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]

The rst pharmaceutical amphetamine was Benzedrine,

a brand of inhalers used to treat a variety of conditions.
Currently, pharmaceutical amphetamine is typically prescribed as Adderall,[note 3] dextroamphetamine, or the
inactive prodrug lisdexamfetamine.
Amphetamine,
through activation of a trace amine receptor, increases
biogenic amine and excitatory neurotransmitter activity
in the brain, with its most pronounced eects targeting
the catecholamine neurotransmitters norepinephrine and
dopamine. At therapeutic doses, this causes emotional
and cognitive eects such as euphoria, change in libido,
increased wakefulness, and improved cognitive control. It
induces physical eects such as decreased reaction time,
fatigue resistance, and increased muscle strength.[sources 2]

Reviews of clinical stimulant research have established

the safety and eectiveness of long-term amphetamine
use for ADHD.[44][45][46] Controlled trials spanning
two years have demonstrated treatment eectiveness
and safety.[44][46] One review highlighted a nine-month
randomized controlled trial in children with ADHD that
found an average increase of 4.5 IQ points, continued increases in attention, and continued decreases in disruptive
behaviors and hyperactivity.[44]

Much larger doses of amphetamine are likely to impair

cognitive function and induce rapid muscle breakdown.
Drug addiction is a serious risk with large recreational
doses, but rarely arises from medical use. Very high
doses can result in psychosis (e.g., delusions and paranoia) which rarely occurs at therapeutic doses even during long-term use. Recreational doses are generally much
larger than prescribed therapeutic doses and carry a far
greater risk of serious side eects.[sources 3]

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

cortex.[47] Psychostimulants like methylphenidate and

amphetamine are eective in treating ADHD because they increase neurotransmitter activity in these
systems.[24][47][48] Approximately 80% of those who
use these stimulants see improvements in ADHD
symptoms.[49] Children with ADHD who use stimulant medications generally have better relationships with
peers and family members, perform better in school, are
less distractible and impulsive, and have longer attention
spans.[50][51] The Cochrane Collaboration's review[note 6]
on the treatment of adult ADHD with pharmaceutical amphetamines stated that while these drugs improve
short-term symptoms, they have higher discontinuation
rates than non-stimulant medications due to their adverse
side eects.[53]
A Cochrane Collaboration review on the treatment of
ADHD in children with tic disorders such as Tourette
syndrome indicated that stimulants in general do not
make tics worse, but high doses of dextroamphetamine
could exacerbate tics in some individuals.[54] Other
Cochrane reviews on the use of amphetamine following
stroke or acute brain injury indicated that it may improve recovery, but further research is needed to conrm
this.[55][56][57]

1.2

Enhancing performance

time primarily through reuptake inhibition and euxion

of dopamine in the central nervous system.[66][67][68] At
therapeutic doses, the adverse eects of amphetamine
do not impede athletic performance;[23][66][67] however,
at much higher doses, amphetamine can induce eects
that severely impair performance, such as rapid muscle
breakdown and elevated body temperature.[22][31][66]

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]

A 2015 meta-analysis of high quality clinical trials

conrmed that therapeutic doses of amphetamine and
methylphenidate result in modest improvements in performance on working memory, episodic memory, and
inhibitory control tests in normal healthy adults.[58] Therapeutic doses of amphetamine also enhance cortical
network eciency, an eect which mediates improvements in working memory in all individuals.[24][59] Amphetamine and other ADHD stimulants also improve
task saliency (motivation to perform a task) and increase
arousal (wakefulness), in turn promoting goal-directed
behavior.[24][60][61] Stimulants such as amphetamine can
improve performance on dicult and boring tasks and
are used by some students as a study and test-taking
aid.[24][60][62] Based upon studies of self-reported illicit
stimulant use, students primarily use stimulants such as
amphetamine for performance enhancement rather than
using them as recreational drugs.[63] However, high amphetamine doses that are above the therapeutic range 3 Side eects
can interfere with working memory and other aspects of
cognitive control.[24][60]
The side eects of amphetamine are varied, and the
Amphetamine is used by some athletes for its psychologi- amount of amphetamine used is the primary faccal and performance-enhancing eects, such as increased tor in determining the likelihood and severity of
stamina and alertness;[23][36] however, its use is prohibited side eects.[22][31][36] Amphetamine products such as
at sporting events regulated by collegiate, national, and in- Adderall, Dexedrine, and their generic equivalents are
ternational anti-doping agencies.[64][65] In healthy people currently approved by the USFDA for long-term theraat oral therapeutic doses, amphetamine has been shown peutic use.[29][31] Recreational use of amphetamine gento increase physical strength, acceleration, stamina, and erally involves much larger doses, which have a greater
endurance, while reducing reaction time.[23][66][67] Am- risk of serious side eects than dosages used for theraphetamine improves stamina, endurance, and reaction peutic reasons.[36]

