Ephedrine is a sympathomimetic
amineAmines are organic compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are derivatives of ammonia, wherein one or more hydrogen atoms have been replaced by a substituent such as an alkyl or aryl group. Important amines include amino acids, biogenic amines,...
commonly used as a
stimulantStimulants are psychoactive drugs which induce temporary improvements in either mental or physical function or both. Examples of these kinds of effects may include enhanced alertness, wakefulness, and locomotion, among others...
, appetite suppressant, concentration aid,
decongestantA decongestant or nasal decongestant is a type of drug that is used to relieve nasal congestion.-Pharmacology:The vast majority of decongestants act via enhancing norepinephrine and epinephrine or adrenergic activity by stimulating the α-adrenergic receptors...
, and to treat
hypotensionIn physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...
associated with anaesthesia.
Ephedrine is similar in structure to the (semi-synthetic) derivatives
amphetamineAmphetamine or amfetamine is a psychostimulant drug of the phenethylamine class which produces increased wakefulness and focus in association with decreased fatigue and appetite.Brand names of medications that contain, or metabolize into, amphetamine include Adderall, Dexedrine, Dextrostat,...
and
methamphetamine Methamphetamine is a psychostimulant of the phenethylamine and amphetamine class of psychoactive drugs...
. Chemically, it is an
alkaloidAlkaloids are a group of naturally occurring chemical compounds that contain mostly basic nitrogen atoms. This group also includes some related compounds with neutral and even weakly acidic properties. Also some synthetic compounds of similar structure are attributed to alkaloids...
derived from various plants in the genus
EphedraEphedra is a genus of gymnosperm shrubs, the only genus in its family, Ephedraceae, and order, Ephedrales. Ephedra grows in dry climates over wide areas of the northern hemisphere, including southwestern North America, Europe, north Africa, and southwest and central Asia, and, in the southern...
(family Ephedraceae). It works mainly by increasing the activity of noradrenaline on adrenergic receptors. It is most usually marketed in the
hydrochloride and
sulfate forms.
In traditional Chinese medicines, the herb
má huáng (麻黄,
Ephedra sinica) contains ephedrine and
pseudoephedrinePseudoephedrine is a sympathomimetic drug of the phenethylamine and amphetamine chemical classes. It is used as a nasal/sinus decongestant and stimulant, or as a wakefulness-promoting agent....
as its principal active constituents. The same is true of other herbal products containing extracts from
Ephedra species.
Chemistry
Ephedrine exhibits optical isomerism and has two chiral centres, giving rise to four stereoisomers. By convention the
enantiomerIn chemistry, an enantiomer is one of two stereoisomers that are mirror images of each other that are non-superposable , much as one's left and right hands are the same except for opposite orientation. It can be clearly understood if you try to place your hands one over the other without...
s with opposite stereochemistry around the chiral centres (1R,2S and 1S,2R) are designated ephedrine, while
pseudoephedrinePseudoephedrine is a sympathomimetic drug of the phenethylamine and amphetamine chemical classes. It is used as a nasal/sinus decongestant and stimulant, or as a wakefulness-promoting agent....
has same stereochemistry around the chiral carbons (1R,2R and 1S,2S).
Ephedrine is a substituted amphetamine and a structural
methamphetamine Methamphetamine is a psychostimulant of the phenethylamine and amphetamine class of psychoactive drugs...
analogue. It differs from methamphetamine only by the presence of a
hydroxylA hydroxyl is a chemical group containing an oxygen atom covalently bonded with a hydrogen atom. In inorganic chemistry, the hydroxyl group is known as the hydroxide ion, and scientists and reference works generally use these different terms though they refer to the same chemical structure in...
(OH). Amphetamines, however, are more potent and have additional biological effects.
The isomer which is marketed is (–)-(1R,2S)-ephedrine.
Ephedrine hydrochloride has a melting point of 187-188°C.
Nomenclature
The
dextrorotaryDextrorotation and levorotation refer, respectively, to the properties of rotating plane polarized light clockwise or counterclockwise , seen by an observer whom the light is approaching...
(+)- or d- enantiomer is (1S,2R)-Ephedrine, whereas the levorotatory (−)- or l- form is (1R,2S)-Ephedrine.
In the outdated
{{drugbox | verifiedrevid = 443728664
| IUPAC_name = (R*,S*)-2-(methylamino)-1-phenylpropan-1-ol
| image = (-)-Ephedrin.svg
| width = 201
| image2 = Ephedrine-3d-CPK.png
| Drugs.com = {{drugs.com|monograph|ephedrine}}
| pregnancy_AU = A
| pregnancy_US = A
| legal_AU = S4
| legal_CA = Schedule VI
| legal_UK = P
| legal_US = OTC
| routes_of_administration = oral, IV, IM, SC
| bioavailability = 85%
| metabolism = minimal hepatic
| elimination_half-life = 3–6 hours
| excretion = 22-99% renal
| CASNo_Ref = {{cascite|correct|CAS}}
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 299-42-3
| ATC_prefix = C01
| ATC_suffix = CA26
| ATC_supplemental = {{ATC|R01|AA03}} {{ATC|R01|AB05}} {{ATC|R03|CA02}} {{ATC|S01|FB02}} {{ATCvet|G04|BX90}}
| PubChem = 5032
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB01364
| ChemSpiderID_Ref =
| ChemSpiderID = 8935
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = GN83C131XS
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D00124
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 15407
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 211456
| C=10 | H=15 | N=1 | O=1
| molecular_weight = 165.23
| smiles = O[C@H](c1ccccc1)[C@@H](NC)C
| InChI = 1/C10H15NO/c1-8(11-2)10(12)9-6-4-3-5-7-9/h3-8,10-12H,1-2H3/t8-,10-/m0/s1
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C10H15NO/c1-8(11-2)10(12)9-6-4-3-5-7-9/h3-8,10-12H,1-2H3/t8-,10-/m0/s1
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = KWGRBVOPPLSCSI-WPRPVWTQSA-N
}}
Ephedrine (icon or ˈ; not to be confused with
ephedroneMethcathinone , is a psychoactive stimulant, sometimes used as a recreational drug and considered addictive. It is usually snorted, but can be smoked, injected, or taken orally...
