Wikipedia's Featured Article - 2015-04-03 - Amphetamine
Wikipedia's Featured Article - 2015-04-03 - Amphetamine
Wikipedia's Featured Article - 2015-04-03 - Amphetamine
This article is about mixtures of levoamphetamine and Amphetamine is also the parent compound of its own
dextroamphetamine. For other uses, see Amphetamine structural class, the substituted amphetamines,[note 4]
(disambiguation).
which includes prominent substances such as bupropion,
cathinone, MDMA (ecstasy), and methamphetamine.
As a member of the phenethylamine class, am[note 1]
i
Amphetamine
(pronunciation:
/mftmin/;
contracted from alphamethylphenethylamine) is a phetamine is also chemically related to the naturally
occurring trace amine neuromodulators, specically
potent central nervous system (CNS) stimulant of the
[note 5]
and N-methylphenethylamine,
phenethylamine class that is used in the treatment of phenethylamine
both
of
which
are
produced within the human
attention decit hyperactivity disorder (ADHD) and
body.
Phenethylamine
is the parent compound of
narcolepsy. Amphetamine was discovered in 1887 and
amphetamine,
while
N-methylphenethylamine
is a
[note 2]
exists as two enantiomers:
levoamphetamine and
constitutional
isomer
that
diers
only
in
the
placement
dextroamphetamine. Amphetamine properly refers to
[sources 4]
a specic chemical, the racemic free base, which is of the methyl group.
equal parts of the two enantiomers, levoamphetamine
and dextroamphetamine, in their pure amine forms.
However, the term is frequently used informally to refer
to any combination of the enantiomers, or to either of
them alone. Historically, it has been used to treat nasal
congestion, depression, and obesity. Amphetamine is
also used as a performance and cognitive enhancer, and
recreationally as an aphrodisiac and euphoriant. It is a
prescription medication in many countries, and unauthorized possession and distribution of amphetamine are
often tightly controlled due to the signicant health risks
associated with substance abuse.[sources 1]
1 Uses
1.1 Medical
Amphetamine is used to treat attention decit hyperactivity disorder (ADHD) and narcolepsy (a sleep disorder), and is sometimes prescribed o-label for its
past medical indications, such as depression, obesity,
and nasal congestion.[11][27] Long-term amphetamine
exposure in some animal species is known to produce abnormal dopamine system development or nerve
damage,[39][40] but, in humans with ADHD, pharmaceutical amphetamines appear to improve brain development
and nerve growth.[41][42][43] Magnetic resonance imaging
(MRI) studies suggest that long-term treatment with amphetamine decreases abnormalities in brain structure and
function found in subjects with ADHD, and improves
function in several parts of the brain, such as the right
caudate nucleus of the basal ganglia.[41][42][43]
Current models of ADHD suggest that it is associated with functional impairments in some of the brains
neurotransmitter systems;[47] these functional impairments involve impaired dopamine neurotransmission in
the mesocorticolimbic projection and norepinephrine
neurotransmission in the locus coeruleus and prefrontal
1
3 SIDE EFFECTS
1.2
Enhancing performance
2 Contraindications
See also: Amphetamine Interactions
According to the International Programme on Chemical
Safety (IPCS) and United States Food and Drug Administration (USFDA),[note 7] amphetamine is contraindicated
in people with a history of drug abuse, heart disease, severe agitation, or severe anxiety.[69][70] It is
also contraindicated in people currently experiencing
arteriosclerosis (hardening of the arteries), glaucoma (increased eye pressure), hyperthyroidism (excessive production of thyroid hormone), or hypertension.[69][70] People who have experienced allergic reactions to other
stimulants in the past or who are taking monoamine
oxidase inhibitors (MAOIs) are advised not to take
amphetamine.[69][70] These agencies also state that anyone with anorexia nervosa, bipolar disorder, depression,
hypertension, liver or kidney problems, mania, psychosis,
Raynauds phenomenon, seizures, thyroid problems, tics,
or Tourette syndrome should monitor their symptoms
while taking amphetamine.[69][70] Evidence from human
studies indicates that therapeutic amphetamine use does
not cause developmental abnormalities in the fetus or
newborns (i.e., it is not a human teratogen), but amphetamine abuse does pose risks to the fetus.[70] Amphetamine has also been shown to pass into breast milk,
