is 1:400 in
case of traditional medicine as against 1:12000 in modern
medicine.
12
Fig 1 shows the Percentage of the population
using Traditional Medicines, Selected Countries in The
Western Pacific Region.

48.5
90
60
40
60
69
57.3
45
50
0 10 20 30 40 50 60 70 80 90 100
Austrialia
China
Hong Kong(China)
Japan
Nauru
Rep. Of Korea
Philippines
Singapore
Viet Nam

Figure 1. Percentage of population using traditional medicine, selected countries in the Western Pacific Region
Sources: Informal Meeting on Strategic Planning on Traditional Medicine, 21-23 May 2001, Manila, Philippines.

Viet nam
A survey conducted in 1997 showed that 50% of
the population preferred to be treated by traditional rather
than modem medicines. Traditional medicine is practiced
at all levels of health care i.e. primary, secondary and
tertiary.
7


Republic of Korea
In the Republic of Korea, annual sales of herbal
medicines was reported to US $543.5 million in 1996.
According to the Ministry of Health document, in 1997
there were reported to be 300 herbal pharmaceutical
companies, 13733 herbal medicine dealers, 820
wholesalers and 10751 drug stores dealing with herbal
medicines in the country.
7


Philippines
In the Philippines, combined sales of four
government and one private herbal medicines
manufacturer in 2000 were about US $ 10 million.
7


India
In India 70% of populations are reported using
traditional medicine for primary health care. 13 The
present annual turnover of herbal medicinal products
manufactured by large companies is estimated to be
approximately US $ 300 million, compared to a turnover
of approximately US $ 2.5 billion for modern drugs.
13a


Pakistan scenario
Traditional healers (Hakims/Tabibs) are
Registered by the Govt. under an Act of the Parliament
but there is no regulatory control on the manufacture,
sale, distribution etc. of traditional medicines. There are
around 46,000 Registered "Hakims" and about 74,000
Registered Homeopaths
14
as against some 102516
Registered Physicians. The number of recognized Tibbia
Colleges and Dispensaries is 28 and 315 respectively.
Safety of medicinal plants

Tibbi Pharmacopoeia published by the National Council
of Tibb lists about 900 single herbs
15
whereas Hamdard
Pharmacopoea of Eastern Medicine lists 186 single
vegetable drugs used exclusively in "unani medicine".
16

According to information collected in 1982, around 200
medicinal plants were found to be extensively used by the
traditional healers in their day-to-day practice as
evidenced by their Annual Consumption by ten leading
"Dawakhana's" (herbal drug manufacturers) in Pakistan.
17

As can be seen from above, the worldwide interest in
herbal medicines has grown tremendously in the last
decade or two.

Factors promoting use of herbal medicines
Amongst several factors contributing towards the
potential use of herbal drugs, holistic approach to the
health problems, safety, lack of adverse reactions and side
effects have been mostly found to particularly influence
the use of such medicines in the developed countries
whereas their accessibility, affordability, historical and
cultural background besides the above factors promote
their use in the developing countries. Added to these
strengths and the clinical evidence of safety provided by
some herbal drugs, traditional herbal therapies have no
doubt the potential to increasingly contribute to a better
health care system in many countries.
15
Fig. 2 shows the
evidence of Safety for some Herbal Medicines.



Figure 2. Good evidence of efficacy exists for some herbal
medicines- but evaluation is inadequate
Percentageof randomized clinical trials (RCTs)
showing benefit of herbal medicines (based on 50 RCTs
with 10 herbal medicines for 18 teutic indications)
Source: Based on data on herbal medicine: an evidence
based look. Thera- peutics Letter, Issue 25, June-July
1998

Herbal drugs-not always safe
There is a general belief amongst the consumers
allover the world that herbal drugs are always safe
because they are " natural" or near to nature but evidence
suggests otherwise.
19-20
The mere fact that a product is
"natural" does not signify that the product is safe, says
Carol. A. Newall, the British Co-author of Herbal
Medicine: A Guide for Health Care Professionals.
According to him, naturalness does not by definition
guarantee harmlessness nor does the general belief that
herbs used since decades or centuries provide enough
evidence of their safety.
21
Although limited evidence
suggests that adverse effects associated with the use of
herbal drugs are less likely to occur than with
conventional drugs, they do occur though usually mild
and only effecting a small number of people. A recent
evidence suggests that some of the herbs considered to be
safe over the last many decades have proven to be
associated with health hazards. The English translation of
The Complete German Commission E Monographs lists
more than 100 ineffective or toxic herbs that have been
used medicinally, but are no longer recommended.
22
The
advancement of technology has enabled the scientists to
detect minute amounts of carcinogenic and toxic
chemicals in these herbs and recognize or evaluate
potentially hazardous effects of some of the herbs which
had been used in traditional medicine since centuries.
Though any organ system Call be effected, the most
common adverse effects involve the skin, liver and
gastro-intestinal tract. There is a long list of medicinal
plants used traditionally that are lately reported to be
hepato-toxic
23.24
, a classical example being of Germander
that had been used with apparent safety for centuries. It
was only in 1990's that this plant was first identified to be
a hepato-toxic drug.
25
Similarly many plants have been
identified to be renotoxic. In Belgium several preparations
based on Chinese plants were reported to be responsible
for 70 cases of renal impairment
26
Animal experiments, though not supported by
human experiments, have also shown that some common
herbs/ medicinal plants like Hollarrhena anti dysenterica,
Aegle marmelos and Terminalia chebula used in
traditional medicine since centl.lries in Pakistan have
lately been reported to produce hepatic lesions while
Terminalia chebula and Withania somnifera gave rise to
marked renal lesions.
27
Another commonly used herb-
Embelia ribes had been reported to cause visual defects
and eventually optic atrophy in animal experiments.
28


