International Programme on Chemical Safety
Poisons Information Monograph 209
1.4 Identification numbers
1.4.2 Other numbers
ATC codes: R01AA03
1.5 Main brand names
Amidrin; Daral; Fluidin; Kidargol; Rhinamide; Tedral;
Tenfril; Vicks decongestive cough syrup
1.6 Main manufacturers and/or importers
2.1 Main risks and target organs
Cardiovascular: heart and arterial vessels
Chronic use can lead to tolerance with dependence
2.2 Summary of clinical effects
Digestive disorders: nausea, vomiting.
Cardiovascular impairment: tachycardia, severe hypertension
and secondary myocardial infarction and/or stroke.
Central effects: anxiety, tremor, irritability,
hallucinations, psychotic states, seizures, intracerebral
Metabolic dysfunction: hyperglycaemia, hypokalaemia
Diagnosis is based on history and/or the presence of
nausea, vomiting, tachycardia, headache, elevated blood
pressure. Ephedrine and its metabolites can be analyzed in
blood and urine by gas chromatography.
2.4 First aid measures and management principles
Supportive and symptomatic care; administration of
propranolol in patients with severe arterial
3. PHYSICO-CHEMICAL PROPERTIES
3.1 Origin of the substance
Ephedra species (particularly E. sinica) contain chiefly
two alkaloids: ephedrine and pseudoephedrine, which is a
stereoisomer of ephedrine. Ephedra species have been used as
a source of ephedrine; ephedrine is also prepared
Ephedra is sold as a traditional Chinese medicinal herb under
the name Ma-huang.
3.2 Chemical structure
C10 H15 NO1
Molecular mass: 165.2
3.3 Physical properties
Colourless or white
Bitter taste; odourless or slight aromatic
odour. In warm weather it slowly volatilizes. The
anhydrous substance melts at 36°C and the hemihydrate
melts at 42°C. It is a weak base, with a pKa = 9.6
Ephedrine decomposes with light. Solutions in oil can
have a garlicky odour. It is soluble in water (1 in
20) and in alcohol, chloroform, ether, glycerol, olive
oil and in liquid paraffin (Windholz, 1983).
Ephedrine and its optical isomer pseudoephedrine are
structurally very similar to methamphetamine. In
illicit drug laboratories simple dehydrogenation is
used to make methamphetamine from ephedrine (Kelley
3.4 Other characteristics
3.4.1 Shelf-life of the substance
3.4.2 Storage conditions
Protect from light.
Temperatures must not exceed 8EC in containers.
The most important uses are:
- as a bronchodilator
- nasal decongestant
- other uses: syndrome of Stokes-Adams; as a
mydriatic and hypertensor in the
spinal-anesthesia. It is also used as
an herbal diet supplement under the
name "Ma-huang" as an anorectic and
4.2 Therapeutic dosage
15 to 60 mg of ephedrine hydrochloride or
sulphate 3 or 4 times daily as a bronchodilator
500 (g/kg body weight of ephedrine
hydrochloride or sulphate 3 or 4 times daily (Parfitt,
Cardiovascular disease; hypertension; hyperthyroidism;
phaeochromocytoma and closed angle glaucoma. Ephedrine
should not be given in patients being treated with MAOI (or
have stopped treatment in the last 14 days) (Dukes, 1988;
Parfitt, 1999; Dawson et al., 1995). It should be used with
caution in patients with prostatic enlargement or with renal
5. ROUTES OF EXPOSURE
Abuse of ephedrine-containing diet pills is a common
occurrence (MMWR, 1996).
Ephedrine salts are used as nasal drops or sprays in the
relief of nasal congestion associated with cold or rhinitis.
Ephedrine can be abused by the nasal route by subjects who
have developed dependence to its vasoconstrictive effect
As an ointments well absorbed.
Eye-drops at 0.1% are effective in congestion of
Subcutaneous or intramuscular injections.
6.1 Absorption by route of exposure
Ephedrine is readily and completely absorbed from the
gastrointestinal tract; plasma peak concentrations are
reached an hour after ingestion
A single oral dose of 24 mg produced an average peak plasma
concentration of 0.10 mg/L (Goldfrank, 1990).
6.2 Distribution by route of exposure
The volume of distribution is about 3L/kg; patients with
toxicity are not good candidates for haemodialysis (Kelley
6.3 Biological half-life by route of exposure
It has a plasma half-life ranging from 3 to 6 hours
depending on urinary pH (Parfitt, 1999).
