Amphetamine

This article is about mixtures of levoamphetamine anddextroamphetamine. For other uses, see Amphetamine(disambiguation).

Amphetamine[note 1] (pronunciation: i/æmˈfɛtəmiːn/;contracted from alpha‑methylphenethylamine) is apotent central nervous system (CNS) stimulant of thephenethylamine class that is used in the treatment ofattention deficit hyperactivity disorder (ADHD) andnarcolepsy. Amphetamine was discovered in 1887 andexists as two enantiomers:[note 2] levoamphetamine anddextroamphetamine. Amphetamine properly refers toa specific chemical, the racemic free base, which isequal parts of the two enantiomers, levoamphetamineand dextroamphetamine, in their pure amine forms.However, the term is frequently used informally to referto any combination of the enantiomers, or to either ofthem alone. Historically, it has been used to treat nasalcongestion, depression, and obesity. Amphetamine isalso used as a performance and cognitive enhancer, andrecreationally as an aphrodisiac and euphoriant. It is aprescription medication in many countries, and unau-thorized possession and distribution of amphetamine areoften tightly controlled due to the significant health risksassociated with substance abuse.[sources 1]

The first pharmaceutical amphetamine was Benzedrine,a brand of inhalers used to treat a variety of conditions.Currently, pharmaceutical amphetamine is typically pre-scribed as Adderall,[note 3] dextroamphetamine, or theinactive prodrug lisdexamfetamine. Amphetamine,through activation of a trace amine receptor, increasesbiogenic amine and excitatory neurotransmitter activityin the brain, with its most pronounced effects targetingthe catecholamine neurotransmitters norepinephrine anddopamine. At therapeutic doses, this causes emotionaland cognitive effects such as euphoria, change in libido,increased wakefulness, and improved cognitive control. Itinduces physical effects such as decreased reaction time,fatigue resistance, and increased muscle strength.[sources 2]

Much larger doses of amphetamine are likely to impaircognitive function and induce rapid muscle breakdown.Drug addiction is a serious risk with large recreationaldoses, but rarely arises from medical use. Very highdoses can result in psychosis (e.g., delusions and para-noia) which rarely occurs at therapeutic doses even dur-ing long-term use. Recreational doses are generally muchlarger than prescribed therapeutic doses and carry a fargreater risk of serious side effects.[sources 3]

Amphetamine is also the parent compound of its ownstructural class, the substituted amphetamines,[note 4]which includes prominent substances such as bupropion,cathinone, MDMA (ecstasy), and methamphetamine.As a member of the phenethylamine class, am-phetamine is also chemically related to the naturallyoccurring trace amine neuromodulators, specificallyphenethylamine[note 5] and N-methylphenethylamine,both of which are produced within the humanbody. Phenethylamine is the parent compound ofamphetamine, while N-methylphenethylamine is aconstitutional isomer that differs only in the placementof the methyl group.[sources 4]

1 Uses

1.1 Medical

Amphetamine is used to treat attention deficit hyper-activity disorder (ADHD) and narcolepsy (a sleep dis-order), and is sometimes prescribed off-label for itspast medical indications, such as depression, obesity,and nasal congestion.[11][27] Long-term amphetamineexposure in some animal species is known to pro-duce abnormal dopamine system development or nervedamage,[39][40] but, in humans with ADHD, pharmaceu-tical amphetamines appear to improve brain developmentand nerve growth.[41][42][43] Magnetic resonance imaging(MRI) studies suggest that long-term treatment with am-phetamine decreases abnormalities in brain structure andfunction found in subjects with ADHD, and improvesfunction in several parts of the brain, such as the rightcaudate nucleus of the basal ganglia.[41][42][43]

Reviews of clinical stimulant research have establishedthe safety and effectiveness of long-term amphetamineuse for ADHD.[44][45][46] Controlled trials spanningtwo years have demonstrated treatment effectivenessand safety.[44][46] One review highlighted a nine-monthrandomized controlled trial in children with ADHD thatfound an average increase of 4.5 IQ points, continued in-creases in attention, and continued decreases in disruptivebehaviors and hyperactivity.[44]