3.1

Physical

Amphetamine has also been shown to produce a

conditioned place preference in humans taking therapeuAt normal therapeutic doses, the physical side eects tic doses,[53][77] meaning that individuals acquire a prefof amphetamine vary widely by age and from person erence for spending time in places where they have preto person.[31] Cardiovascular side eects can include viously used amphetamine.[77][78]
hypertension or hypotension from a vasovagal response,
Raynauds phenomenon (reduced blood ow to extremities), and tachycardia (increased heart rate).[31][36][71]
Sexual side eects in males may include erectile dysfunction, frequent erections, or prolonged erections.[31]
Abdominal side eects may include stomach pain, loss
4 Overdose
of appetite, nausea, and weight loss.[31] Other potential side eects include dry mouth, excessive grinding
of the teeth, acne, profuse sweating, blurred vision, reAn amphetamine overdose can lead to many dierent
duced seizure threshold, and tics (a type of movement
symptoms, but is rarely fatal with appropriate care.[70][79]
disorder).[31][36][71] Dangerous physical side eects are
The severity of overdose symptoms increases with dosage
rare at typical pharmaceutical doses.[36]
and decreases with drug tolerance to amphetamine.[36][70]
Amphetamine stimulates the medullary respiratory cen- Tolerant individuals have been known to take as much as
ters, producing faster and deeper breaths.[36] In a nor- 5 grams of amphetamine in a day, which is roughly 100
mal person at therapeutic doses, this eect is usually times the maximum daily therapeutic dose.[70] Symptoms
not noticeable, but when respiration is already compro- of a moderate and extremely large overdose are listed bemised, it may be evident.[36] Amphetamine also induces low; fatal amphetamine poisoning usually also involves
contraction in the urinary bladder sphincter, the mus- convulsions and coma.[22][36] In 2013, overdose on amcle which controls urination, which can result in dif- phetamine, methamphetamine, and other compounds imculty urinating. This eect can be useful in treat- plicated in an "amphetamine use disorder" resulted in an
ing bed wetting and loss of bladder control.[36] The estimated 3,788 deaths worldwide (3,4254,145 deaths,
eects of amphetamine on the gastrointestinal tract 95% condence).[note 9][80]
are unpredictable.[36] If intestinal activity is high, amPathological overactivation of the mesolimbic pathway,
phetamine may reduce gastrointestinal motility (the rate
a dopamine pathway that connects the ventral tegmenat which content moves through the digestive system);[36]
tal area to the nucleus accumbens, plays a central role
however, amphetamine may increase motility when the
in amphetamine addiction.[81][82] Individuals who fresmooth muscle of the tract is relaxed.[36] Amphetamine
quently overdose on amphetamine during recreational use
also has a slight analgesic eect and can enhance the pain
have a high risk of developing an amphetamine addiction,
relieving eects of opioids.[36]
since repeated overdoses gradually increase the level of
USFDA-commissioned studies from 2011 indicate that in accumbal FosB, a molecular switch and master conchildren, young adults, and adults there is no association trol protein for addiction.[83][84][85] Once nucleus accumbetween serious adverse cardiovascular events (sudden bens FosB is suciently overexpressed, it begins to indeath, heart attack, and stroke) and the medical use of crease the severity of addictive behavior (e.g., compulsive
amphetamine or other ADHD stimulants.[sources 5]
drug-seeking).[83][86] While there are currently no eective drugs for treating amphetamine addiction, regularly
engaging in sustained aerobic exercise appears to reduce
3.2 Psychological
the risk of developing such an addiction.[87] Sustained
aerobic exercise on a regular basis also appears to be an
Common psychological eects of therapeutic doses can eective treatment for amphetamine addiction;[86][87][88]
include increased alertness, apprehension, concentration, exercise therapy improves clinical treatment outcomes
decreased sense of fatigue, mood swings (elated mood and may be used as a combination therapy with cognitive
followed by mildly depressed mood), increased ini- behavioral therapy, which is currently the best clinical
tiative, insomnia or wakefulness, self-condence, and treatment available.[87][88][89]
sociability.[31][36] Less common side eects include
anxiety, change in libido, grandiosity, irritability, repetitive or obsessive behaviors, and restlessness;[sources 6] these
eects depend on the users personality and current mental state.[36] Amphetamine psychosis (e.g., delusions and
paranoia) can occur in heavy users.[22][31][32] Although 4.1 Addiction
very rare, this psychosis can also occur at therapeutic
doses during long-term therapy.[22][31][33] According to
the USFDA, there is no systematic evidence that stim- Signaling cascade in the nucleus accumbens that results
in amphetamine addiction
ulants produce aggressive behavior or hostility.[31]

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

Note: colored text contains article links.

Nuclear pore
Nuclear membrane
Plasma membrane
Ca1.2
NMDAR
AMPAR
DRD1
DRD5
DRD2
DRD3
DRD4
G
G/
cAMP
cAMP
PKA
CaM

-P

-P

DNA
+P
-P
+P

This diagram depicts the signaling

+e events in the brains
reward center that are induced by chronic high-dose
-e
exposure to psychostimulants that increase the con+P of synaptic dopamine, like amphetamine,
Long-term
centration
methylphenidate, and phenethylamine. adaptive
Following
changes inby
presynaptic dopamine and glutamate co-release
the receptors
brain
such psychostimulants,[92][93] postsynaptic
for these neurotransmitters trigger internal signaling
events through a cAMP pathway and calcium-dependent
pathway that ultimately result in increased CREB
phosphorylation.[81][94] Phosphorylated CREB increases
levels of FosB, which in turn represses the c-fos gene
with the help of corepressors;[94] c-fos repression acts
as a molecular switch that enables the accumulation of
FosB in the neuron.[95] A highly stable (phosphorylated) form of FosB, one that persists in neurons for one
or two months, slowly accumulates following repeated
+ethrough this process.[85][96]
Legend exposure to stimulants
Gene expression
FosB functions as one-e
of the master control proteins
Neurotransmitter
repression
that produces addiction-relatedGene
structural
changes in the
or ion traicking
+P
brain,
and
upon
sucient
accumulation,
with
the help of
Gene product
Phosphorylation
targets (e.g., nuclear factor kappa B), it
(protein its
or downstream
mRNA)
-P[85][96]
Dephosphorylation
Complexinduces
of twoan addictive state.
gene products
DNA