Side effect/ad reactions & interactions of some
common herbs
Following are some of the examples of side
effects/ adverse actions and interactions associated with
the use of common herbal drugs used in traditional
medicine routinely since centuries.
Inamul Haq
a) Liquorice: Traditionally liquorice root has been used
to treat many ailments including asthma, stomach and
duodenal ulcers, singles (caused by a Herpes virus),
arthritis, chronic depression etc. Lately however it has
been observed that one of the active ingredients,
glycyrrhizinic acid, when taken in large quantities, can
promote sodium and water retention as well as potassium
depletion, making it risky for people with blood pressure,
kidney or heart disease. Potential unwanted effects
include edema and hypertension due to excessive use. To
avoid these problems, liquorice root should not be taken
continuously as a tea, tincture or in tablet for more than 4
to 6 weeks.
5
Liquorice is a common ingredient of classical
household cold and flu preparation! remedy,
"JOSHANDA" used in Indo-Pakistan subcontinent.

b) Ephedm: The herb has been used in traditional
Chinese medicine since antiquity for the treatment of
respiratory ailments. The drug has been advertised as a
supposedly safe, natural product for weight loss, body
building and mood evaluation. Recently the drug became
highly controversial due to its use in slimming formulas
and products claiming to deliver a "legal high" resulting
in serious health hazards. According to FDA, there has
been 15 deaths attributed due to the intake of ephedra
based drugs since 1990 necessitating legal restrictions on
the duration and dose of such drugs.
5
According to
another report, the drug has been blamed for 20-30 deaths
and 800 adverse reactions since 1993.
3
Ephedra has many
side effects including restlessness, irritability, increased
blood pressure and heart rhythm disorders. The alkaloid
ephedrine contained in ephedra herb can cause serious
toxic reactions ranging from liver damage to severe high
blood pressure and heart problems when taken with MAO
and also with ergot alkaloid derivatives or oxytocin,
cardiac glycosides,halothane, guanethedine.
22
Due to its
many side effects and adverse reactions, the herb should
not be taken with any MAO-inhibitors (monoamine
oxidase inhibitors, such as those in some antidepressants)
or heart or blood pressure medications Pregnant women
should avoid ephedra because it induces uterine
contractions.
5
Many herbal cough preparations marketed
in Pakist:m contains ephedra as one of their ingredients.

c) Aloevera: Seventh most widely used herb for centuries
as a treatment for minor bruises and is increasingly being
used in products for internal consumption.
Long term use of aloe latex could results in potassium
deficiency so the laxatives containing anthraquinone
glycosides should not be used continuously for longer
than 1-2 weeks owing to the danger of electrolyte
imbalance.
29a
Certain medications can interact positively
or negatively with the glycosides contained in the drug.
29
d) Sassafras: The herb has been used in traditional
medicine since centuries in North America for the
treatment of rheumatism, arthritis, cold and flu. The
root bark contains small amount of a potent
carcinogen toxic to liver if taken in large quantities
or over extended period of time.
5


e) Ginkgo biloba: Ginkgo fruits and seeds have been
used medicinally for thousands of years. Extract of the
plant is an OTC herbal drug marketed in many countries
including Pakistan (under the name CRATEX), as a
supplement to improve mental alertness and related
memory problems. Researchers have shown that the
extract is a potent inhibitor of platelet-activating factor
30

and long term use has been associated with increased
bleeding time, spontaneous hemorrhage and sub dural
haematomas.31 Adverse reactions that have been reported
to WHO include hypertension, leucopoenia,
thrombocytopenia and hallucinations.
32