Current models of ADHD suggest that it is associ-ated with functional impairments in some of the brain’sneurotransmitter systems;[47] these functional impair-ments involve impaired dopamine neurotransmission inthe mesocorticolimbic projection and norepinephrineneurotransmission in the locus coeruleus and prefrontal

1

2 3 SIDE EFFECTS

cortex.[47] Psychostimulants like methylphenidate andamphetamine are effective in treating ADHD be-cause they increase neurotransmitter activity in thesesystems.[24][47][48] Approximately 80% of those whouse these stimulants see improvements in ADHDsymptoms.[49] Children with ADHD who use stimu-lant medications generally have better relationships withpeers and family members, perform better in school, areless distractible and impulsive, and have longer attentionspans.[50][51] The Cochrane Collaboration's review[note 6]

on the treatment of adult ADHD with pharmaceuti-cal amphetamines stated that while these drugs improveshort-term symptoms, they have higher discontinuationrates than non-stimulant medications due to their adverseside effects.[53]

A Cochrane Collaboration review on the treatment ofADHD in children with tic disorders such as Tourettesyndrome indicated that stimulants in general do notmake tics worse, but high doses of dextroamphetaminecould exacerbate tics in some individuals.[54] OtherCochrane reviews on the use of amphetamine followingstroke or acute brain injury indicated that it may im-prove recovery, but further research is needed to confirmthis.[55][56][57]

1.2 Enhancing performance

A 2015 meta-analysis of high quality clinical trialsconfirmed that therapeutic doses of amphetamine andmethylphenidate result in modest improvements in per-formance on working memory, episodic memory, andinhibitory control tests in normal healthy adults.[58] Ther-apeutic doses of amphetamine also enhance corticalnetwork efficiency, an effect which mediates improve-ments in working memory in all individuals.[24][59] Am-phetamine and other ADHD stimulants also improvetask saliency (motivation to perform a task) and increasearousal (wakefulness), in turn promoting goal-directedbehavior.[24][60][61] Stimulants such as amphetamine canimprove performance on difficult and boring tasks andare used by some students as a study and test-takingaid.[24][60][62] Based upon studies of self-reported illicitstimulant use, students primarily use stimulants such asamphetamine for performance enhancement rather thanusing them as recreational drugs.[63] However, high am-phetamine doses that are above the therapeutic rangecan interfere with working memory and other aspects ofcognitive control.[24][60]

Amphetamine is used by some athletes for its psychologi-cal and performance-enhancing effects, such as increasedstamina and alertness;[23][36] however, its use is prohibitedat sporting events regulated by collegiate, national, and in-ternational anti-doping agencies.[64][65] In healthy peopleat oral therapeutic doses, amphetamine has been shownto increase physical strength, acceleration, stamina, andendurance, while reducing reaction time.[23][66][67] Am-phetamine improves stamina, endurance, and reaction

time primarily through reuptake inhibition and effluxionof dopamine in the central nervous system.[66][67][68] Attherapeutic doses, the adverse effects of amphetaminedo not impede athletic performance;[23][66][67] however,at much higher doses, amphetamine can induce effectsthat severely impair performance, such as rapid musclebreakdown and elevated body temperature.[22][31][66]