Activation/Interaction

Addiction is a serious risk with

heavy recreational amInhibition
phetamine use but is unlikely to arise from typical medical use at therapeutic doses.[34][35][36] Tolerance develops
rapidly in amphetamine abuse (i.e., a recreational amphetamine overdose), so periods of extended use require
increasingly larger doses of the drug in order to achieve
the same eect.[97][98]

4.1.1 Biomolecular mechanisms

Current models of addiction from chronic drug use involve alterations in gene expression in certain parts of
the brain, particularly the nucleus accumbens.[99][100][101]
The most important transcription factors[note 10] that produce these alterations are FosB, cAMP response element binding protein (CREB), and nuclear factor kappa
B (NFB).[100] FosB plays a crucial role in the development of drug addictions, since its overexpression
in D1-type medium spiny neurons in the nucleus accumbens is necessary and sucient[note 11] for most of

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

As of May 2014, there is no eective pharmacotherapy

for amphetamine addiction.[107][108][109] Amphetamine
addiction is largely mediated through increased activation of dopamine receptors and co-localized NMDA receptors[note 12] in the nucleus accumbens;[82] magnesium
ions inhibit NMDA receptors by blocking the receptor calcium channel.[82][110] One review suggested that,
based upon animal testing, pathological (addictioninducing) amphetamine use signicantly reduces the
level of intracellular magnesium throughout the brain.[82]
Supplemental magnesium[note 13]

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]

presynaptic neuron (internalize) and cease transport.

Axon terminal
PKC-phosphorylated DAT may either operate in reverse

DAT
phosphorylation

DAT
internalization

PHARMACOLOGY

or, like PKA-phosphorylated DAT, internalize and cease

transport.[30] Amphetamine is also known to increase
intracellular calcium, a known eect of TAAR1 activation, which is associated with DAT phosphorylation
through a CAMK-dependent pathway, in turn producing
dopamine eux.[126][127][128]

+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]

Amphetamine has been identied as a potent full ag-PKA

onist of trace amine-associated receptor 1 (TAAR1),
-PKC
Diuse
a G -coupled and G -coupled G protein-coupled reacross
ceptor (GPCR) discovered in 2001, which is impormembrane
tant for regulationCompetitive
of brain monoamines.[30][126] AcDopamine
tivation of TAAR1
increases cAMP production via
reuptake
release
adenylyl cyclase activation and inhibits monoamine transinhibition
Reduced post-synaptic
porter function.[30][129] Monoamine autoreceptors (e.g.,
Synaptic
cleft
receptor ring rate
D2 short, presynaptic 2 , and presynaptic 5-HTA) have
the
opposite eect of TAAR1, and together these recepL-Phenylalanine
Synaptic vesicle with
Legend tors provide a regulatory
system for monoamines.[30] NoVMAT2 (right)
Dopamine
tably, amphetamine and trace amines bind to TAAR1,
Amphetamine
but not monoamine autoreceptors.[30] Imaging studies
Dopaminereuptake
transporter
indicate that monoamine
inhibition by amPhenethylamine
(DAT)
phetamine
and
trace
amines
is
site
specic and deProtein Kinase
pends
upon
the
presence
of
TAAR1
co-localization
in
Dopamine traicking
[30]
the
associated
monoamine
neurons.
As
of
2010,
coPhosphorylated
Trace amine traicking
localization of Dopamine
TAAR1 andtransporter
the dopamine transporter
Amphetamine traicking
(DAT)
has
been
visualized
in
rhesus monkeys, but coProtein kinase traicking
localization of TAAR1 with the norepinephrine transTrace amine-associated
Dopamine receptor
porter (NET) and the serotonin transporter (SERT)
receptor 1 (TAAR1)
D2 short
has only been evidenced by messenger RNA (mRNA)
expression.[30]
via AADC
Amphetamine enters the presynaptic neuron across
the neuronal membrane or through DAT.[30] Once
inside, it binds to TAAR1 or enters synaptic vesicles
through VMAT2.[30][123] When amphetamine enters
the synaptic vesicles through VMAT2, dopamine is
released into the cytosol (yellow-orange area).[123] When
amphetamine binds to TAAR1, it reduces dopamine
receptor ring rate via potassium channels and triggers
protein kinase A (PKA) and protein kinase C (PKC)
signaling, resulting in DAT phosphorylation.[30][124][125]
PKA-phosphorylation causes DAT to withdraw into the

In addition to the neuronal monoamine transporters,

amphetamine also inhibits vesicular monoamine
transporter 2 (VMAT2), SLC1A1, SLC22A3, and
SLC22A5.[sources 8] SLC1A1 is excitatory amino acid
transporter 3 (EAAT3), a glutamate transporter located
in neurons, SLC22A3 is an extraneuronal monoamine
transporter that is present in astrocytes and SLC22A5 is a
high-anity carnitine transporter.[sources 8] Amphetamine
is known to strongly induce cocaine- and amphetamineregulated transcript (CART) gene expression,[134] a
neuropeptide involved in feeding behavior, stress, and
reward, which induces observable increases in neuronal
development and survival in vitro.[135][136][137] The CART
receptor has yet to be identied, but there is signicant

6.2

Pharmacokinetics

evidence that CART binds to a unique G/G-coupled

GPCR.[137][138] Amphetamine also inhibits monoamine
oxidase at very high doses, resulting in less dopamine and
phenethylamine metabolism and consequently higher
concentrations of synaptic monoamines.[12][139] The
full prole of amphetamines short-term drug eects
is derived through increased cellular communication
or neurotransmission of dopamine,[30] serotonin,[30]
norepinephrine,[30] epinephrine,[123] histamine,[123]
CART peptides,[134] acetylcholine,[140][141] endogenous
opioids,[142][143] and glutamate,[92][144] which it eects
through interactions with CART, EAAT3, TAAR1, and
VMAT2.[sources 9]