f) Senna: Senna, another so called weight loss herbal
drug used traditionally for constipation, can have adverse
effects on the heart because regular consumption is
reported to deplete the body of potassium causing
fatalities. Other adverse reactions include grand mal
seizures, circulatory failure, hypertension and
anaphylactic reaction.
32

g) Sil ybum marianum: Silymarin obtained from the
herb and widely promoted as a liver tonic, has been
associated with cerebral hemorrhage, hepatic coma and
neuropathy.
32


h) Ginseng: Fourth most widely used Chinese medicinal
herb for the treatment of a variety of conditions since
times immemorial, Ginseng is used as a general tonic and
is claimed to increase body's resistance to stress and
builds up general vitality besides treating hypertension,
diabetes, depression,
4
Lately the herb has been reported to
cause hypertension and mastalgia as documented side
effects.
33
Taking Ginseng may keep blood thinners from
working correctly resulting in problems with blood
clotting.
34
Some recent reports have also linked ginseng to
potential medication interactions with warfarin and
digoxin. Taking Ginseng and Digoxin together may cause
an increase in Digoxin levels in the blood, leading to
Digoxin poisoning.
35
Ginseng and antidiabetic drugs
taken together may make blood sugar too low leading to
blurred vision, tremor (shaking), hunger, sweating,
headache, skipped heart beats, confusion, nervousness
and extreme tiredness.36 Ginseng is reported to interact
with many other drugs which include steroids, anti
Safety of medicinal plants

depressants, water pills, estrogens etc.
37,38,39,40
Excessive
doses of ginseng have been reported to cause agitation,
insomnia and raised blood pressure.

j) Alfa alfa: The herb widely used in Homeopathy, is said
to contain vitamins A,C,E and K as well as calcium,
potassium, phosphorus and iron. However it has been
reported that the use of this herb can induce systemic
lupus erythromatosus) (SLE) like syndrome in individuals
predisposed to this condition.
32

k) Comferey: The herb was used by Greek Physicians in
the first century as a safe drug in the form of poultice to
heal wounds and as a tea to help knit broken bones. In late
1970,s scientists discovered that it contains pyrrolizidine
alkaloids which are known to be hepatotoxic and has been
associated with obstruction of blood flow to the liver,
possibly leading to hepatotoxic reactions32 besides being
a risk for cancer. Products containing comfrey should not
be taken internally and the topical application of comfrey
containing preparations to broken skin should be avoided
.
32

l) Aconite: Aconite alkaloids contained in the root-stocks
of plants of Aconitum family are accredited with
analgesic and anti-inflammatory effects within several
systems of traditional medicine and are still widely
proposed for the treatment of rheumatism, neuralgia and
cardiac complaints. However aconite poisoning is
common. In China alone it has been reported that over
600 cases of aconite poisoning have been attributed to the
use of these substances in herbal medicines over the past
30 years up to 1995.
41


m) Ispaghula: Ispaghula which is considered to be the
safest and largely used for its demulcent and laxative
properties since centuries is reported to have adverse
reactions including bronchospasm, asthma and intestinal
obstruction. If swallowed dried it may cause oesophageal
obstruction.
32

n) St. Johns wort: An anti depressant and dietary
supplement has a potential market in Europe and
America. The German doctors are prescribing millions of
daily doses and the value of prescriptions for this anti-
depressant drug is reported to be twice that of latest
Allopathic drug-PROZAC.
42
A study conducted by the
N.I.H in USA however showed a significant drug
interaction between St. Johns wort and Indinavir, a
protease inhibitor used to treat infection.43 Based on
these results, it is expected that the herb may significantly
decrease blood concentration of all the currently marketed
HIV protease inhibitors (PIS) and possibly other drugs.
Table 2 summarizes the general Side Effects and
Adverse Reactions/ Interactions of some selected Herbal
Drugs Based on Clinical evidence.

Table 2: Side effects/ adverse reactions & interactions

Medicinal plant Side effect/ad. reaction & interaction
Liquorice


Ephedra




Aloe vera


Ginkgo biloba



Sylibum marianum


Ginseng


Comferey

Aconite

Ispaghula

St. John's wort

ic, Ginger, Ginseng Feverfew, Ginkgo bilob.
Glycyrrhizinic acid promote sodium and water retention & potassium depletion- risky for people with
B.P, Kidney aI1c1 Heart diseases.

Insomnia, restlessness, irritability. Since 1993 responsible for 20-30 deaths and 800 adverse
reactions. Can cause toxic reactions when taken with Monoamine oxydase inhibitors and some other
drugs like ergot alkaloid derivatives, oxytocin, guanethedine etc.

Aloe latex could result in potassium deficiency thus endangering electrolyte imbalance.