2 Contraindications

See also: Amphetamine § Interactions

According to the International Programme on ChemicalSafety (IPCS) andUnited States Food andDrugAdminis-tration (USFDA),[note 7] amphetamine is contraindicatedin people with a history of drug abuse, heart dis-ease, severe agitation, or severe anxiety.[69][70] It isalso contraindicated in people currently experiencingarteriosclerosis (hardening of the arteries), glaucoma (in-creased eye pressure), hyperthyroidism (excessive pro-duction of thyroid hormone), or hypertension.[69][70] Peo-ple who have experienced allergic reactions to otherstimulants in the past or who are taking monoamineoxidase inhibitors (MAOIs) are advised not to takeamphetamine.[69][70] These agencies also state that any-one with anorexia nervosa, bipolar disorder, depression,hypertension, liver or kidney problems, mania, psychosis,Raynaud’s phenomenon, seizures, thyroid problems, tics,or Tourette syndrome should monitor their symptomswhile taking amphetamine.[69][70] Evidence from humanstudies indicates that therapeutic amphetamine use doesnot cause developmental abnormalities in the fetus ornewborns (i.e., it is not a human teratogen), but am-phetamine abuse does pose risks to the fetus.[70] Am-phetamine has also been shown to pass into breast milk,so the IPCS and USFDA advise mothers to avoid breast-feeding when using it.[69][70] Due to the potential for re-versible growth impairments,[note 8] the USFDA advisesmonitoring the height and weight of children and adoles-cents prescribed an amphetamine pharmaceutical.[69]

3 Side effects

The side effects of amphetamine are varied, and theamount of amphetamine used is the primary fac-tor in determining the likelihood and severity ofside effects.[22][31][36] Amphetamine products such asAdderall, Dexedrine, and their generic equivalents arecurrently approved by the USFDA for long-term thera-peutic use.[29][31] Recreational use of amphetamine gen-erally involves much larger doses, which have a greaterrisk of serious side effects than dosages used for thera-peutic reasons.[36]

3

3.1 Physical

At normal therapeutic doses, the physical side effectsof amphetamine vary widely by age and from personto person.[31] Cardiovascular side effects can includehypertension or hypotension from a vasovagal response,Raynaud’s phenomenon (reduced blood flow to extrem-ities), and tachycardia (increased heart rate).[31][36][71]Sexual side effects in males may include erectile dys-function, frequent erections, or prolonged erections.[31]Abdominal side effects may include stomach pain, lossof appetite, nausea, and weight loss.[31] Other poten-tial side effects include dry mouth, excessive grindingof the teeth, acne, profuse sweating, blurred vision, re-duced seizure threshold, and tics (a type of movementdisorder).[31][36][71] Dangerous physical side effects arerare at typical pharmaceutical doses.[36]

Amphetamine stimulates the medullary respiratory cen-ters, producing faster and deeper breaths.[36] In a nor-mal person at therapeutic doses, this effect is usuallynot noticeable, but when respiration is already compro-mised, it may be evident.[36] Amphetamine also inducescontraction in the urinary bladder sphincter, the mus-cle which controls urination, which can result in dif-ficulty urinating. This effect can be useful in treat-ing bed wetting and loss of bladder control.[36] Theeffects of amphetamine on the gastrointestinal tractare unpredictable.[36] If intestinal activity is high, am-phetamine may reduce gastrointestinal motility (the rateat which content moves through the digestive system);[36]however, amphetamine may increase motility when thesmooth muscle of the tract is relaxed.[36] Amphetaminealso has a slight analgesic effect and can enhance the painrelieving effects of opioids.[36]

USFDA-commissioned studies from 2011 indicate that inchildren, young adults, and adults there is no associationbetween serious adverse cardiovascular events (suddendeath, heart attack, and stroke) and the medical use ofamphetamine or other ADHD stimulants.[sources 5]

3.2 Psychological

Common psychological effects of therapeutic doses caninclude increased alertness, apprehension, concentration,decreased sense of fatigue, mood swings (elated moodfollowed by mildly depressed mood), increased ini-tiative, insomnia or wakefulness, self-confidence, andsociability.[31][36] Less common side effects includeanxiety, change in libido, grandiosity, irritability, repeti-tive or obsessive behaviors, and restlessness;[sources 6] theseeffects depend on the user’s personality and current men-tal state.[36] Amphetamine psychosis (e.g., delusions andparanoia) can occur in heavy users.[22][31][32] Althoughvery rare, this psychosis can also occur at therapeuticdoses during long-term therapy.[22][31][33] According tothe USFDA, “there is no systematic evidence” that stim-ulants produce aggressive behavior or hostility.[31]

Amphetamine has also been shown to produce aconditioned place preference in humans taking therapeu-tic doses,[53][77] meaning that individuals acquire a pref-erence for spending time in places where they have pre-viously used amphetamine.[77][78]