6.1.2 Norepinephrine

Dextroamphetamine is a more potent agonist of TAAR1

than levoamphetamine.[145] Consequently, dextroamphetamine produces greater CNS stimulation than
levoamphetamine, roughly three to four times more, but
levoamphetamine has slightly stronger cardiovascular and
peripheral eects.[36][145]

6.1.3 Serotonin

6.1.1

6.1.4 Other neurotransmitters and peptides

Dopamine

In certain brain regions, amphetamine increases the

concentration of dopamine in the synaptic cleft.[30]
Amphetamine can enter the presynaptic neuron either through DAT or by diusing across the neuronal
membrane directly.[30] As a consequence of DAT uptake, amphetamine produces competitive reuptake inhibition at the transporter.[30] Upon entering the presynaptic neuron, amphetamine activates TAAR1 which,
through protein kinase A (PKA) and protein kinase C
(PKC) signaling, causes DAT phosphorylation.[30] Phosphorylation by either protein kinase can result in DAT
internalization (non-competitive reuptake inhibition),
but PKC-mediated phosphorylation alone induces reverse transporter function (dopamine eux).[30][146] Amphetamine is also known to increase intracellular calcium,
a known eect of TAAR1 activation, which is associated
with DAT phosphorylation through a Ca2+/calmodulindependent protein kinase (CAMK)-dependent pathway, in turn producing dopamine eux.[126][127][128]
Through direct activation of G protein-coupled inwardlyrectifying potassium channels and an indirect increase
in dopamine autoreceptor signaling, TAAR1 reduces the
ring rate of postsynaptic dopamine receptors, preventing a hyper-dopaminergic state.[147][124][125]
Amphetamine is also a substrate for the presynaptic vesicular monoamine transporter, VMAT2.[123] Following amphetamine uptake at VMAT2, the synaptic
vesicle releases dopamine molecules into the cytosol
in exchange.[123] Subsequently, the cytosolic dopamine
molecules exit the presynaptic neuron via reverse transport at DAT.[30][123]

Similar to dopamine, amphetamine dose-dependently

increases the level of synaptic norepinephrine, the
direct precursor of epinephrine.[38][48] Based upon
neuronal TAAR1 mRNA expression, amphetamine
is thought to aect norepinephrine analogously to
dopamine.[30][123][146] In other words, amphetamine induces TAAR1-mediated eux and non-competitive reuptake inhibition at phosphorylated NET, competitive
NET reuptake inhibition, and norepinephrine release
from VMAT2.[30][123]

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

7 PHYSICAL AND CHEMICAL PROPERTIES

into epinephrine.[38][158] Like amphetamine, both

phenethylamine and Nmethylphenethylamine regulate
monoamine neurotransmission via TAAR1;[30][158]
unlike amphetamine, both of these substances are broken
therefore have a
The half-life of amphetamine enantiomers dier and down by monoamine oxidase B, and
[38][158]
shorter
half-life
than
amphetamine.
[3]
vary with urine pH. At normal urine pH, the half-lives
of dextroamphetamine and levoamphetamine are 911
hours and 1114 hours, respectively.[3] An acidic diet will
reduce the enantiomer half-lives to 811 hours; an alka- 7 Physical and chemical properties
line diet will increase the range to 1631 hours.[150][151]
The immediate-release and extended release variants of Racemic amphetamine
salts of both isomers reach peak plasma concentrations
at 3 hours and 7 hours post-dose respectively.[3] Amphetamine is eliminated via the kidneys, with 3040%
of the drug being excreted unchanged at normal urinary
pH.[3] When the urinary pH is basic, amphetamine is in its
free base form, so less is excreted.[3] When urine pH is abnormal, the urinary recovery of amphetamine may range Levoamphetamine
from a low of 1% to a high of 75%, depending mostly Dextroamphetamine
upon whether urine is too basic or acidic, respectively.[3]
Amphetamine is usually eliminated within two days of The skeletal structures of L-amph and D-amph
the last oral dose.[150] Apparent half-life and duration of
eect increase with repeated use and accumulation of the
drug.[152]
pH means the drug is predominantly in a water soluble cationic (salt) form, and less is absorbed.[3] Approximately 1540% of amphetamine circulating in the bloodstream is bound to plasma proteins.[2]

The prodrug lisdexamfetamine is not as sensitive to pH as

amphetamine when being absorbed in the gastrointestinal tract;[153] following absorption into the blood stream,
it is converted by red blood cell-associated enzymes to
dextroamphetamine via hydrolysis.[153] The elimination
half-life of lisdexamfetamine is generally less than one
hour.[153]
CYP2D6, dopamine -hydroxylase, avin-containing
monooxygenase 3, butyrate-CoA ligase, and glycine
N-acyltransferase are the enzymes known to metabolize
amphetamine or its metabolites in humans.[sources 10]
A vial of the colorless amphetamine free base

6.3

Related endogenous compounds

For more details on related compounds, see Trace

amines.
Amphetamine has a very similar structure and function to
the endogenous trace amines, which are naturally occurring neurotransmitter molecules produced in the human
body and brain.[30][38] Among this group, the most closely
related compounds are phenethylamine, the parent compound of amphetamine, and N-methylphenethylamine,
an isomer of amphetamine (i.e., it has an identical molecular formula).[30][38][158] In humans, phenethylamine is
produced directly from L-phenylalanine by the aromatic
amino acid decarboxylase (AADC) enzyme, which
converts L-DOPA into dopamine as well.[38][158] In turn, Amphetamine hydrochloride (left bowl)
Nmethylphenethylamine is metabolized from phenethy- Phenyl-2-nitropropene (right cups)
lamine by phenylethanolamine N-methyltransferase,
the same enzyme that metabolizes norepinephrine Amphetamine is a methyl homolog of the mammalian

7.3

Detection in body uids

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

For a more comprehensive list, see Substituted amphetamine.