No change in half-life from that seen with therapeutic dosing
was observed in an otherwise healthy patient with massive
overdose (Snook et al., 1992).
The ephedrine concentrations in three fatalities were 3.49;
7.85 and 20.5 mg/L (Ellenhorn, 1988).
Only a small amount of ephedrine is metabolized in the
6.5 Elimination by route of exposure
It is largely excreted unchanged in the urine, with some
deaminated metabolites and N-demethylated metabolites.
Elimination is enhanced in acid urine.
Less than 10% of ephedrine is excreted as norephedrine. In
normal subjects 70-80% of a dose is eliminated unchanged in
the urine within 48 hours. 4% is present as norephedrine
(Baselt and Cravey 1995)
7. PHARMACOLOGY AND TOXICOLOGY
7.1 Mode of action
Ephedrine can produce stimulation at the
adrenergic receptors and neuronal norepinephrine
release (Kelley 1998).
Ephedrine has both alpha- and beta-adrenergic
activities, and both direct and indirect effects on
receptors. It raises blood pressure both by increasing
cardiac output and inducing peripheral
vasoconstriction (Shufman et al., 1994; Parfitt,
It can produce bronchodilation. In local application
it causes pupils dilation. The main metabolic effects
in overdose are hyperglycaemia and hypokalaemia.
Ephedrine is a centrally acting respiratory stimulant
and can increase motor activity.
7.2.1 Human data
The ephedrine concentrations in
three fatalities were 3.49, 7.85, and
20.5mg/L (Kelley 1998). However survival at
levels of 23mg/L has been reported (Baselt
and Cravey 1995)
7.2.2 Relevant animal data
7.2.3 Relevant in vitro data
No data available
No data available
No data available
A serotonin syndrome has been reported in a patient
taking paroxetine and an over-the-counter cold medicine
containing ephedrine (Skop et al., 1994).
Combination of ephedrine and a MAOI can produce
life-threatening reactions (Dawson et al., 1995). It should
also be avoided in patients undergoing anaesthesia with
cyclopropane, halothane or other volatile anaesthesia. An
increased risk of arrhythmias may occur if given to patients
receiving cardiac glycosides, quinidine or tricyclic
antidepressants, ergot alkaloids, oxytocin (Parfitt
7.7 Main adverse effects
Central effects of sympathomimetic agents include:
tremor, fear, anxiety, confusion, irritability, insomnia, and
psychotic states. Paranoid psychosis, delusions and
hallucinations may also follow ephedrine overdose.
Effects on the cardiovascular system are complex:
vasoconstriction, hypertension, or hypotension and
bradycardia, tachycardia, palpitations, cardiac arrest.
It can cause local ischaemia in chronic topical use (Parfitt,
8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
8.1 Material sampling plan
8.1.1 Sampling and specimen collection
220.127.116.11 Toxicological analyses
18.104.22.168 Biomedical analyses
22.214.171.124 Arterial blood gas analysis
126.96.36.199 Haematological analyses
188.8.131.52 Other (unspecified) analyses
8.1.2 Storage of laboratory samples and specimens
184.108.40.206 Toxicological analyses
220.127.116.11 Biomedical analyses
18.104.22.168 Arterial blood gas analysis
22.214.171.124 Haematological analyses
126.96.36.199 Other (unspecified) analyses
8.1.3 Transport of laboratory samples and specimens
188.8.131.52 Toxicological analyses
184.108.40.206 Biomedical analyses
220.127.116.11 Arterial blood gas analysis
18.104.22.168 Haematological analyses
22.214.171.124 Other (unspecified) analyses
8.2 Toxicological analyses and their interpretation
8.2.1 Tests on toxic ingredient(s) of material
126.96.36.199 Simple qualitative test(s)
188.8.131.52 Advanced qualitative confirmation test(s)
184.108.40.206 Simple quantitative method(s)
220.127.116.11 Advanced quantitative method(s)
8.2.2 Tests for biological specimens
18.104.22.168 Simple qualitative test(s)
22.214.171.124 Advanced qualitative confirmation test(s)
126.96.36.199 Simple quantitative method(s)
188.8.131.52 Advanced quantitative method(s)
184.108.40.206 Other dedicated method(s)
8.2.3 Interpretation of toxicological analyses
8.3 Biomedical investigations and their interpretation
8.3.1 Biochemical analysis
220.127.116.11 Blood, plasma or serum
18.104.22.168 Other fluids
8.3.2 Arterial blood gas analyses
8.3.3 Haematological analyses
8.3.4 Interpretation of biomedical investigations
8.4 Other biomedical (diagnostic) investigations and their
8.5 Overall interpretation of all toxicological analyses and
9. CLINICAL EFFECTS
9.1 Acute poisoning
Early clinical manifestations of ingestion of
high doses of ephedrine consist of nausea and
vomiting, followed by insomnia, cardiac arrhythmia,
myocardial ischemia, agitation, psychosis and
No data available
9.1.3 Skin exposure
No data available
9.1.4 Eye contact
No data available
9.1.5 Parenteral exposure
The parenteral use of ephedrine may cause
intracerebral haemorrhage as a result of a rise in
arterial pressure. Ventricular arrhythmias have been
described (Ellenhorn 1988).