4 Overdose

An amphetamine overdose can lead to many differentsymptoms, but is rarely fatal with appropriate care.[70][79]The severity of overdose symptoms increases with dosageand decreases with drug tolerance to amphetamine.[36][70]Tolerant individuals have been known to take as much as5 grams of amphetamine in a day, which is roughly 100times the maximum daily therapeutic dose.[70] Symptomsof a moderate and extremely large overdose are listed be-low; fatal amphetamine poisoning usually also involvesconvulsions and coma.[22][36] In 2013, overdose on am-phetamine, methamphetamine, and other compounds im-plicated in an "amphetamine use disorder" resulted in anestimated 3,788 deaths worldwide (3,425–4,145 deaths,95% confidence).[note 9][80]

Pathological overactivation of the mesolimbic pathway,a dopamine pathway that connects the ventral tegmen-tal area to the nucleus accumbens, plays a central rolein amphetamine addiction.[81][82] Individuals who fre-quently overdose on amphetamine during recreational usehave a high risk of developing an amphetamine addiction,since repeated overdoses gradually increase the level ofaccumbal ΔFosB, a “molecular switch” and “master con-trol protein” for addiction.[83][84][85] Once nucleus accum-bens ΔFosB is sufficiently overexpressed, it begins to in-crease the severity of addictive behavior (e.g., compulsivedrug-seeking).[83][86] While there are currently no effec-tive drugs for treating amphetamine addiction, regularlyengaging in sustained aerobic exercise appears to reducethe risk of developing such an addiction.[87] Sustainedaerobic exercise on a regular basis also appears to be aneffective treatment for amphetamine addiction;[86][87][88]exercise therapy improves clinical treatment outcomesand may be used as a combination therapy with cognitivebehavioral therapy, which is currently the best clinicaltreatment available.[87][88][89]

4.1 Addiction

Signaling cascade in the nucleus accumbens that resultsin amphetamine addiction

4 4 OVERDOSE

Synaptic cleft Dendrite(Postsynaptic neuron)

-P

DNA

Long-termadaptive

changes inthe brain

+e-e

Legend

+P

-P

Calcium (Ca2+) ions

+eGene expression

Gene repression

Inhibition

Neurotransmitter or ion trafficking

Chronically highlevels of synaptic dopamine

Glutamate(cotransmitted)

NMDA receptorco-agonist

Dopamine

Cyclic adenosinemonophosphate DNA

+P

+P

+P

+P

+P

-P

-P -P

Phosphorylation

Dephosphorylation

Activation/Interaction

Gene product(protein or mRNA)

Complex of twogene products

-e

Molecule

Note: colored text contains article links.Nuclear poreNuclear membranePlasma membraneCaᵥ1.2NMDARAMPARDRD1DRD5DRD2DRD3DRD4GGᵢ/ₒcAMPcAMPPKACaM

CaMKIIDARPP-32PP1PP2BCREBΔFosBJunDc-FosSIRT1HDAC1[Color legend 1]

This diagram depicts the signaling events in the brain’sreward center that are induced by chronic high-doseexposure to psychostimulants that increase the con-centration of synaptic dopamine, like amphetamine,methylphenidate, and phenethylamine. Followingpresynaptic dopamine and glutamate co-release bysuch psychostimulants,[92][93] postsynaptic receptorsfor these neurotransmitters trigger internal signalingevents through a cAMP pathway and calcium-dependentpathway that ultimately result in increased CREBphosphorylation.[81][94] Phosphorylated CREB increaseslevels of ΔFosB, which in turn represses the c-fos genewith the help of corepressors;[94] c-fos repression actsas a molecular switch that enables the accumulation ofΔFosB in the neuron.[95] A highly stable (phosphory-lated) form of ΔFosB, one that persists in neurons for oneor two months, slowly accumulates following repeatedexposure to stimulants through this process.[85][96]ΔFosB functions as “one of the master control proteins”that produces addiction-related structural changes in thebrain, and upon sufficient accumulation, with the help ofits downstream targets (e.g., nuclear factor kappa B), itinduces an addictive state.[85][96]