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]

A number of chiral resolutions have been developed to

separate the two enantiomers of amphetamine.[167] For
example, racemic amphetamine can be treated with dtartaric acid to form a diastereoisomeric salt which is
fractionally crystallized to yield dextroamphetamine.[175]
Chiral resolution remains the most economical method
for obtaining optically pure amphetamine on a large
scale.[176] In addition, several enantioselective syntheses of amphetamine have been developed. In one example, optically pure (R)1-phenyl-ethanamine is con7.2 Synthesis
densed with phenylacetone to yield a chiral Schi base.
In the key step, this intermediate is reduced by catalytic
For more details on illicit amphetamine synthesis, see hydrogenation with a transfer of chirality to the carIllegal synthesis of substituted amphetamines.
bon atom alpha to the amino group. Cleavage of the
benzylic amine bond by hydrogenation yields optically
[165]
pure dextroamphetamine.[176]
Since the rst preparation was reported in 1887,
numerous synthetic routes to amphetamine have been
developed.[166][167] Many of these syntheses are based
on classic organic reactions. One such example is the 7.3 Detection in body uids
FriedelCrafts alkylation of chlorobenzene by allyl chloride to yield beta chloropropylbenzene which is then re- Amphetamine is frequently measured in urine or blood
acted with ammonia to produce racemic amphetamine as part of a drug test for sports, employment, poisoning
(method 1).[168] Another example employs the Ritter re- diagnostics, and forensics.[sources 11] Techniques such
action (method 2). In this route, allylbenzene is re- as immunoassay, which is the most common form
acted acetonitrile in sulfuric acid to yield an organosulfate of amphetamine test, may cross-react with a number
which in turn is treated with sodium hydroxide to of sympathomimetic drugs.[180] Chromatographic
give amphetamine via an acetamide intermediate.[169][170] methods specic for amphetamine are employed to
A third route starts with ethyl 3-oxobutanoate which prevent false positive results.[181] Chiral separation
through a double alkylation with methyl iodide followed techniques may be employed to help distinguish the
by benzyl chloride can be converted into 2-methyl- source of the drug, whether prescription amphetamine,
3-phenyl-propanoic acid. This synthetic intermediate prescription amphetamine prodrugs, (e.g., selegiline),
can be transformed into amphetamine using either a over-the-counter drug products (e.g., the American
Amphetamine derivatives, often referred to as amphetamines or substituted amphetamines, are a
broad range of chemicals that contain amphetamine
as a backbone.[162][163] The class includes stimulants
like methamphetamine, serotonergic empathogens like
MDMA, and decongestants like ephedrine, among other
subgroups.[162][163] This class of chemicals is sometimes
referred to collectively as the amphetamine family.[164]

10

9 NOTES

version of Vicks VapoInhaler,[182] which contains

levomethamphetamine) or illicitly obtained substituted amphetamines.[181][183][184] Several prescription
drugs produce amphetamine as a metabolite, including benzphetamine, clobenzorex, famprofazone,
fenproporex, lisdexamfetamine, mesocarb, methamphetamine, prenylamine, and selegiline, among
others.[27][185][186] These compounds may produce
positive results for amphetamine on drug tests.[185][186]
Amphetamine is generally only detectable by a standard
drug test for approximately 24 hours, although a high
dose may be detectable for two to four days.[180]

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]

8.1 Legal status

History, society, and culture

Main article: History and culture of substituted amphetamines

Amphetamine was rst synthesized in 1887 in Germany by Romanian chemist Lazr Edeleanu who named
it phenylisopropylamine;[165][188][189] its stimulant eects
remained unknown until 1927, when it was independently
resynthesized by Gordon Alles and reported to have
sympathomimetic properties.[189] Amphetamine had no
pharmacological use until 1934, when Smith, Kline and
French began selling it as an inhaler under the trade name
Benzedrine as a decongestant.[28] During World War II,
amphetamine and methamphetamine were used extensively by both the Allied and Axis forces for their stimulant and performance-enhancing eects.[165][190][191] As
the addictive properties of the drug became known, governments began to place strict controls on the sale of
amphetamine.[165] For example, during the early 1970s
in the United States, amphetamine became a schedule
II controlled substance under the Controlled Substances
Act.[192] In spite of strict government controls, amphetamine has been used legally or illicitly by people
from a variety of backgrounds, including authors,[193]
musicians,[194] mathematicians,[195] and athletes.[23]
Amphetamine is still illegally synthesized today in

As a result of the United Nations 1971 Convention on

Psychotropic Substances, amphetamine became a schedule II controlled substance, as dened in the treaty,
in all (183) state parties.[21] Consequently, it is heavily regulated in most countries.[197][198] Some countries,
such as South Korea and Japan, have banned substituted amphetamines even for medical use.[199][200] In
other nations, such as Canada (schedule I drug),[201] the
Netherlands (List I drug),[202] (Dutch) the United States
(schedule II drug),[22] Thailand (category 1 narcotic),[203]
and United Kingdom (class B drug),[204] amphetamine is
in a restrictive national drug schedule that allows for its
use as a medical treatment.[26][187]

8.2 Pharmaceutical products

The only currently prescribed amphetamine formulation
that contains both enantiomers is Adderall.[note 3][15][27]
Amphetamine is also prescribed in enantiopure and
prodrug form as dextroamphetamine and lisdexamfetamine respectively.[29][205] Lisdexamfetamine is structurally dierent from amphetamine, and is inactive until it metabolizes into dextroamphetamine.[205] The free
base of racemic amphetamine was previously available
as Benzedrine, Psychedrine, and Sympatedrine.[15][27]
Levoamphetamine was previously available as Cydril.[27]
All current amphetamine pharmaceuticals are salts
due to the comparatively high volatility of the free
base.[27][29][37] Some of the current brands and their
generic equivalents are listed below.