) is a sympathomimetic
amineAmines are organic compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are derivatives of ammonia, wherein one or more hydrogen atoms have been replaced by a substituent such as an alkyl or aryl group. Important amines include amino acids, biogenic amines,...
commonly used as a
stimulantStimulants are psychoactive drugs which induce temporary improvements in either mental or physical function or both. Examples of these kinds of effects may include enhanced alertness, wakefulness, and locomotion, among others...
, appetite suppressant, concentration aid,
decongestantA decongestant or nasal decongestant is a type of drug that is used to relieve nasal congestion.-Pharmacology:The vast majority of decongestants act via enhancing norepinephrine and epinephrine or adrenergic activity by stimulating the α-adrenergic receptors...
, and to treat
hypotensionIn physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...
associated with anaesthesia.
Ephedrine is similar in structure to the (semi-synthetic) derivatives
amphetamineAmphetamine or amfetamine is a psychostimulant drug of the phenethylamine class which produces increased wakefulness and focus in association with decreased fatigue and appetite.Brand names of medications that contain, or metabolize into, amphetamine include Adderall, Dexedrine, Dextrostat,...
and
methamphetamine Methamphetamine is a psychostimulant of the phenethylamine and amphetamine class of psychoactive drugs...
. Chemically, it is an
alkaloidAlkaloids are a group of naturally occurring chemical compounds that contain mostly basic nitrogen atoms. This group also includes some related compounds with neutral and even weakly acidic properties. Also some synthetic compounds of similar structure are attributed to alkaloids...
derived from various plants in the genus
EphedraEphedra is a genus of gymnosperm shrubs, the only genus in its family, Ephedraceae, and order, Ephedrales. Ephedra grows in dry climates over wide areas of the northern hemisphere, including southwestern North America, Europe, north Africa, and southwest and central Asia, and, in the southern...
(family Ephedraceae). It works mainly by increasing the activity of noradrenaline on adrenergic receptors. It is most usually marketed in the
hydrochloride and
sulfate forms.
In traditional Chinese medicines, the herb
má huáng (麻黄,
Ephedra sinica) contains ephedrine and
pseudoephedrinePseudoephedrine is a sympathomimetic drug of the phenethylamine and amphetamine chemical classes. It is used as a nasal/sinus decongestant and stimulant, or as a wakefulness-promoting agent....
as its principal active constituents. The same is true of other herbal products containing extracts from
Ephedra species.
Chemistry
Ephedrine exhibits optical isomerism and has two chiral centres, giving rise to four stereoisomers. By convention the
enantiomerIn chemistry, an enantiomer is one of two stereoisomers that are mirror images of each other that are non-superposable , much as one's left and right hands are the same except for opposite orientation. It can be clearly understood if you try to place your hands one over the other without...
s with opposite stereochemistry around the chiral centres (1R,2S and 1S,2R) are designated ephedrine, while
pseudoephedrinePseudoephedrine is a sympathomimetic drug of the phenethylamine and amphetamine chemical classes. It is used as a nasal/sinus decongestant and stimulant, or as a wakefulness-promoting agent....
has same stereochemistry around the chiral carbons (1R,2R and 1S,2S).
Ephedrine is a substituted amphetamine and a structural
methamphetamine Methamphetamine is a psychostimulant of the phenethylamine and amphetamine class of psychoactive drugs...
analogue. It differs from methamphetamine only by the presence of a
hydroxylA hydroxyl is a chemical group containing an oxygen atom covalently bonded with a hydrogen atom. In inorganic chemistry, the hydroxyl group is known as the hydroxide ion, and scientists and reference works generally use these different terms though they refer to the same chemical structure in...
(OH). Amphetamines, however, are more potent and have additional biological effects.
The isomer which is marketed is (–)-(1R,2S)-ephedrine.
Ephedrine hydrochloride has a melting point of 187-188°C.
Nomenclature
The
dextrorotaryDextrorotation and levorotation refer, respectively, to the properties of rotating plane polarized light clockwise or counterclockwise , seen by an observer whom the light is approaching...
(+)- or d- enantiomer is (1S,2R)-Ephedrine, whereas the levorotatory (−)- or l- form is (1R,2S)-Ephedrine.
In the outdated
{{drugbox | verifiedrevid = 443728664
| IUPAC_name = (R*,S*)-2-(methylamino)-1-phenylpropan-1-ol
| image = (-)-Ephedrin.svg
| width = 201
| image2 = Ephedrine-3d-CPK.png
| Drugs.com = {{drugs.com|monograph|ephedrine}}
| pregnancy_AU = A
| pregnancy_US = A
| legal_AU = S4
| legal_CA = Schedule VI
| legal_UK = P
| legal_US = OTC
| routes_of_administration = oral, IV, IM, SC
| bioavailability = 85%
| metabolism = minimal hepatic
| elimination_half-life = 3–6 hours
| excretion = 22-99% renal
| CASNo_Ref = {{cascite|correct|CAS}}
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 299-42-3
| ATC_prefix = C01
| ATC_suffix = CA26
| ATC_supplemental = {{ATC|R01|AA03}} {{ATC|R01|AB05}} {{ATC|R03|CA02}} {{ATC|S01|FB02}} {{ATCvet|G04|BX90}}
| PubChem = 5032
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB01364
| ChemSpiderID_Ref =
| ChemSpiderID = 8935
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = GN83C131XS
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D00124
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 15407
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 211456
| C=10 | H=15 | N=1 | O=1
| molecular_weight = 165.23
| smiles = O[C@H](c1ccccc1)[C@@H](NC)C
| InChI = 1/C10H15NO/c1-8(11-2)10(12)9-6-4-3-5-7-9/h3-8,10-12H,1-2H3/t8-,10-/m0/s1
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C10H15NO/c1-8(11-2)10(12)9-6-4-3-5-7-9/h3-8,10-12H,1-2H3/t8-,10-/m0/s1
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = KWGRBVOPPLSCSI-WPRPVWTQSA-N
}}
Ephedrine (icon or ˈ; not to be confused with
ephedroneMethcathinone , is a psychoactive stimulant, sometimes used as a recreational drug and considered addictive. It is usually snorted, but can be smoked, injected, or taken orally...