Addiction is a serious risk with heavy recreational am-phetamine use but is unlikely to arise from typical medi-cal use at therapeutic doses.[34][35][36] Tolerance developsrapidly in amphetamine abuse (i.e., a recreational am-phetamine overdose), so periods of extended use requireincreasingly larger doses of the drug in order to achievethe same effect.[97][98]

4.1.1 Biomolecular mechanisms

Current models of addiction from chronic drug use in-volve alterations in gene expression in certain parts ofthe brain, particularly the nucleus accumbens.[99][100][101]The most important transcription factors[note 10] that pro-duce these alterations are ΔFosB, cAMP response ele-ment binding protein (CREB), and nuclear factor kappaB (NFκB).[100] ΔFosB plays a crucial role in the de-velopment of drug addictions, since its overexpressionin D1-type medium spiny neurons in the nucleus ac-cumbens is necessary and sufficient[note 11] for most of

5

the behavioral and neural adaptations that arise fromaddiction.[83][84][100] Once ΔFosB is sufficiently overex-pressed, it induces an addictive state that becomes in-creasingly more severe with further increases in ΔFosBexpression.[83][84] It has been implicated in addictionsto alcohol, cannabinoids, cocaine, nicotine, opioids,phencyclidine, and substituted amphetamines, amongothers.[86][100][103]

ΔJunD, a transcription factor, and G9a, a histone methyl-transferase enzyme, both directly oppose the induc-tion of ΔFosB in the nucleus accumbens (i.e., they op-pose increases in its expression).[84][100][104] Sufficientlyoverexpressing ΔJunD in the nucleus accumbens withviral vectors can completely block many of the neuraland behavioral alterations seen in chronic drug abuse(i.e., the alterations mediated by ΔFosB).[100] ΔFosBalso plays an important role in regulating behavioral re-sponses to natural rewards, such as palatable food, sex,and exercise.[86][100][105] Since both natural rewards andaddictive drugs induce expression of ΔFosB (i.e., theycause the brain to produce more of it), chronic acquisi-tion of these rewards can result in a similar pathologi-cal state of addiction.[86][100] Consequently, ΔFosB is themost significant factor involved in both amphetamine ad-diction and amphetamine-induced sex addictions, whichare compulsive sexual behaviors that result from exces-sive sexual activity and amphetamine use.[86][106] Thesesex addictions are associated with a dopamine dysreg-ulation syndrome which occurs in some patients takingdopaminergic drugs.[86][105][106]

The effects of amphetamine on gene regulation are bothdose- and route-dependent.[101] Most of the research ongene regulation and addiction is based upon animal stud-ies with intravenous amphetamine administration at veryhigh doses.[101] The few studies that have used equiv-alent (weight-adjusted) human therapeutic doses andoral administration show that these changes, if they oc-cur, are relatively minor.[101] This suggests that medicaluse of amphetamine does not significantly affect generegulation.[101]

4.1.2 Pharmacological treatments

As of May 2014, there is no effective pharmacotherapyfor amphetamine addiction.[107][108][109] Amphetamineaddiction is largely mediated through increased activa-tion of dopamine receptors and co-localized NMDA re-ceptors[note 12] in the nucleus accumbens;[82] magnesiumions inhibit NMDA receptors by blocking the recep-tor calcium channel.[82][110] One review suggested that,based upon animal testing, pathological (addiction-inducing) amphetamine use significantly reduces thelevel of intracellular magnesium throughout the brain.[82]Supplemental magnesium[note 13]