so the IPCS and USFDA advise mothers to avoid breastfeeding when using it.[69][70] Due to the potential for reversible growth impairments,[note 8] the USFDA advises
monitoring the height and weight of children and adolescents prescribed an amphetamine pharmaceutical.[69]
3.1
Physical
4 OVERDOSE
Synaptic cleft
CaMKII
DARPP-32
Dendrite
PP1
(Postsynaptic neuron)
PP2B
CREB
FosB
+P
JunD
c-Fos
SIRT1
+P
HDAC1
[Color legend 1]
-P
Chronically high
levels of synaptic
dopamine
Molecule
Dopamine
Glutamate
(cotransmitted)
NMDA receptor
co-agonist
Calcium (Ca2+) ions
Cyclic adenosine
monophosphate
-P
-P
DNA
+P
-P
+P
Activation/Interaction
5
the behavioral and neural adaptations that arise from 5 Interactions
addiction.[83][84][100] Once FosB is suciently overexpressed, it induces an addictive state that becomes increasingly more severe with further increases in FosB
expression.[83][84] It has been implicated in addictions See also: Amphetamine Contraindications
to alcohol, cannabinoids, cocaine, nicotine, opioids,
phencyclidine, and substituted amphetamines, among
Many types of substances are known to interact with amothers.[86][100][103]
phetamine, resulting in altered drug action or metabolism
JunD, a transcription factor, and G9a, a histone methyl- of amphetamine, the interacting substance, or both.[3][122]
transferase enzyme, both directly oppose the induc- Inhibitors of the enzymes that metabolize amphetamine
tion of FosB in the nucleus accumbens (i.e., they op- (e.g., CYP2D6 and avin-containing monooxygenase
pose increases in its expression).[84][100][104] Suciently 3) will prolong its elimination half-life, meaning that
overexpressing JunD in the nucleus accumbens with its eects will last longer.[7][122] Amphetamine also inviral vectors can completely block many of the neural teracts with MAOIs, particularly monoamine oxidase
and behavioral alterations seen in chronic drug abuse A inhibitors, since both MAOIs and amphetamine
(i.e., the alterations mediated by FosB).[100] FosB increase plasma catecholamines (i.e., norepinephrine
also plays an important role in regulating behavioral re- and dopamine);[122] therefore, concurrent use of both
sponses to natural rewards, such as palatable food, sex, is dangerous.[122] Amphetamine modulates the activand exercise.[86][100][105] Since both natural rewards and ity of most psychoactive drugs. In particular, amaddictive drugs induce expression of FosB (i.e., they phetamine may decrease the eects of sedatives and
cause the brain to produce more of it), chronic acquisi- depressants and increase the eects of stimulants and
tion of these rewards can result in a similar pathologi- antidepressants.[122] Amphetamine may also decrease the
cal state of addiction.[86][100] Consequently, FosB is the eects of antihypertensives and antipsychotics due to its
most signicant factor involved in both amphetamine ad- eects on blood pressure and dopamine respectively.[122]
diction and amphetamine-induced sex addictions, which In general, there is no signicant interaction when conare compulsive sexual behaviors that result from exces- suming amphetamine with food, but the pH of gastroinsive sexual activity and amphetamine use.[86][106] These testinal content and urine aects the absorption and exsex addictions are associated with a dopamine dysreg- cretion of amphetamine, respectively.[122] Acidic subulation syndrome which occurs in some patients taking stances reduce the absorption of amphetamine and indopaminergic drugs.[86][105][106]
crease urinary excretion, and alkaline substances do the
[122]
Due to the eect pH has on absorption, amThe eects of amphetamine on gene regulation are both opposite.
phetamine
also
interacts with gastric acid reducers such
[101]
dose- and route-dependent.
Most of the research on
as
proton
pump
inhibitors and H2 antihistamines, which
gene regulation and addiction is based upon animal studincrease
gastrointestinal
pH (i.e., make it less acidic).[122]
ies with intravenous amphetamine administration at very
high doses.[101] The few studies that have used equivalent (weight-adjusted) human therapeutic doses and
oral administration show that these changes, if they occur, are relatively minor.[101] This suggests that medical
use of amphetamine does not signicantly aect gene
regulation.[101]
4.1.2
Pharmacological treatments
6 Pharmacology
6.1 Pharmacodynamics
For a simpler and less technical explanation of amphetamines mechanism of action, see the mechanism of
action section in the Adderall article.