) is a sympathomimetic
amineAmines are organic compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are derivatives of ammonia, wherein one or more hydrogen atoms have been replaced by a substituent such as an alkyl or aryl group. Important amines include amino acids, biogenic amines,...
commonly used as a
stimulantStimulants are psychoactive drugs which induce temporary improvements in either mental or physical function or both. Examples of these kinds of effects may include enhanced alertness, wakefulness, and locomotion, among others...
, appetite suppressant, concentration aid,
decongestantA decongestant or nasal decongestant is a type of drug that is used to relieve nasal congestion.-Pharmacology:The vast majority of decongestants act via enhancing norepinephrine and epinephrine or adrenergic activity by stimulating the α-adrenergic receptors...
, and to treat
hypotensionIn physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...
associated with anaesthesia.
Ephedrine is similar in structure to the (semi-synthetic) derivatives
amphetamineAmphetamine or amfetamine is a psychostimulant drug of the phenethylamine class which produces increased wakefulness and focus in association with decreased fatigue and appetite.Brand names of medications that contain, or metabolize into, amphetamine include Adderall, Dexedrine, Dextrostat,...
and
methamphetamine Methamphetamine is a psychostimulant of the phenethylamine and amphetamine class of psychoactive drugs...
. Chemically, it is an
alkaloidAlkaloids are a group of naturally occurring chemical compounds that contain mostly basic nitrogen atoms. This group also includes some related compounds with neutral and even weakly acidic properties. Also some synthetic compounds of similar structure are attributed to alkaloids...
derived from various plants in the genus
EphedraEphedra is a genus of gymnosperm shrubs, the only genus in its family, Ephedraceae, and order, Ephedrales. Ephedra grows in dry climates over wide areas of the northern hemisphere, including southwestern North America, Europe, north Africa, and southwest and central Asia, and, in the southern...
(family Ephedraceae). It works mainly by increasing the activity of noradrenaline on adrenergic receptors. It is most usually marketed in the
hydrochloride and
sulfate forms.
In traditional Chinese medicines, the herb
má huáng (麻黄,
Ephedra sinica) contains ephedrine and
pseudoephedrinePseudoephedrine is a sympathomimetic drug of the phenethylamine and amphetamine chemical classes. It is used as a nasal/sinus decongestant and stimulant, or as a wakefulness-promoting agent....
as its principal active constituents. The same is true of other herbal products containing extracts from
Ephedra species.
Chemistry
Ephedrine exhibits optical isomerism and has two chiral centres, giving rise to four stereoisomers. By convention the
enantiomerIn chemistry, an enantiomer is one of two stereoisomers that are mirror images of each other that are non-superposable , much as one's left and right hands are the same except for opposite orientation. It can be clearly understood if you try to place your hands one over the other without...
s with opposite stereochemistry around the chiral centres (1R,2S and 1S,2R) are designated ephedrine, while
pseudoephedrinePseudoephedrine is a sympathomimetic drug of the phenethylamine and amphetamine chemical classes. It is used as a nasal/sinus decongestant and stimulant, or as a wakefulness-promoting agent....
has same stereochemistry around the chiral carbons (1R,2R and 1S,2S).
Ephedrine is a substituted amphetamine and a structural
methamphetamine Methamphetamine is a psychostimulant of the phenethylamine and amphetamine class of psychoactive drugs...
analogue. It differs from methamphetamine only by the presence of a
hydroxylA hydroxyl is a chemical group containing an oxygen atom covalently bonded with a hydrogen atom. In inorganic chemistry, the hydroxyl group is known as the hydroxide ion, and scientists and reference works generally use these different terms though they refer to the same chemical structure in...
(OH). Amphetamines, however, are more potent and have additional biological effects.
The isomer which is marketed is (–)-(1R,2S)-ephedrine.
Ephedrine hydrochloride has a melting point of 187-188°C.
Nomenclature
The
dextrorotaryDextrorotation and levorotation refer, respectively, to the properties of rotating plane polarized light clockwise or counterclockwise , seen by an observer whom the light is approaching...
(+)- or d- enantiomer is (1S,2R)-Ephedrine, whereas the levorotatory (−)- or l- form is (1R,2S)-Ephedrine.
In the outdated {{smallcaps (+)-Ephedrine is also referred to as {{smallcaps|l-}}Ephedrine and (—)-Ephedrine as {{smallcaps|d-}}Ephedrine (in the Fisher projection then the phenylring is drawn at bottom).
Often the {{smallcaps|d/l}} system (with
small capsIn typography, small capitals are uppercase characters set at the same height and weight as surrounding lowercase letters or text figures...
) and the d/l system (with lower-case) are confused. The result is that the levorotary l-Ephedrine is wrongly named {{smallcaps|l-}}Ephedrine and the dextrorotary d-Pseudoephedrine (the diastereomer) wrongly {{smallcaps|d-}}Pseudoephedrine.
The IUPAC names of the two enantiomers are (1R,2S)- respectively (1S,2R)-2-methylamino-1-phenylpropan-1-ol. A synonym is erythro-Ephedrine.
Agricultural sources
Raw materials for the production of ephedrine and traditional Chinese medicine are produced in China on a large scale. In 2007, companies produced for export extract US$13 million worth of ephedrine from 30,000 tons of ephedra annually, 10 times the amount that is used in traditional Chinese medicine.