5 Interactions

See also: Amphetamine § Contraindications

Many types of substances are known to interact with am-phetamine, resulting in altered drug action or metabolismof amphetamine, the interacting substance, or both.[3][122]Inhibitors of the enzymes that metabolize amphetamine(e.g., CYP2D6 and flavin-containing monooxygenase3) will prolong its elimination half-life, meaning thatits effects will last longer.[7][122] Amphetamine also in-teracts with MAOIs, particularly monoamine oxidaseA inhibitors, since both MAOIs and amphetamineincrease plasma catecholamines (i.e., norepinephrineand dopamine);[122] therefore, concurrent use of bothis dangerous.[122] Amphetamine modulates the activ-ity of most psychoactive drugs. In particular, am-phetamine may decrease the effects of sedatives anddepressants and increase the effects of stimulants andantidepressants.[122] Amphetamine may also decrease theeffects of antihypertensives and antipsychotics due to itseffects on blood pressure and dopamine respectively.[122]In general, there is no significant interaction when con-suming amphetamine with food, but the pH of gastroin-testinal content and urine affects the absorption and ex-cretion of amphetamine, respectively.[122] Acidic sub-stances reduce the absorption of amphetamine and in-crease urinary excretion, and alkaline substances do theopposite.[122] Due to the effect pH has on absorption, am-phetamine also interacts with gastric acid reducers suchas proton pump inhibitors and H2 antihistamines, whichincrease gastrointestinal pH (i.e., make it less acidic).[122]

6 Pharmacology

6.1 Pharmacodynamics

For a simpler and less technical explanation of am-phetamine’s mechanism of action, see the mechanism ofaction section in the Adderall article.Pharmacodynamics of amphetamine enantiomers in adopamine neuron

6 6 PHARMACOLOGY

Dopamine release

DAT internalization

DAT phosphorylation

+PKA+PKC

-PKA-PKCDiffuse

acrossmembrane

CompetitivereuptakeinhibitionReduced post-synaptic

receptor firing rate

L-Phenylalanine

Dopamine

Amphetamine

Phenethylamine

Protein Kinase

Phosphorylated Dopamine transporter

Trace amine-associatedreceptor 1 (TAAR1)

Dopamine transporter(DAT)

Dopamine receptorD2 short

Synaptic vesicle withVMAT2 (right)

Axon terminal

Synaptic cleft

Dopamine (out)

Trace amine or Amphetamine (in)

Dopamine traffickingTrace amine traffickingAmphetamine traffickingProtein kinase trafficking

From axon

Legend

via AADC

Amphetamine enters the presynaptic neuron acrossthe neuronal membrane or through DAT.[30] Onceinside, it binds to TAAR1 or enters synaptic vesiclesthrough VMAT2.[30][123] When amphetamine entersthe synaptic vesicles through VMAT2, dopamine isreleased into the cytosol (yellow-orange area).[123] Whenamphetamine binds to TAAR1, it reduces dopaminereceptor firing rate via potassium channels and triggersprotein kinase A (PKA) and protein kinase C (PKC)signaling, resulting in DAT phosphorylation.[30][124][125]PKA-phosphorylation causes DAT to withdraw into the

presynaptic neuron (internalize) and cease transport.[30]PKC-phosphorylated DAT may either operate in reverseor, like PKA-phosphorylated DAT, internalize and ceasetransport.[30] Amphetamine is also known to increaseintracellular calcium, a known effect of TAAR1 acti-vation, which is associated with DAT phosphorylationthrough a CAMK-dependent pathway, in turn producingdopamine efflux.[126][127][128]

Amphetamine exerts its behavioral effects by altering theuse of monoamines as neuronal signals in the brain, pri-marily in catecholamine neurons in the reward and exec-utive function pathways of the brain.[30][48] The concen-trations of the main neurotransmitters involved in rewardcircuitry and executive functioning, dopamine and nore-pinephrine, increase dramatically in a dose-dependentmanner by amphetamine due to its effects on monoaminetransporters.[30][48][123] The reinforcing and task saliencyeffects of amphetamine are mostly due to enhanceddopaminergic activity in the mesolimbic pathway.[24]