9.2 Chronic poisoning
Neurological symptoms that have been described
include headache, anxiety, tremor, insomnia,
dizziness, seizures (MMWR, 1996). Several cases of
psychosis have been reported (Roxanas & Spalding,
1977; Shufman et al., 1994; Copwell, 1995; Doyle &
Kargin, 1996; Jacobs & Kirsch, 2000).
Cardiovascular disorders associated with the chronic
use of ephedrine may include chest pain, hypertension,
arrhythmia, myocardial infarction, cerebral vascilitis
and stroke (MMWR, 1996).
No data available
9.2.3 Skin exposure
Local applications of ephedrine may cause
contact dermatitis (Tomb et al., 1991).
9.2.4 Eye contact
No data available.
9.2.5 Parenteral exposure
The intravenous use of ephedrine causes similar
effects as oral ingestion.
The vasoconstrictive effects of ephedrine
applied topically as nasal spray or drops may cause
local ischaemia (Parfitt, 1999).
9.3 Course, prognosis, cause of death
Early clinical manifestations of ephedrine overdose
consist of nausea and vomiting, followed by headache,
agitation, anxiety, tremor, seizures, tachycardia and
hypertensive crisis. Severe rise in blood pressure may
produce cerebral haemorrhage and myocardial infarction.
Ventricular arrhythmia may progress to cardiac arrest and
death. Although fatalities have been reported the prognosis
is usually good (Burkhart, 1992; Snook et al., 1992; MMWR,
1996; Backer et al., 1997; Theoharides, 1997; Hedetoft et
9.4 Systematic description of clinical effects
The most common symptoms are arterial
hypertension and tachycardia; ventricular arrhythmia,
chest pain, myocardial infarction, ischaemic or
haemorrhagic stroke, cardiac arrest may rarely occur
(Burkhart, 1992; Snook et al., 1992; MMWR, 1996;
Parfitt, 1999; Matthews et al., 1997; Hedetoft et al.,
Respiratory stimulation, bronchodilation,
pulmonary oedema apnea (Parfitt, 1999).
CNS stimulation: anxiety, agitation,
tremor, mental confusion, hallucinations,
mania, paranoid psychosis may occur;
convulsions have been reported.
(Roxanas & Spalding, 1977; Snook et al.,
1992; Shufman et al., 1994; Copwell, 1995;
Doyle & Kargin, 1996; Jacobs & Kirsch,
22.214.171.124 Peripheral nervous system
No data available.
126.96.36.199 Autonomic nervous system
Ephedrine causes stimulation of the
sympathetic nervous system acting on both
alpha and beta receptors. Symptoms include
tachycardia, arterial hypertension, tremor,
188.8.131.52 Skeletal and smooth muscle
Ephedrine produces relaxation of
smooth muscle. In overdose it may also cause
rhabdomyolysis (Salmon and Nicholson
Nausea and vomiting are common.
No data available.
No data available.
Ephedrine relaxes the vesical
detrusor muscle, and increases contraction of
the vesical sphincter (alpha agonist action),
and can produce acute retention of urine
9.4.7 Endocrine and reproductive systems
Inhibition of insulin secretion.
No data available
9.4.9 Eye, ear, nose, throat: local effects
Chronic administration of nasal drops or spray
can result in rebound nasal congestion and rhinorrhoea
(Parfitt, 1996; Bismuth, 2000).
No data available.