Synthetic sources
Most of the L-ephedrine produced today for official medical use is made synthetically as the extraction and isolation process from Herba Ephedra is tedious and no longer cost effective.
Mechanism of action
Ephedrine is a sympathomimetic amine. The principal mechanism of its action relies on its indirect stimulation of the
adrenergic receptorThe adrenergic receptors are a class of metabotropic G protein-coupled receptors that are targets of the catecholamines, especially noradrenaline and adrenaline ....
system, which is part of the
sympathetic nervous systemThe sympathetic nervous system is one of the three parts of the autonomic nervous system, along with the enteric and parasympathetic systems. Its general action is to mobilize the body's nervous system fight-or-flight response...
(
SNS), by increasing the activity of noradrenaline at the post-synaptic α- and β-receptors. The presence of direct interactions with α-receptors is unlikely, but still controversial. L-Ephedrine, and particularly its stereoisomer norpseudoephedrine (which is also present in Catha edulis) has indirect sympathomimetic effects and due to its ability to cross the blood brain barrier, it is a
CNSThe central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
stimulantStimulants are psychoactive drugs which induce temporary improvements in either mental or physical function or both. Examples of these kinds of effects may include enhanced alertness, wakefulness, and locomotion, among others...
similar to amphetamines but less pronounced, as it releases noradrenaline and
dopamineDopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
in the
substantia nigraThe substantia nigra is a brain structure located in the mesencephalon that plays an important role in reward, addiction, and movement. Substantia nigra is Latin for "black substance", as parts of the substantia nigra appear darker than neighboring areas due to high levels of melanin in...
.
The presence of an
N-
methyl groupMethyl group is a functional group derived from methane, containing one carbon atom bonded to three hydrogen atoms —CH3. The group is often abbreviated Me. Such hydrocarbon groups occur in many organic compounds. The methyl group can be found in three forms: anion, cation and radical. The anion...
decreases binding affinities at α-receptors, compared with norephedrine. On the other hand ephedrine binds better than
N-methylephedrine, which has an additional methyl group at the N-atom. Also the
stericStereochemistry, a subdiscipline of chemistry, involves the study of the relative spatial arrangement of atoms within molecules. An important branch of stereochemistry is the study of chiral molecules....
orientation of the
hydroxylA hydroxyl is a chemical group containing an oxygen atom covalently bonded with a hydrogen atom. In inorganic chemistry, the hydroxyl group is known as the hydroxide ion, and scientists and reference works generally use these different terms though they refer to the same chemical structure in...
group is important for receptor binding and functional activity.
Medical use
Indications
In traditional Chinese medicine,
ma huang has been used in the treatment of asthma and bronchitis for centuries.
Both ephedrine and pseudoephedrine act as a
bronchodilatorA bronchodilator is a substance that dilates the bronchi and bronchioles, decreasing resistance in the respiratory airway and increasing airflow to the lungs. Bronchodilators may be endogenous , or they may be medications administered for the treatment of breathing difficulties...
, but pseudoephedrine has considerably less effect. Both also increase blood pressure, with again pseudoephedrine being considerably less effective.
Ephedrine promotes
weight lossWeight loss, in the context of medicine, health or physical fitness, is a reduction of the total body mass, due to a mean loss of fluid, body fat or adipose tissue and/or lean mass, namely bone mineral deposits, muscle, tendon and other connective tissue...
, specifically fat loss in humans and mice. In mice it is known to stimulate
thermogenesisThermogenesis is the process of heat production in organisms. It occurs mostly in warm-blooded animals, but a few species of thermogenic plants exist.-Types:...
in the
brown adipose tissueBrown adipose tissue or brown fat is one of two types of fat or adipose tissue found in mammals....
, however because adult humans have only small amounts of brown fat it is assumed that thermogenesis takes place mostly in the
skeletal muscleSkeletal muscle is a form of striated muscle tissue existing under control of the somatic nervous system- i.e. it is voluntarily controlled. It is one of three major muscle types, the others being cardiac and smooth muscle...
. Ephedrine also decreases gastric emptying. Methylxanthines like
caffeineCaffeine is a bitter, white crystalline xanthine alkaloid that acts as a stimulant drug. Caffeine is found in varying quantities in the seeds, leaves, and fruit of some plants, where it acts as a natural pesticide that paralyzes and kills certain insects feeding on the plants...
and
theophyllineTheophylline, also known as dimethylxanthine, is a methylxanthine drug used in therapy for respiratory diseases such as COPD and asthma under a variety of brand names. Because of its numerous side-effects, the drug is now rarely administered for clinical use. As a member of the xanthine family, it...
have a synergistic effect with ephedrine with respect to weight loss, and so does
aspirinAspirin , also known as acetylsalicylic acid , is a salicylate drug, often used as an analgesic to relieve minor aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory medication. It was discovered by Arthur Eichengrun, a chemist with the German company Bayer...
. This led to creation and marketing of compound products. One of them is known as the
ECA stackThe ECA stack is a drug combination used in weight loss and as a stimulant. ECA is an acronym for ephedrine, caffeine, and aspirin, with variants of it including the EC stack, which removes the aspirin for those that can not tolerate it...