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

Dependence and withdrawal

orientation.[17]
Levoamphetamine and dextroamphetamine are also
known as L-amph or levamfetamine (INN) and D-amph
or dexamfetamine (INN) respectively.[12]

[3] Adderall is a brand name as opposed to a nonproprietary

name; because the latter ("dextroamphetamine sulfate,
dextroamphetamine saccharate, amphetamine sulfate, and
amphetamine aspartate"[29] ) is excessively long, this article exclusively refers to this amphetamine mixture by the
brand name.
[4] Due to confusion that may arise from use of the plural
form, this article will only use the terms amphetamine
and amphetamines to refer to racemic amphetamine,
levoamphetamine, and dextroamphetamine and reserve
the term substituted amphetamines for the class.
[5] Again, due to confusion that may arise from use of the plural form, this article will only use phenethylamine and
phenethylamines to refer to the compound itself and reserve the term substituted phenethylamines for the class.
[6] Cochrane Collaboration reviews are high quality metaanalytic systematic reviews of randomized controlled
trials.[52]
[7] The statements supported by the USFDA come from prescribing information, which is the copyrighted intellectual property of the manufacturer and approved by the
USFDA.
[8] In individuals who experience sub-normal height and
weight gains, a rebound to normal levels is expected to
occur if stimulant therapy is briey interrupted.[44][46][71]
The average reduction in nal adult height from continuous stimulant therapy over a 3 year period is 2 cm.[71]
[9] The 95% condence interval indicates that there is a 95%
probability that the true number of deaths lies between
3,425 and 4,145.
[10] Transcription factors are proteins that increase or decrease
the expression of specic genes.[102]
[11] In simpler terms, this necessary and sucient relationship
means that FosB overexpression in the nucleus accumbens and addiction-related behavioral and neural adaptations always occur together and never occur alone.
[12] NMDA receptors are voltage-dependent ligand-gated ion
channels that requires simultaneous binding of glutamate
and a co-agonist (D-serine or glycine) to open the ion
channel.[110]
[13] The review indicated that magnesium L-aspartate and
magnesium chloride produce signicant changes in addictive behavior;[82] other forms of magnesium were
not mentioned.xiety] and uoxetine treatment have been
shown to reduce amphetamine self-administration (doses
given to oneself) in humans, but neither is an eective
monotherapy for amphetamine addiction.[82][111]

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

Dependence and withdrawal

According to another Cochrane Collaboration review

on withdrawal in individuals who compulsively use amphetamine and methamphetamine, when chronic heavy
users abruptly discontinue amphetamine use, many report
a time-limited withdrawal syndrome that occurs within
24 hours of their last dose.[112] This review noted that
withdrawal symptoms in chronic, high-dose users are frequent, occurring in up to 87.6% of cases, and persist for
three to four weeks with a marked crash phase occurring during the rst week.[112] Amphetamine withdrawal
symptoms can include anxiety, drug craving, depressed
mood, fatigue, increased appetite, increased movement
or decreased movement, lack of motivation, sleeplessness
or sleepiness, and lucid dreams.[112] The review indicated
that withdrawal symptoms are associated with the degree
of dependence, suggesting that therapeutic use would result in far milder discontinuation symptoms.[112] Manufacturer prescribing information does not indicate the presence of withdrawal symptoms following discontinuation
of amphetamine use after an extended period at therapeutic doses.[113][114][115]

9.2

Toxicity and psychosis

See also: Stimulant psychosis

In rodents and primates, suciently high doses of amphetamine cause dopaminergic neurotoxicity, or damage to dopamine neurons, which is characterized by reduced transporter and receptor function.[116] There is
no evidence that amphetamine is directly neurotoxic in
humans.[117][118] However, large doses of amphetamine
may cause indirect neurotoxicity as a result of increased oxidative stress from reactive oxygen species
and autoxidation of dopamine.[39][119][120] A severe amphetamine overdose can result in a stimulant psychosis
that may involve a variety of symptoms, such as paranoia
and delusions.[32] A Cochrane Collaboration review on
treatment for amphetamine, dextroamphetamine, and
methamphetamine psychosis states that about 515%

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.

[14] Enantiomers are molecules that are mirror images of one

another; they are structurally identical, but of the opposite
orientation.[17]

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]

with r Amphetamine has a variety of excreted metabolic products, including

4-hydroxyamfetamine,
4-hydroxynorephedrine,
4hydroxyphenylacetone, benzoic acid, hippuric acid,
norephedrine, and phenylacetone.[3][150][154] Among
these metabolites, the active sympathomimetics are
4hydroxyamphetamine,[155] 4hydroxynorephedrine,[156]
and norephedrine.[157] The main metabolic pathways
involve aromatic para-hydroxylation, aliphatic alpha- and
beta-hydroxylation, N-oxidation, N-dealkylation, and
deamination.[3][150] The known pathways and detectable
metabolites in humans include the following:[3][7][154]
Metabolic pathways of amphetamine

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%
is excreted as the active metabolites.[3] Benzoic acid is
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]

11

[23][177][178][179]