184.108.40.206 Acid base disturbances
220.127.116.11 Fluid and electrolyte disturbances
Hypokalaemia resulting from
9.4.13 Allergic reactions
Contact dermatitis after local application.
Sensitization and systemic allergic reactions (severe
eczema) have been reported after oral administration
(Audicana et al., 1991; Tomb et al., 1991).
9.4.14 Other clinical effects
9.4.15 Special risks
Ephedrine is present in breast-milk in
sufficient concentrations to be harmful to the baby,
and is contraindicated in women who are
breast-feeding. Patients with ischaemic heart disease,
hypertension, acute angle glaucoma, hyperthyroidism,
prostatic enlargement, or taking MAOI antidepressants
should also avoid ephedrine.
Chronic use can lead to tolerance with dependence.
Ephedrine abuse is a common occurrence and has been
associated with several deaths (Roxanas & Spalding, 1977;
Copwell, 1995; Doyle & Kargin, 1996; Gualtieri & Harris,
1996; MMWR, 1996; Theoharides, 1997; Jacobs & Kirsch,
10.1 General principles
Establish airway patency, breathing and circulation.
Establish baseline blood pressure and pulse.
Treatment is primarily supportive.
ECG monitoring is necessary. Monitor urine output.
Gastrointestinal decontamination may be indicated
There is no antidote.
10.2 Life supportive procedures and symptomatic/specific treatment
Severe hypertension and tachycardia should be treated
with the intravenous administration of a short-acting,
selective beta-blocker such as esmolol (Burkhart, 1992;
Bismuth, 2000). (Care should be taken as hypertension may be
aggrevated with use of beta-blockers owing to unopposed
alpha-agonist effects). Alternative treatments for
hypertension include nitroprusside or nitroglycerin infusion
In the treatment of ventricular dysrhythmias, lidocaine or
bretylium may be required.
Convulsions require administration of intravenous
Gastric lavage may be performed within 2 hours of
ingestion but can also increase intracranial pressure. Emesis
Administration of activated charcoal.
10.4 Enhanced elimination
Maintenance of adequate urine output is essential;
although ephedrine elimination is best achieved in acidic
urine, however the risk of this procedure in this setting
probably outweighs the potential benefits (Kelley 1998);
there is no evidence of the usefulness of forced diuresis,
hemodialysis or peritoneal dialysis in enhancing ephedrine
10.5 Antidote treatment
10.6 Management discussion
11. ILLUSTRATIVE CASES
11.1 Case reports from literature
A 20 y-o woman ingested 300 diet pills containing a
total of 7.5 g of ephedrine in a suicide attempt. She
presented to the ED two hours post ingestion, with a HR of
116, BP 146-60 mmHg, she was agitated and anxious, with
tremor and vomiting. Treatment included gastric lavage,
activated charcoal, and 1 mg propranolol. Serum ephedrine
level was 22.8 nanog/mL (therapeutic range: 0.04-0.08
nanog/mL) at 90 minutes post ingestion. The patient made an
uneventful recovery (Snook et al., 1992).
After ingesting 17500 mg of ephedrine, a 29 y-o female
developed a BP of 168-106. Her BP was 124-90 five minutes
after IV propranolol (Burkhart, 1992).
A 19 y-o woman ingested 1000 mg of ephedrine in combination
with 10000 mg of caffeine. She developed severe toxic
manifestations from the heart, CNS, muscles, liver and
kidneys leading to multiorgan failure, cardiac arrests and
died subsequently of cerebral oedema on the fourth day of
hospitalization (Hedetoft et al., 1999).
A 57 y-o woman had been taking a usual dose of ephedrine for
bronchial asthma (50 mg 3 times a day) for more than 30
years. When her husband died she developed depression, for
which she tried to use ephedrine as an antidepressant,
increasing the dose to 500 to 1000 mg a day over the course
of half a year. She developed paranoid psychosis with
delusions of persecution and auditory hallucinations.