, containing
caffeineCaffeine is a bitter, white crystalline xanthine alkaloid that acts as a stimulant drug. Caffeine is found in varying quantities in the seeds, leaves, and fruit of some plants, where it acts as a natural pesticide that paralyzes and kills certain insects feeding on the plants...
and
aspirinAspirin , also known as acetylsalicylic acid , is a salicylate drug, often used as an analgesic to relieve minor aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory medication. It was discovered by Arthur Eichengrun, a chemist with the German company Bayer...
besides ephedrine and is a popular supplement taken by
body buildersBodybuilding is a form of body modification involving intensive muscle hypertrophy. An individual who engages in this activity is referred to as a bodybuilder. In competitive and professional bodybuilding, bodybuilders display their physiques to a panel of judges, who assign points based on their...
to cut down body fat before a competition.{{citation needed|date=January 2011}}
For many years, the US Coast Guard recommended ephedrine together with an equal 25 mg dose of
promethazinePromethazine is a first-generation antihistamine of the phenothiazine family. The drug has anti-motion sickness, antiemetic, and anticholinergic effects, as well as a strong sedative effect and in some countries is prescribed for insomnia when benzodiazepines are contraindicated...
to its sailors to combat seasickness. Promethazine manages nausea and ephedrine fights the ensuing drowsiness. Commonly referred to as the Coast Guard cocktail, ephedrine may still be available for prescription for this purpose.{{Citation needed|reason = Sept 2010|date=September 2010}}
Adverse effects
Adverse drug reactionAn adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...
s (ADRs) are more common with systemic administration (e.g. injection or oral administration) compared to topical administration (e.g. nasal instillations). ADRs associated with ephedrine therapy include:
- Cardiovascular: tachycardia
Tachycardia comes from the Greek words tachys and kardia . Tachycardia typically refers to a heart rate that exceeds the normal range for a resting heart rate...
, cardiac arrhythmias, angina pectoris, vasoconstrictionVasoconstriction is the narrowing of the blood vessels resulting from contraction of the muscular wall of the vessels, particularly the large arteries, small arterioles and veins. The process is the opposite of vasodilation, the widening of blood vessels. The process is particularly important in...
with hypertensionHypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
- Dermatological
Dermatology is the branch of medicine dealing with the skin and its diseases, a unique specialty with both medical and surgical aspects. A dermatologist takes care of diseases, in the widest sense, and some cosmetic problems of the skin, scalp, hair, and nails....
: flushing, sweating, acne vulgarisAcne vulgaris is a common human skin disease, characterized by areas of skin with seborrhea , comedones , papules , pustules , Nodules and possibly scarring...
- Gastrointestinal
The human gastrointestinal tract refers to the stomach and intestine, and sometimes to all the structures from the mouth to the anus. ....
: anorexiaAnorexia is the decreased sensation of appetite...
, nausea
- Genitourinary
In anatomy, the genitourinary system or urogenital system is the organ system of the reproductive organs and the urinary system. These are grouped together because of their proximity to each other, their common embryological origin and the use of common pathways, like the male urethra...
: decreased urination due to vasoconstriction of renal arteries. Also, difficulty urinating is not uncommon, as alpha-agonists such as ephedrine constrict the internal urethral sphincter, mimicking the effects of sympathetic nervous system stimulation.
- Nervous system
The nervous system is an organ system containing a network of specialized cells called neurons that coordinate the actions of an animal and transmit signals between different parts of its body. In most animals the nervous system consists of two parts, central and peripheral. The central nervous...
: restlessness, confusionConFusion is an annual science fiction convention organized by the Stilyagi Air Corps and its parent organization, the Ann Arbor Science Fiction Association. Commonly, it is held the third weekend of January. It is the oldest science fiction convention in Michigan, a regional, general SF con...
, insomniaInsomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
, mild euphoria, maniaMania, the presence of which is a criterion for certain psychiatric diagnoses, is a state of abnormally elevated or irritable mood, arousal, and/ or energy levels. In a sense, it is the opposite of depression...
/hallucinations (rare except in previously existing psychiatric conditions), delusions, formicationFormication is the medical term for a sensation that resembles that of insects crawling on the skin. It is one specific form of a set of sensations known as paresthesia, which also include the more common prickling, tingling sensation of "pins and needles"...
(may be possible, but lacks documented evidence) paranoiaParanoia [] is a thought process believed to be heavily influenced by anxiety or fear, often to the point of irrationality and delusion. Paranoid thinking typically includes persecutory beliefs, or beliefs of conspiracy concerning a perceived threat towards oneself...
, hostilityHostility is a form of angry internal rejection or denial in psychology. It is a part of personal construct psychology, developed by George Kelly...
, panicPanic is a sudden sensation of fear which is so strong as to dominate or prevent reason and logical thinking, replacing it with overwhelming feelings of anxiety and frantic agitation consistent with an animalistic fight-or-flight reaction...
, agitationPsychomotor agitation is a series of unintentional and purposeless motions that stem from mental tension and anxiety of an individual. This includes pacing around a room, wringing one's hands, pulling off clothing and putting it back on and other similar actions...
- Respiratory
The respiratory system is the anatomical system of an organism that introduces respiratory gases to the interior and performs gas exchange. In humans and other mammals, the anatomical features of the respiratory system include airways, lungs, and the respiratory muscles...
: dyspneaDyspnea , shortness of breath , or air hunger, is the subjective symptom of breathlessness.It is a normal symptom of heavy exertion but becomes pathological if it occurs in unexpected situations...
, pulmonary edema
- Miscellaneous: dizziness, headache, tremor, hyperglycemic
Hyperglycemia or Hyperglycæmia, or high blood sugar, is a condition in which an excessive amount of glucose circulates in the blood plasma. This is generally a glucose level higher than 13.5mmol/l , but symptoms may not start to become noticeable until even higher values such as 15-20 mmol/l...
reactions, dry mouth
The neurotoxicity of l-Ephedrine is disputed.
Contraindications
Ephedrine should not be used in conjunction with certain antidepressants, namely
SNRISerotonin–norepinephrine reuptake inhibitors are a class of antidepressant drugs used in the treatment of major depression and other mood disorders...
s (serotonin-norepinephrine re-uptake inhibitors), as this increases the risk of the above symptoms due to excessive serum levels of norepinephrine.