Pharmacodynamics of amphetamine enantiomers in a
dopamine neuron
From
axon
[30]
DAT
phosphorylation
DAT
internalization
PHARMACOLOGY
+PKA
Amphetamine exerts its behavioral eects by altering the
+PKC
use of monoamines as neuronal signals in the brain, priTrace amine or marily in catecholamine neurons in the reward and execAmphetamine (in) utive function pathways of the brain.[30][48] The concentrations of the main neurotransmitters involved in reward
circuitry and executive functioning, dopamine and norepinephrine, increase dramatically in a dose-dependent
manner by amphetamine due to its eects on monoamine
Dopamine (out) transporters.[30][48][123] The reinforcing and task saliency
eects of amphetamine are mostly due to enhanced
dopaminergic activity in the mesolimbic pathway.[24]
6.2
Pharmacokinetics
6.1.2 Norepinephrine
6.1.3 Serotonin
6.1.1
Dopamine
Amphetamine exerts analogous, yet less pronounced, eects on serotonin as on dopamine and
norepinephrine.[30][48] Amphetamine aects serotonin
via VMAT2 and, like norepinephrine, is thought to phosphorylate SERT via TAAR1.[30][123] Like dopamine,
amphetamine has low, micromolar anity at the human
5-HT1A receptor.[148][149]
Amphetamine has no direct eect on acetylcholine neurotransmission, but several studies have noted that acetylcholine release increases after its use.[140][141] In lab animals, amphetamine increases acetylcholine levels in certain brain regions as a downstream eect.[140] In humans, a similar phenomenon occurs via the ghrelinmediated cholinergicdopaminergic reward link in the
ventral tegmental area.[141] Acute amphetamine administration in humans also increases endogenous opioid
release in several brain structures in the reward system.[142][143]
Extracellular levels of glutamate, the primary excitatory
neurotransmitter in the brain, have been shown to
increase upon exposure to amphetamine.[92][144] This
cotransmission eect was found in the mesolimbic
pathway, an area of the brain implicated in reward,
where amphetamine is known to aect dopamine
neurotransmission.[92][144] Amphetamine also induces efuxion of histamine from synaptic vesicles in CNS mast
cells and histaminergic neurons through VMAT2.[123]
6.2 Pharmacokinetics
The oral bioavailability of amphetamine varies with
gastrointestinal pH;[122] it is well absorbed from the
gut, and bioavailability is typically over 75% for
dextroamphetamine.[1] Amphetamine is a weak base with
a pKa of 910;[3] consequently, when the pH is basic,
more of the drug is in its lipid soluble free base form,
and more is absorbed through the lipid-rich cell membranes of the gut epithelium.[3][122] Conversely, an acidic
6.3
7.3
neurotransmitter phenethylamine with the chemical formula C9 H13 N. The carbon atom adjacent to the primary
amine is a stereogenic center, and amphetamine is composed of a racemic 1:1 mixture of two enantiomeric
mirror images.[15] This racemic mixture can be separated into its optical isomers:[note 14] levoamphetamine
and dextroamphetamine.[15] Physically, at room temperature, the pure free base of amphetamine is a
mobile, colorless, and volatile liquid with a characteristically strong amine odor, and acrid, burning
taste.[14] Frequently prepared solid salts of amphetamine
include amphetamine aspartate,[22] hydrochloride,[159]
phosphate,[160] saccharate,[22] and sulfate,[22] the last of
which is the most common amphetamine salt.[37] Amphetamine is also the parent compound of its own structural class, which includes a number of psychoactive
derivatives.[15] In organic chemistry, amphetamine is an
excellent chiral ligand for the stereoselective synthesis of
1,1'-bi-2-naphthol.[161]
7.1
Derivatives
9
Hofmann or Curtius rearrangement (method 3).[171]
A signicant number of amphetamine syntheses feature
a reduction of a nitro, imine, oxime or other nitrogencontaining functional groups.[166] In one such example, a Knoevenagel condensation of benzaldehyde with
nitroethane yields phenyl-2-nitropropene. The double
bond and nitro group of this intermediate is reduced using either catalytic hydrogenation or by treatment with
lithium aluminium hydride (method 4).[172][173] Another
method is the reaction of phenylacetone with ammonia,
producing an imine intermediate that is reduced to the
primary amine using hydrogen over a palladium catalyst
or lithium aluminum hydride (method 5).[173]
The most common route of both legal and illicit amphetamine synthesis employs a non-metal reduction
known as the Leuckart reaction (method 6).[37][173]
In the rst step, a reaction between phenylacetone
and formamide, either using additional formic acid
or formamide itself as a reducing agent, yields Nformylamphetamine. This intermediate is then hydrolyzed using hydrochloric acid, and subsequently basied, extracted with organic solvent, concentrated, and
distilled to yield the free base. The free base is then dissolved in an organic solvent, sulfuric acid added, and amphetamine precipitates out as the sulfate salt.[173][174]
10
9 NOTES