Recovery was rapid after ephedrine was gradually reduced to
200 mg a day (Shufman et al., 1994)
12. ADDITIONAL INFORMATION
12.1 Specific preventive measures
Audicana M, Urrutia I, Echechipia S, Munoz D, Fernandez de
Corres L (1991) Sensitization to ephedrine in oral anticatarrhal
drugs. Contact Dermatitis, 24: 223
Backer R, tautman D, Lowry S, Harvey CM, Poklis A (1997) Fatal
ephedrine intoxication. J Forensic Sci, 42: 157-159
Bacelt RC, Cravey RH. (1995) Disposition of toxic drugs and
chemicals in man. 4th Edition. Pub Chemical Toxicology Institute,
Bismuth C Ed. (2000) Toxicologie clinique, 5čme Ed, Flammarion,
Burkhart KK (1992) Intravenous propranolol reverses hypertension
after sympathomimetic overdose: two case reports. J Toxicol Clin
Toxicol, 30: 109-114
Copwell RR (1995) Ephedrine-induced mania from an herbal diet
supplement. Am J Psychiatry, 152: 647
Dawson JK, Earnshaw SM, Graham CS (1995) Dangerous monoamine
oxidase inhibitor interactions are still occurring in the 1990's.
J Accid Emerg Med, 12: 49-51
Doyle H & Kargin M (1996) Herbal stimulant containing ephedrine
has also caused psychosis. BMJ, 313: 756
Dukes, MNG (1988) Meylers Side effects of drugs, 11th ed.,
Ellenhorn MJ, Barceloux DG (1988) Medical Toxicology - Diagnosis
and treatment of human poisoning, 521-543.
Goldfrank LR, Flomenbaum NE, Lewin NA, Weisman RS, Howland MA
(1990) Toxicological Emergencies 4th ed, 422.
Goodman y Gilman (1986) Las Bases Farmacológicas de la
Terapéutica, 7a ed 155-175.
Gualtieri J & Harris C (1996) Dilated cardiomyopathy in a heavy
ephedrine abuser. Clin Toxicol, 34: 581 (abstract)
Hedetoft C, Jensen CH, Christensen MR, Christensen O (1999) Fatal
poisoning with Letigen. Ugeskr Laeger, 161: 6937-6938
Jacobs KM & Kirsch KA (2000) Psychiatric complications of
Ma-huang. Psychosomatics, 41: 58-62
Kelley MT (1998). Chapter 39 Sympathiomimetics. In Clinical
Management of Poisioning and Drug Overdose 3rd Edition. Eds
Haddad, Shannon, Winchester. Pub WB Saunders Company Philidelphia,
Matthews G, Smolinske S, White S (1997) Ephedrine-related stroke
in a teenager. Clin Toxicol, 35: 555 (abstract)
MMWR Morb Mortal Wkly Rep (1996) Adverse events associated with
ephedrine-containing products-Texas, December 1993-September 1995.
Parfitts K. (1999) The Extra Pharmacopoeia, 31 Ed, The
pharmaceutical Press, London
Roxanas MG & Spalding J (1977) Ephedrine abuse psychosis. Med J
Aust, 2: 639-640
Salmon J, Nicholson D. DIC and rhabdomyolysis following
pseudoephedrine overdose. Am J Emerg Med 1988;6:545-546
Shufman NE, Witztum E, Vass A (1994) Ephedrine psychosis.
Harefuah, 127: 166-8, 215
Skop BP, Finkelstein JA, Mareth TR, Magoon MR, Brown TM (1994) The
serotonin syndrome associated with paroxetine, an over-the-counter
cold remedy and vascular disease. Am J Emerg Med, 12: 642-644
Snook C, Otten M, Hassan M (1992) Massive ephedrine overdose: case
report and toxicokinetic analysis. Vet Human Toxicol, 34: 335
Theoharides TC (1997) Sudden death of a healthy college student
related to ephedrine toxicity from a Ma-huang-containing drink. J
Clin Psychopharmacol, 17: 437-439
Tomb RR, Lepoittevin JP, Espinassouze F, Heid E, Foussereau J
(1991) Systemic contact dermatitis from pseudoephedrine, Contact
Dermatitis, 24: 86-88
Windholz M ed. (1983) 10 ED The Merck Index: an encyclopaedia of
chemicals, drugs and biologicals, Rahway, New Jersey Merck and
14. AUTHOR(S), REVIEWER(S) DATA (INCLUDING EACH UPDATING), COMPLETE
Author: Dr Mabel Burger
Address: CIAT - Piso 7E
Hospital de Clinicas
Avenida Italia s/n
Tel: (598 2) 80 40 00
(598 2) 47 03 00
Fax: (598 2) 47 03 00
Date: July 1991
Update: MO Rambourg Schepens, September 2000
Reviewed at INTOX 12, Erfurt, Germany, November 2000
Reviewers M. Balali-Mood, W. Temple, B. Groszek, N. Langford.