BupropionBupropion is an atypical antidepressant and smoking cessation aid. The drug is a non-tricyclic antidepressant and differs from most commonly prescribed antidepressants such as SSRIs, as its primary pharmacological action is thought to be norepinephrine-dopamine reuptake inhibition...
is an example of an antidepressant with an amphetamine-like structure similar to ephedrine, and it is known as an
NDRIA norepinephrine-dopamine reuptake inhibitor is a drug which acts as a reuptake inhibitor for the neurotransmitters norepinephrine and dopamine by blocking the action of the norepinephrine transporter and the dopamine transporter , respectively...
(norepinephrine-dopamine re-uptake inhibitor). It has an action which bears more resemblance to amphetamine than to
fluoxetineFluoxetine is an antidepressant of the selective serotonin reuptake inhibitor class. It is manufactured and marketed by Eli Lilly and Company...
in that its primary mode of therapeutic action involves norepinephrine and to a lesser degree dopamine, but it also releases some serotonin from presynaptic clefts. It should not be used with ephedrine as it may increase the likelihood of the above side effects.
Ephedrine should be used with caution in patients with inadequate fluid replacement, impaired adrenal function,
hypoxiaHypoxia, or hypoxiation, is a pathological condition in which the body as a whole or a region of the body is deprived of adequate oxygen supply. Variations in arterial oxygen concentrations can be part of the normal physiology, for example, during strenuous physical exercise...
,
hypercapniaHypercapnia or hypercapnea , also known as hypercarbia, is a condition where there is too much carbon dioxide in the blood...
,
acidosisAcidosis is an increased acidity in the blood and other body tissue . If not further qualified, it usually refers to acidity of the blood plasma....
,
hypertensionHypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
,
hyperthyroidismHyperthyroidism is the term for overactive tissue within the thyroid gland causing an overproduction of thyroid hormones . Hyperthyroidism is thus a cause of thyrotoxicosis, the clinical condition of increased thyroid hormones in the blood. Hyperthyroidism and thyrotoxicosis are not synonymous...
, prostatic hypertrophy,
diabetes mellitusDiabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...
, cardiovascular disease, during delivery if maternal BP > 130/80 mmHg, and lactation.
Contraindications for the use of ephedrine include: closed angle glaucoma, phaeochromocytoma, asymmetric septal hypertrophy (idiopathic hypertrophic subaortic stenosis), concomitant or recent (previous 14 days)
monoamine oxidase inhibitorMonoamine oxidase inhibitors are a class of antidepressant drugs prescribed for the treatment of depression. They are particularly effective in treating atypical depression....
(MAOI) therapy, general anaesthesia with halogenated hydrocarbons (particularly halothane), tachyarrhythmias or ventricular fibrillation, hypersensitivity to ephedrine or other stimulants.
Ephedrine should not be used at any time during pregnancy unless specifically indicated by a qualified physician and only when other options are unavailable.
Recreational and illicit use
Anecdotal reports have suggested that ephedrine helps studying, thinking, or concentrating to a greater extent than caffeine. Some students and some
white-collar workerThe term white-collar worker refers to a person who performs professional, managerial, or administrative work, in contrast with a blue-collar worker, whose job requires manual labor...
s have used ephedrine (or Ephedra-containing herbal supplements) for this purpose, as well as some professional athletes and weightlifters. It is common for many athletes to use
stimulants while exercisingStimulants, such as caffeine, ephedrine/Ma Huang, amphetamine, methamphetamine, and cocaine, are commonly believed to grant users increased physical strength and endurance, and resistance to pain. These substances, however, may cause serious health problems....
. Such use of ephedrine has been associated with stimulant dependence, as well as deaths from
heatstrokeHyperthermia is an elevated body temperature due to failed thermoregulation. Hyperthermia occurs when the body produces or absorbs more heat than it can dissipate...
in athletes and circulatory problems such as
aortic aneurysmAn aortic aneurysm is a general term for any swelling of the aorta to greater than 1.5 times normal, usually representing an underlying weakness in the wall of the aorta at that location...
in weightlifters, though these side effects are rare.
As a phenylethylamine, ephedrine has a similar chemical structure to
amphetaminesSubstituted amphetamines are a chemical class of stimulants, entactogens, hallucinogens, and other drugs. They feature a phenethylamine core with a methyl group attached to the alpha carbon resulting in amphetamine, along with additional substitutions...
and is a
methamphetamine Methamphetamine is a psychostimulant of the phenethylamine and amphetamine class of psychoactive drugs...
analogue having the methamphetamine structure with a
hydroxylA hydroxyl is a chemical group containing an oxygen atom covalently bonded with a hydrogen atom. In inorganic chemistry, the hydroxyl group is known as the hydroxide ion, and scientists and reference works generally use these different terms though they refer to the same chemical structure in...
group at the β position. Because of ephedrine's structural similarity to methamphetamine it can be used to create methamphetamine using chemical reduction in which ephedrine's hydroxy group is removed; this has made ephedrine a highly sought-after chemical precursor in the
illicit manufactureClandestine chemistry is chemistry carried out in secret, and particularly in illegal drug laboratories. Larger labs are usually run by gangs or organized crime intending to produce for distribution on the black market...
of
methamphetamine Methamphetamine is a psychostimulant of the phenethylamine and amphetamine class of psychoactive drugs...
. The most popular method for reducing ephedrine to methamphetamine is similar to the
Birch reductionThe Birch Reduction is an organic reaction which is particularly useful in synthetic organic chemistry. The reaction was reported in 1944 by the Australian chemist Arthur Birch working in the Dyson Perrins Laboratory in the University of Oxford, building on earlier work by Wooster and Godfrey in...
, in that it uses anhydrous ammonia and
lithiumLithium is a soft, silver-white metal that belongs to the alkali metal group of chemical elements. It is represented by the symbol Li, and it has the atomic number 3. Under standard conditions it is the lightest metal and the least dense solid element. Like all alkali metals, lithium is highly...
metal in the
reactionA chemical reaction is a process that leads to the transformation of one set of chemical substances to another. Chemical reactions can be either spontaneous, requiring no input of energy, or non-spontaneous, typically following the input of some type of energy, such as heat, light or electricity...