Amphetamine has been identified as a potent full ag-onist of trace amine-associated receptor 1 (TAAR1),a G -coupled and G -coupled G protein-coupled re-ceptor (GPCR) discovered in 2001, which is impor-tant for regulation of brain monoamines.[30][126] Ac-tivation of TAAR1 increases cAMP production viaadenylyl cyclase activation and inhibits monoamine trans-porter function.[30][129] Monoamine autoreceptors (e.g.,D2 short, presynaptic α2, and presynaptic 5-HT₁A) havethe opposite effect of TAAR1, and together these recep-tors provide a regulatory system for monoamines.[30] No-tably, amphetamine and trace amines bind to TAAR1,but not monoamine autoreceptors.[30] Imaging studiesindicate that monoamine reuptake inhibition by am-phetamine and trace amines is site specific and de-pends upon the presence of TAAR1 co-localization inthe associated monoamine neurons.[30] As of 2010, co-localization of TAAR1 and the dopamine transporter(DAT) has been visualized in rhesus monkeys, but co-localization of TAAR1 with the norepinephrine trans-porter (NET) and the serotonin transporter (SERT)has only been evidenced by messenger RNA (mRNA)expression.[30]

In addition to the neuronal monoamine transporters,amphetamine also inhibits vesicular monoaminetransporter 2 (VMAT2), SLC1A1, SLC22A3, andSLC22A5.[sources 8] SLC1A1 is excitatory amino acidtransporter 3 (EAAT3), a glutamate transporter locatedin neurons, SLC22A3 is an extraneuronal monoaminetransporter that is present in astrocytes and SLC22A5 is ahigh-affinity carnitine transporter.[sources 8] Amphetamineis known to strongly induce cocaine- and amphetamine-regulated transcript (CART) gene expression,[134] aneuropeptide involved in feeding behavior, stress, andreward, which induces observable increases in neuronaldevelopment and survival in vitro.[135][136][137] The CARTreceptor has yet to be identified, but there is significant

6.2 Pharmacokinetics 7

evidence that CART binds to a unique Gᵢ/Gₒ-coupledGPCR.[137][138] Amphetamine also inhibits monoamineoxidase at very high doses, resulting in less dopamine andphenethylamine metabolism and consequently higherconcentrations of synaptic monoamines.[12][139] Thefull profile of amphetamine’s short-term drug effectsis derived through increased cellular communicationor neurotransmission of dopamine,[30] serotonin,[30]norepinephrine,[30] epinephrine,[123] histamine,[123]CART peptides,[134] acetylcholine,[140][141] endogenousopioids,[142][143] and glutamate,[92][144] which it effectsthrough interactions with CART, EAAT3, TAAR1, andVMAT2.[sources 9]

Dextroamphetamine is a more potent agonist of TAAR1than levoamphetamine.[145] Consequently, dextroam-phetamine produces greater CNS stimulation thanlevoamphetamine, roughly three to four times more, butlevoamphetamine has slightly stronger cardiovascular andperipheral effects.[36][145]

6.1.1 Dopamine

In certain brain regions, amphetamine increases theconcentration of dopamine in the synaptic cleft.[30]Amphetamine can enter the presynaptic neuron ei-ther through DAT or by diffusing across the neuronalmembrane directly.[30] As a consequence of DAT up-take, amphetamine produces competitive reuptake in-hibition at the transporter.[30] Upon entering the presy-naptic neuron, amphetamine activates TAAR1 which,through protein kinase A (PKA) and protein kinase C(PKC) signaling, causes DAT phosphorylation.[30] Phos-phorylation by either protein kinase can result in DATinternalization (non-competitive reuptake inhibition),but PKC-mediated phosphorylation alone induces re-verse transporter function (dopamine efflux).[30][146] Am-phetamine is also known to increase intracellular calcium,a known effect of TAAR1 activation, which is associatedwith DAT phosphorylation through a Ca2+/calmodulin-dependent protein kinase (CAMK)-dependent path-way, in turn producing dopamine efflux.[126][127][128]Through direct activation of G protein-coupled inwardly-rectifying potassium channels and an indirect increasein dopamine autoreceptor signaling, TAAR1 reduces thefiring rate of postsynaptic dopamine receptors, prevent-ing a hyper-dopaminergic state.[147][124][125]