Potent inhibitor of platelet-activating factor- long term use associated with increased bleeding time.
Adverse reactions including hypertension, leucopoenia, thrombo penia and hallucinations

Silymarin associated with cerebral hemorrhage, hepatic coma and neuropathy.


May create blood clotting problem. Potential medication interaction with Warfarin, Digoxin,Anti
diabetic and other drugs.

Hepato-toxic.

Acute poisoning

May cause bronchospasm, asthma and intestinal obstruction.

Significant interaction with lndinavir-a protease inhibitor and, some other drugs.

Delay blood clotting time- interaction with Aspirin & Warfarin.

Inamul Haq


Many different and not very significant
interactions can occur between herbs containing large
amounts of mucilage including Aloe, Flaxseed (Linum
usitatissimum), Ispagula. These herbs may slow the
absorption of any drug when taken orally at the same
time. To avoid any absorption problem, it is advisable to
take the herb and the drug at least several hours apart.
Interactions are likely to cause problems in case
of herbs reported to possess cardiac, anti diabetic,
diuretic, sedative, hypertensive, hypotensive or anti
coagulant effect.
Many medicinal herbs known to lower blood
sugar levels which include Momordica charantia (Karela),
Gymnema sylvestre (Gurmar) and Pterocarpus
marsupium (Indian Kino tree) when combined with
Insulin could result in hypoglycemia, To avoid this, it is
necessary to constantly monitor blood sugar levels and
make necessary adjustments in the dosage of insulin
accordingly.
Some most popular herbs like Garlic (Alium
sativum), Ginkgo biloba, Ginger (Zingiber officinalis),
Ginseng, Fever few (Tanacetum par.) are known to delay
the blood clotting time. So if the patient take anti-
coagulant drugs like OTC aspirin or the potent
prescription drug Warfarin, he should use these herbs
after checking with his doctor because they are likely to
cause hemorrhage.
44

Several cases of bleeding involving anti-
coagulant therapy and herbals have been reported. The
American Society of Anaesthesiologists has issued
warnings against using herbals such as ginger, ginkgo,
kava kava and St. Johns wort before undergoing surgery
because these herbs may cause increased risk of bleeding
or prolong the effect of anesthesia.
45


Need for regulatory controls on herbal drugs
These are some examples of problems apparently
associated with the uncontrolled use of "natural" products
and traditional herbal medicines. It needs to be mentioned
here that most serious side effects originates from overuse
or misuse of such medicines. The likelihood of side
effects increases when the production and sale of such
products is largely uncontrolled and or unregulated and
the consumer is not adequately informed about their
proper uses. While in some countries herbal medicines are
regulated through official controls and rigorous
manufacturing standards, this is not so everywhere. In
Germany, for example, where herbal products are sold as
"phytomedicines" they are subject to the same criteria for
their safety, efficacy and quality as applicable to other
drugs.
46
Regulatory controls are therefore considered
necessary to safeguard
Drug interactions with herbal drugs have not
been adequately researched but there are increasing
number of case reports of herbal-drug inter actins in
literature.
Under the National Toxicology Program, studies are
underway in USA to the potential of herb/ herb and
herb/drug interactions and the clinical responses of some
sensitize populations such as pregnant women, the young,
the developing fetus, the elderly etc. using herbal
products.
As the clinicians and scientists gain experience
with using medicinal herbs, it is likely that other side
effects and interactions comes to light. So it is always
wise to consult a qualified medical practitioner having
clinical herbal experience in case of any doubt about the
compatibility of herb and the drugs you intend to take.

Role of physicians and pharmacists:
Physicians generally do not ask the patients
about having used herbal preparations while taking their
history. But because of the biological potency, side effects
and adverse reactions of many of the herbal preparations
and their increasing popularity and availability, it is
necessary that patients should be asked specifically about
their use, especially when presenting with unusual
symptoms or signs while prescribing any allopathic
medicine. Apart from the role the physicians have to play
in safeguarding the public health, pharmacist's
interventions in the appropriate use of herbal medicines
are necessary to make the overall health delivery system
safe and effective. Pharmacists should therefore be
Safety of medicinal plants

knowledgeable about the medicinal plants, herbal
therapies and other herbal based dietary supplements in
view of their increasing popularity and utilization so as to
be able to provide objective information to the consumers.
Some important sources, among others, that
provide detailed information about herbal drugs/ products
are:

a. WHO Adverse Drug Reactions Database, Uppsla,
Sweden.
b. WHO Monographs on Selected Medicinal Plants. Vol.
1&1I. WHO Geneva 1999.
c. Traditional Medicine Program. WHO- Geneva.
Switzerland.
d. NAPRALERT (Natural Product ALERT) database
(computerized database on the medicinal uses of
natural products, especially plant profiles) USA.
e. English translation of the German Commission E
monographs published by the American Botanical
Council.

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