. The second most popular method uses red
phosphorusPhosphorus is the chemical element that has the symbol P and atomic number 15. A multivalent nonmetal of the nitrogen group, phosphorus as a mineral is almost always present in its maximally oxidized state, as inorganic phosphate rocks...
,
iodineIodine is a chemical element with the symbol I and atomic number 53. The name is pronounced , , or . The name is from the , meaning violet or purple, due to the color of elemental iodine vapor....
, and ephedrine in the reaction.
In
E for EcstasyE for Ecstasy is a book written by Nicholas Saunders and published in May of 1993. Available freely online, it describes in detail the psychoactive substance MDMA, also known as ecstasy, the people that use it and the law concerning it, all enhanced through the backdrop of the author's personal...
(a book examining the uses of the drug
MDMAMDMA is an entactogenic drug of the phenethylamine and amphetamine class of drugs. In popular culture, MDMA has become widely known as "ecstasy" , usually referring to its street pill form, although this term may also include the presence of possible adulterants...
in the UK) the writer, activist and Ecstasy advocate Nicholas Saunders highlighted test results showing that certain consignments of the drug also contained ephedrine. Consignments of Ecstasy known as "Strawberry" contained what Saunders described as a "potentially dangerous combination of
ketamineKetamine is a drug used in human and veterinary medicine. Its hydrochloride salt is sold as Ketanest, Ketaset, and Ketalar. Pharmacologically, ketamine is classified as an NMDA receptor antagonist...
, ephedrine and
selegilineSelegiline is a drug used for the treatment of early-stage Parkinson's disease, depression and senile dementia. In normal clinical doses it is a selective irreversible MAO-B inhibitor, however in larger doses it loses its specificity and also inhibits MAO-A...
," as did a consignment of "Sitting Duck" Ecstasy tablets.
Through oxidation, ephedrine can be easily synthesized into
methcathinoneMethcathinone , is a psychoactive stimulant, sometimes used as a recreational drug and considered addictive. It is usually snorted, but can be smoked, injected, or taken orally...
. Ephedrine is listed as a Table I precursor under the
United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic SubstancesThe United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances of 1988 is one of three major drug control treaties currently in force. It provides additional legal mechanisms for enforcing the 1961 Single Convention on Narcotic Drugs and the 1971 Convention on...
.
Detection of use
Ephedrine may be quantitated in blood, plasma or urine to monitor possible abuse by athletes, confirm a diagnosis of poisoning or assist in a medicolegal death investigation. Many commercial immunoassay screening tests directed at the amphetamines cross-react appreciably with ephedrine, but chromatographic techniques can easily distinguish ephedrine from other phenethylamine derivatives. Blood or plasma ephedrine concentrations are typically in the 20-200 µg/L range in persons taking the drug therapeutically, 300-3000 µg/L in abusers or poisoned patients and 3–20 mg/L in cases of acute fatal overdosage. The current
WADAThe World Anti-Doping Agency , , is an independent foundation created through a collective initiative led by the International Olympic Committee . It was set up on November 10, 1999 in Lausanne, Switzerland, as a result of what was called the "Declaration of Lausanne", to promote, coordinate and...
limit for ephedrine in an athlete's urine is 10 µg/L.
Other uses
In
chemical synthesisIn chemistry, chemical synthesis is purposeful execution of chemical reactions to get a product, or several products. This happens by physical and chemical manipulations usually involving one or more reactions...
, ephedrine is used in bulk quantities to produce
chiral auxiliaryA chiral auxiliary is a chemical compound or unit that is temporarily incorporated into an organic synthesis so that it can be carried out asymmetrically with the selective formation of one of two enantiomers...
groups.
USA
Ephedrine distribution is controlled by the government, and pharmacists may refuse to sell it to customers without a prescription.
In 1997, the
FDAThe Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
proposed a regulation on ephedra (the herb from which ephedrine is obtained), which limited an ephedra dose to 8 mg (of active ephedrine) with no more than 24 mg per day. This proposed rule was withdrawn in part in 2000 because of "concerns regarding the agency's basis for proposing a certain dietary ingredient level and a duration of use limit for these products." In 2004, the FDA created a ban on ephedrine alkaloids that are marketed for reasons other than asthma, colds, allergies, other disease, or traditional Asian use. On April 14, 2005, the
U.S. District Court for the District of UtahThe United States District Court for the District of Utah is the Federal district court whose jurisdiction is the state of Utah...
ruled that the FDA did not have proper evidence that low dosages of ephedrine alkaloids are actually unsafe,
http://www.ephedrinehydrochloride.com/204cv409-28.pdf but on August 17, 2006, the
U.S. Court of Appeals for the Tenth CircuitThe United States Court of Appeals for the Tenth Circuit is a federal court with appellate jurisdiction over the district courts in the following districts:* District of Colorado* District of Kansas...
in Denver upheld the FDA's final rule declaring all dietary supplements containing ephedrine alkaloids adulterated, and therefore illegal for marketing in the United States.
http://www.ck10.uscourts.gov/opinions/05/05-4151.pdf Furthermore, ephedrine is banned by NCAA, MLB, NFL, and PGA TOUR Ephedrine is, however, still legal in many applications outside of dietary supplements. However, purchasing is currently limited and monitored, with specifics varying from state to state.
The
HouseThe United States House of Representatives is one of the two Houses of the United States Congress, the bicameral legislature which also includes the Senate.The composition and powers of the House are established in Article One of the Constitution...
passed the
Combat Methamphetamine Epidemic Act of 2005The Combat Methamphetamine Epidemic Act of 2005 is federal legislation enacted in the United States on March 9, 2006, to regulate, among other things, retail over-the-counter sales of ephedrine, pseudoephedrine, and phenylpropanolamine products because of their use in the manufacture of illegal...
as an amendment to the renewal of the
USA PATRIOT ActThe USA PATRIOT Act is an Act of the U.S. Congress that was signed into law by President George W. Bush on October 26, 2001...