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[2] Pharmacology. Amphetamine. DrugBank. University
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[3] Adderall XR Prescribing Information (PDF). United
States Food and Drug Administration. Shire US Inc. December 2013. pp. 1213. Retrieved 30 December 2013.
[4] Lemke TL, Williams DA, Roche VF, Zito W (2013).
Foyes Principles of Medicinal Chemistry (7th ed.).
Philadelphia, USA: Wolters Kluwer Health/Lippincott
Williams & Wilkins. p. 648. ISBN 9781609133450.
Alternatively, direct oxidation of amphetamine by DA hydroxylase can aord norephedrine.
[5] Taylor KB (January 1974).
Dopamine-betahydroxylase. Stereochemical course of the reaction
(PDF). J. Biol. Chem. 249 (2): 454458. PMID
4809526. Retrieved 6 November 2014. Dopamine-hydroxylase catalyzed the removal of the pro-R
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(2S,1R)2-amino-1-hydroxyl-1-phenylpropane,
from
d-amphetamine.
[6] Horwitz D, Alexander RW, Lovenberg W, Keiser
HR (May 1973).
Human serum dopamine-hydroxylase.
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doi:10.1161/01.RES.32.5.594. PMID 4713201. Subjects with exceptionally low levels of serum dopamine-hydroxylase activity showed normal cardiovascular
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[7] Krueger SK, Williams DE (June 2005). Mammalian
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[8] Cashman JR, Xiong YN, Xu L, Janowsky A (March
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[9] Substrate/Product. butyrate-CoA ligase. BRENDA.
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[12] Compound Summary. Amphetamine. PubChem Compound. National Center for Biotechnology Information.
11 April 2015. Retrieved 17 April 2015.
[13] Properties: Predicted EP|Suite. Amphetamine. Chemspider. Retrieved 6 November 2013.
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[17] Enantiomer.
IUPAC Goldbook.
International Union of Pure and Applied Chemistry.
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Archived from the
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One of a pair of molecular entities which are mirror
images of each other and non-superposable.
[18] Amphetamine. Medical Subject Headings. National Institutes of Health, National Library of Medicine. Retrieved 16 December 2013.
[19] Guidelines on the Use of International Nonproprietary
Names (INNS) for Pharmaceutical Substances. World
Health Organization. 1997. Retrieved 1 December 2014.
In principle, INNs are selected only for the active part
of the molecule which is usually the base, acid or alcohol. In some cases, however, the active molecules need to
be expanded for various reasons, such as formulation purposes, bioavailability or absorption rate. In 1975 the experts designated for the selection of INN decided to adopt
a new policy for naming such molecules. In future, names
for dierent salts or esters of the same active substance
should dier only with regard to the inactive moiety of
the molecule. ... The latter are called modied INNs (INNMs).
[20] Yoshida T (1997). Chapter 1: Use and Misuse of Amphetamines: An International Overview. In Klee H.
Amphetamine Misuse: International Perspectives on Current Trends. Amsterdam, Netherlands: Harwood Academic Publishers. p. 2. ISBN 9789057020810. Retrieved 1 December 2014. Amphetamine, in the singular form, properly applies to the racemate of 2-amino-1phenylpropane. ... In its broadest context, however, the
term can even embrace a large number of structurally and
pharmacologically related substances.

[10]

[21] Convention on psychotropic substances. United Nations

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[22] Adderall XR Prescribing Information (PDF). United

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[23] Liddle DG, Connor DJ (June 2013). Nutritional supplements and ergogenic AIDS. Prim. Care 40 (2): 487
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Amphetamines and caeine are stimulants that increase
alertness, improve focus, decrease reaction time, and delay fatigue, allowing for an increased intensity and duration of training ...
Physiologic and performance eects
Amphetamines increase dopamine/norepinephrine release and inhibit their reuptake, leading to central nervous
system (CNS) stimulation
Amphetamines seem to enhance athletic performance in
anaerobic conditions 39 40
Improved reaction time
Increased muscle strength and delayed muscle fatigue
Increased acceleration
Increased alertness and attention to task
[24] Malenka RC, Nestler EJ, Hyman SE (2009). Chapter 13: Higher Cognitive Function and Behavioral Control. In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.).
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[25] Montgomery KA (June 2008). Sexual desire disorders.
Psychiatry (Edgmont) 5 (6): 5055. PMC 2695750.
PMID 19727285.
[26] Wilens TE, Adler LA, Adams J, Sgambati S, Rotrosen
J, Sawtelle R, Utzinger L, Fusillo S (January 2008).
Misuse and diversion of stimulants prescribed for
ADHD: a systematic review of the literature. J. Am.
Acad. Child Adolesc. Psychiatry 47 (1): 2131.
doi:10.1097/chi.0b013e31815a56f1. PMID 18174822.
Stimulant misuse appears to occur both for performance
enhancement and their euphorogenic eects, the latter being related to the intrinsic properties of the stimulants
(e.g., IR versus ER prole) ...
Although useful in the treatment of ADHD, stimulants are
controlled II substances with a history of preclinical and
human studies showing potential abuse liability.
[27] Heal DJ, Smith SL, Gosden J, Nutt DJ (June 2013).
Amphetamine, past and present a pharmacological and
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[28] Rasmussen N (July 2006). Making the rst antidepressant: amphetamine in American medicine, 1929
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[29] National Drug Code Amphetamine Search Results. National Drug Code Directory. United States Food and Drug
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[30] Miller GM (January 2011). The emerging role of trace
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of monoamine transporters and dopaminergic activity.
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11

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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

23

13
13.1

Text and image sources, contributors, and licenses

Text

Amphetamine Source: http://en.wikipedia.org/wiki/Amphetamine?oldid=658456014 Contributors: Damian Yerrick, AxelBoldt, Kpjas,