clandestine labs and sold on the black market, primarily in European countries.[187] Among European Union
(EU) member states, 1.2 million young adults used illicit
amphetamine or methamphetamine in 2013.[196] During 2012, approximately 5.9 metric tons of illicit amphetamine were seized within EU member states;[196]
the street price of illicit amphetamine within the EU
ranged from 638 per gram during the same period.[196]
Outside Europe, the illicit market for amphetamine is
much smaller than the market for methamphetamine and
MDMA.[187]
For the assays, a study noted that an enzyme multiplied immunoassay technique (EMIT) assay for amphetamine and methamphetamine may produce more
false positives than liquid chromatographytandem mass
spectrometry.[183] Gas chromatographymass spectrometry (GCMS) of amphetamine and methamphetamine
with the derivatizing agent (S)-()-triuoroacetylprolyl
chloride allows for the detection of methamphetamine
in urine.[181] GCMS of amphetamine and methamphetamine with the chiral derivatizing agent Moshers
acid chloride allows for the detection of both dextroamphetamine and dextromethamphetamine in urine.[181]
Hence, the latter method may be used on samples that
test positive using other methods to help distinguish between the various sources of the drug.[181]
9 Notes
[1] Synonyms and alternate spellings include:
1phenylpropan-2-amine
(IUPAC
name),
methylbenzeneethanamine,
-methylphenethylamine,
amfetamine (International Nonproprietary Name [INN]),
-phenylisopropylamine,
desoxynorephedrine,
and
speed.[12][15][16]
[2] Enantiomers are molecules that are mirror images of one
another; they are structurally identical, but of the opposite
9.1
11
9.0.1
Behavioral treatments
Cognitive behavioral therapy is currently the most eective clinical treatment for psychostimulant addiction.[89]
Additionally, research on the neurobiological eects of
physical exercise suggests that daily aerobic exercise, especially endurance exercise (e.g., marathon running), prevents the development of drug addiction and is an eective adjunct (supplemental) treatment for amphetamine
addiction.[86][87][88] Exercise leads to better treatment outcomes when used as an adjunct treatment, particularly for
psychostimulant addictions.[87][88] In particular, aerobic
exercise decreases psychostimulant self-administration,
reduces the reinstatement (i.e., relapse) of drug-seeking,
and induces increased dopamine receptor D2 (DRD2)
density in the striatum.[86] This is the opposite of pathological stimulant use, which induces decreased striatal DRD2
density.[86]
9.1
9.2
12
10 REFERENCE NOTES
of users fail to recover completely.[32][121] According to
the same review, there is at least one trial that shows
antipsychotic medications eectively resolve the symptoms of acute amphetamine psychosis.[32] Psychosis very
rarely arises from therapeutic use.[33] sms | journal =
J. Psychoactive Adderall XR Prescribing Information
(PDF). United States Food and Drug Administration. Shire
US Inc. December 2013. pp. 46. Retrieved 30 December 2013.
Image legend
[1]
10
Reference notes
[1]
[18][19][20][21][22][23][24][25][26][27][28]
[2]
[11][23][24][25][27][28][30][31]
[3]
[22][24][32][33][34][35][36]
[4]
[37][38]
[5]
[72][73][74][75]
[6]
[25][31][36][76]
[7]
[16][22][36][79][90]
[8]
[123][127][130][131][132][133]
[9]
[30][123][130][134]
[10]
[3][4][5][6][7][8][9][10]
4-Hydroxyphenylacetone
Phenylacetone
Benzoic acid
Hippuric acid
Amphetamine
Norephedrine
4-Hydroxyamphetamine
4-Hydroxynorephedrine
ParaHydroxylation
ParaHydroxylation
ParaHydroxylation
BetaHydroxylation
BetaHydroxylation
Oxidative
Deamination
Oxidation
Glycine
Conjugation
The primary active metabolites of amphetamine are
4-hydroxyamphetamine and norephedrine;[154] at normal
urine pH, about 3040% of amphetamine is excreted
unchanged and roughly 50% is excreted as the inactive
metabolites (bottom row).[3] The remaining 1020%
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metabolized by butyrate-CoA ligase into an intermediate
product, benzoyl-CoA,[9] which is then metabolized by
glycine N-acyltransferase into hippuric acid.cit hyperactivity disSubstrate/Product. glycine N-acyltransferase.
BRENDA. Technische Universitt Braunschweig. Retrieved 7 May 2014.
13
[11]
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clock, activity. For instance, amphetamine, which increases concentrations of dopamine at the synaptic cleft
advances the start of responding during interval timing,
whereas antagonists of D2 type dopamine receptors typically slow timing;... Depletion of dopamine in healthy
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22
12
EXTERNAL LINKS
12 External links
CID 5826 from PubChem (dextroamphetamine)
CID 3007 from PubChem (racemic amphetamine)
CID 32893 from PubChem (levoamphetamine)
Comparative Toxicogenomics Database entry: Amphetamine
Comparative Toxicogenomics Database entry:
CARTPT
U.S. National Library of Medicine: Drug Information Portal Amphetamine
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