. Signed into law by president
George W. BushGeorge Walker Bush is an American politician who served as the 43rd President of the United States, from 2001 to 2009. Before that, he was the 46th Governor of Texas, having served from 1995 to 2000....
on March 6, 2006, the act amended the US Code (21 USC 830) concerning the sale of ephedrine-containing products. The federal statute included the following requirements for merchants who sell these products:
- A retrievable record of all purchases identifying the name and address of each party to be kept for two years
- Required verification of proof of identity of all purchasers
- Required protection and disclosure methods in the collection of personal information
- Reports to the Attorney General
In most common law jurisdictions, the attorney general, or attorney-general, is the main legal advisor to the government, and in some jurisdictions he or she may also have executive responsibility for law enforcement or responsibility for public prosecutions.The term is used to refer to any person...
of any suspicious payments or disappearances of the regulated products
- Non-liquid dose form of regulated product may only be sold in unit dose blister packs
- Regulated products are to be sold behind the counter or in a locked cabinet in such a way as to restrict access
- Daily sales of regulated products not to exceed 3.6 grams without regard to the number of transactions
- Monthly sales not to exceed 9 grams of pseudoephedrine base in regulated products
The law gives similar regulations to mail-order purchases, except the monthly sales limit is only 7.5 grams.
As a pure herb or tea, má huáng, containing ephedrine, is still sold legally in the USA. The law restricts/prohibits its being sold as a dietary supplement(pill) or as an ingredient/additive to other products, like diet pills.
UK
In the UK ephedrine is regulated as a P medicine: it may only be lawfully supplied within a registered pharmacy and while a pharmacist is present. It is not a currently Controlled Drug under the Misuse of Drugs Act.
South Africa
In South Africa ephedrine was rescheduled to Schedule 6 on 27 May 2008, which makes the substance legal to possess but available via a prescription only.
Synthesis
Ephedrine, L-erythro-1-phenyl-2-methylaminopropanol-1, is synthesized from
benzaldehydeBenzaldehyde is an organic compound consisting of a benzene ring with a formyl substituent. It is the simplest aromatic aldehyde and one of the most industrially useful. This colorless liquid has a characteristic pleasant almond-like odor...
in a few different ways. According to the first, benzaldehyde is condensed with
nitroethaneNitroethane is an organic compound having the chemical formula C2H5NO2. Similar in many regards to nitromethane, nitroethane is an oily liquid at standard temperature and pressure. Pure nitroethane is colourless and has a fruity odor.- Preparation :...
, giving 2-methyl-2-nitro-1-phenylethanol, which is reduced to 2-methyl-2-amino-1-phenylethanol. The necessary L-isomer is isolated from the mixture of isomers by crystallization.
MethylationIn the chemical sciences, methylation denotes the addition of a methyl group to a substrate or the substitution of an atom or group by a methyl group. Methylation is a form of alkylation with, to be specific, a methyl group, rather than a larger carbon chain, replacing a hydrogen atom...
of this gives ephedrine.
- Spath, K. Gohring, Monatsh. Chem., 41, 319 (1920).
The second method consists of the
fermentationFermentation in food processing typically is the conversion of carbohydrates to alcohols and carbon dioxide or organic acids using yeasts, bacteria, or a combination thereof, under anaerobic conditions. Fermentation in simple terms is the chemical conversion of sugars into ethanol...
of
glucoseGlucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...
by
yeastYeasts are eukaryotic micro-organisms classified in the kingdom Fungi, with 1,500 species currently described estimated to be only 1% of all fungal species. Most reproduce asexually by mitosis, and many do so by an asymmetric division process called budding...
carboligase in the presence of benzaldehyde, which during the process turns into (–)-1-phenyl-2-ketopropanol. This is reduced by
hydrogenHydrogen is the chemical element with atomic number 1. It is represented by the symbol H. With an average atomic weight of , hydrogen is the lightest and most abundant chemical element, constituting roughly 75% of the Universe's chemical elemental mass. Stars in the main sequence are mainly...
in the presence of methylamine, to give the desired ephedrine.
- W. Klawehn, G. Hilderbrandt, {{US Patent|1956950}} (1934).
- Merck Chem. Fab. E, {{Cite patent|DE|469782}} (1926).
See also
- Ephedra
Ephedra refers to the plant Ephedra sinica. E. sinica, known in Chinese as ma huang , has been used in traditional Chinese medicine for 5,000 years for the treatment of asthma and hay fever, as well as for the common cold...
- Methamphetamine
Methamphetamine is a psychostimulant of the phenethylamine and amphetamine class of psychoactive drugs...
- Methcathinone
Methcathinone , is a psychoactive stimulant, sometimes used as a recreational drug and considered addictive. It is usually snorted, but can be smoked, injected, or taken orally...
- Phenethylamine
Phenylethylamine or phenethylamine is a natural monoamine alkaloid, trace amine, and also the name of a class of chemicals with many members well known for psychoactive drug and stimulant effects. Studies suggest that phenylethylamine functions as a neuromodulator or neurotransmitter in the...
- Pseudoephedrine
Pseudoephedrine is a sympathomimetic drug of the phenethylamine and amphetamine chemical classes. It is used as a nasal/sinus decongestant and stimulant, or as a wakefulness-promoting agent....
- Soma
Carisoprodol is a centrally-acting skeletal muscle relaxant. Carisoprodol is slightly soluble in water and freely soluble in alcohol, chloroform and acetone. The drug's solubility is practically independent of pH. Carisoprodol is manufactured and marketed in the United States by Meda Pharmaceuticals...
- Synephrine
Synephrine is a drug commonly used for weight loss. While its effectiveness is widely debated, synephrine has gained significant popularity as an alternative to ephedrine, a related substance which has been made illegal or restricted in many countries due to health risks and its use as a precursor...