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Woood, SBoyd415, WJBscribe, HazyM, DMCer, Use the force, Pdcook, Ja 62, David Sulzer, Halmstad, Scuro, CardinalDan, Jkhamlin,
Funandtrvl, Spellcast, CWii, Annanda, Je G., JohnBlackburne, Pharmacophore, Rei-bot, Edward Bower, Piperh, Oxfordwang, Corvus
cornix, Jackfork, LeaveSleaves, Snowbot, Redrey, Thepokeduck, Blurpeace, Cregq, Icecreammaninthegarbagecan, Softlavender, Unused0030, K10wnsta, Marcoel, Roybristow, Mary quite contrary, Doc James, Metrowestjp, Petergans, Monkeybubbles, CMBJ, Gaelen S.,
SieBot, Eurocrat123, Cowpepper, Tresiden, Graham Beards, Filcollins, Gravitan, LeadSongDog, Mizukind, Keilana, JetLover, Elangsto,
Xe7al, Steven Zhang, Jess4less, Hoyiu, Svick, Mojoworker, Debug2007, Ascidian, Funkbrother3000, MrADHD, Velvetron, Angel caboodle, ImageRemovalBot, Martarius, Delighted eyes, Leahtwosaints, ClueBot, Fyyer, The Thing That Should Not Be, Cheveux, ArdClose,
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Leadwind, Dpspendragon, Maxtitan, Ohnoitsthefuzz, Starstylers, Puchiko, Haniel777, Bethwilk, DragonBot, Zywxn, Nvcozzi, Astral Zen,
Alexbot, Jusdafax, Panyd, Abrech, Pixelpty, Sun Creator, ParisianBlade, NuclearWarfare, Medos2, Dekisugi, Black Platypus, Thingg, Versus22, Adouglass, MelonBot, Adamnmo, JonM.D., DumZiBoT, XLinkBot, Hotcrocodile, Pichpich, Snarlinmonsta, Vanished 45kd09la13,
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Insaneclown510, Anypodetos, Mongoletsi, Insidious1, IW.HG, AnomieBOT, Nutriveg, Casforty, 1exec1, The Parting Glass, Anton42,
Outslider, Jim1138, Auranor, Bluerasberry, RobertEves92, Kasey1123, Woodmand0809, Citation bot, Jobo123, ArthurBot, Me86532,
Bronckobuster, IllusionalFate, S h i v a (Visnu), RickyTheJanitor, , Ponticalibus, J, Br77rino, , Harbinary, Maddie!,
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L Kensington, DFerret, Allethrin, Lawstubes, Peteb4, Carmichael, Chris857, Noodles32236, DASHBotAV, Spicemix, Louisajb, Will
Beback Auto, ClueBot NG, Jack Greenmaven, Gilderien, Pashihiko, Chester Markel, Bped1985, Diogenes2000, SubDural12, Frietjes,

24

13

TEXT AND IMAGE SOURCES, CONTRIBUTORS, AND LICENSES

Bezwenalife, Killergreenleg, Omer123hussain, Bibcode Bot, Kinaro, Badmusician, BG19bot, Petrarchan47, Jon990, Nikos 1993, Mark
Arsten, Donated, Threemeans, Lazord00d, Exercisephys, Felidofractals, Zhu Haifeng, Snow Blizzard, Quandarical, Loriendrew, Stevereichh, Dr Iowa, Anbu121, Fuse809, Biosthmors, Mort459, Hm20, Plutoniumjesus, Berzserk2070, ChrisGualtieri, Wesdxc523, Khazar2,
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RotlinkBot, Hillbillyholiday, Gary Battle, Smith 62, Jamesmcmahon0, MKidd9221, AmericanLemming, DopersWin, Dvwynn, InItForTheLutz, ArmbrustBot, Clr324, TFA Protector Bot, Seppi333, Bloodshade707, SwampFox556, 3AlarmLampscooter, Doublecamel,
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Dosenfant, WholeNewJourney, Medgirl131, FACBot, Sizeont, Non-pupulus-impilium and Anonymous: 1037

13.2

Images

File:Amph_Pathway.png Source: http://upload.wikimedia.org/wikipedia/commons/4/4e/Amph_Pathway.png License: CC BY-SA 3.0

Contributors: Own work Original artist: Seppi333
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File:Amphetamine_Friedel-Crafts_alkylation.svg Source: http://upload.wikimedia.org/wikipedia/commons/3/37/Amphetamine_
Friedel-Crafts_alkylation.svg License: CC BY-SA 3.0 Contributors: Own work Original artist: Boghog
File:Amphetamine_Hofmann_Curtius_Synthesis.svg Source: http://upload.wikimedia.org/wikipedia/commons/b/bd/Amphetamine_
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File:Amphetamine_Knoevenagel_synthesis.svg Source:
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File:Amphetamine_Ritter_Synthesis.svg Source:
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File:Amphetamine_and_P2P.png Source: http://upload.wikimedia.org/wikipedia/commons/4/49/Amphetamine_and_P2P.png License:
Public domain Contributors: http://www.justice.gov/dea/pr/micrograms/2007/mg0707.pdf#page=1&zoom=auto,0,557 Original artist:
U.S. Drug Enforcement Agency
File:Amphetamine_p2p_ammonia_synthesis.svg Source: http://upload.wikimedia.org/wikipedia/commons/7/72/Amphetamine_p2p_
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File:Amphetamine_resolution_and_chiral_synthesis.svg
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File:Racemic_amphetamine.svg Source: http://upload.wikimedia.org/wikipedia/commons/f/f2/Racemic_amphetamine.svg License:
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File:Speakerlink-new.svg Source: http://upload.wikimedia.org/wikipedia/commons/3/3b/Speakerlink-new.svg License: CC0 Contributors: Own work Original artist: Kelvinsong
File:TAAR1_Dopamine.svg
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