Amphetamine is also a substrate for the presynap-tic vesicular monoamine transporter, VMAT2.[123] Fol-lowing amphetamine uptake at VMAT2, the synapticvesicle releases dopamine molecules into the cytosolin exchange.[123] Subsequently, the cytosolic dopaminemolecules exit the presynaptic neuron via reverse trans-port at DAT.[30][123]

6.1.2 Norepinephrine

Similar to dopamine, amphetamine dose-dependentlyincreases the level of synaptic norepinephrine, thedirect precursor of epinephrine.[38][48] Based uponneuronal TAAR1 mRNA expression, amphetamineis thought to affect norepinephrine analogously todopamine.[30][123][146] In other words, amphetamine in-duces TAAR1-mediated efflux and non-competitive re-uptake inhibition at phosphorylated NET, competitiveNET reuptake inhibition, and norepinephrine releasefrom VMAT2.[30][123]

6.1.3 Serotonin

Amphetamine exerts analogous, yet less pro-nounced, effects on serotonin as on dopamine andnorepinephrine.[30][48] Amphetamine affects serotoninvia VMAT2 and, like norepinephrine, is thought to phos-phorylate SERT via TAAR1.[30][123] Like dopamine,amphetamine has low, micromolar affinity at the human5-HT1A receptor.[148][149]

6.1.4 Other neurotransmitters and peptides

Amphetamine has no direct effect on acetylcholine neu-rotransmission, but several studies have noted that acetyl-choline release increases after its use.[140][141] In lab ani-mals, amphetamine increases acetylcholine levels in cer-tain brain regions as a downstream effect.[140] In hu-mans, a similar phenomenon occurs via the ghrelin-mediated cholinergic–dopaminergic reward link in theventral tegmental area.[141] Acute amphetamine admin-istration in humans also increases endogenous opioidrelease in several brain structures in the reward sys-tem.[142][143]

Extracellular levels of glutamate, the primary excitatoryneurotransmitter in the brain, have been shown toincrease upon exposure to amphetamine.[92][144] Thiscotransmission effect was found in the mesolimbicpathway, an area of the brain implicated in reward,where amphetamine is known to affect dopamineneurotransmission.[92][144] Amphetamine also induces ef-fluxion of histamine from synaptic vesicles in CNS mastcells and histaminergic neurons through VMAT2.[123]

6.2 Pharmacokinetics

The oral bioavailability of amphetamine varies withgastrointestinal pH;[122] it is well absorbed from thegut, and bioavailability is typically over 75% fordextroamphetamine.[1] Amphetamine is a weak base witha pKa of 9–10;[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 mem-branes of the gut epithelium.[3][122] Conversely, an acidic

8 7 PHYSICAL AND CHEMICAL PROPERTIES

pH means the drug is predominantly in a water solu-ble cationic (salt) form, and less is absorbed.[3] Approxi-mately 15–40% of amphetamine circulating in the blood-stream is bound to plasma proteins.[2]

The half-life of amphetamine enantiomers differ andvary with urine pH.[3] At normal urine pH, the half-livesof dextroamphetamine and levoamphetamine are 9–11hours and 11–14 hours, respectively.[3] An acidic diet willreduce the enantiomer half-lives to 8–11 hours; an alka-line diet will increase the range to 16–31 hours.[150][151]The immediate-release and extended release variants ofsalts of both isomers reach peak plasma concentrationsat 3 hours and 7 hours post-dose respectively.[3] Am-phetamine is eliminated via the kidneys, with 30–40%of the drug being excreted unchanged at normal urinarypH.[3]When the urinary pH is basic, amphetamine is in itsfree base form, so less is excreted.[3]When urine pH is ab-normal, the urinary recovery of amphetamine may rangefrom a low of 1% to a high of 75%, depending mostlyupon whether urine is too basic or acidic, respectively.[3]Amphetamine is usually eliminated within two days ofthe last oral dose.[150] Apparent half-life and duration ofeffect increase with repeated use and accumulation of thedrug.[152]

The prodrug lisdexamfetamine is not as sensitive to pH asamphetamine when being absorbed in the gastrointesti-nal tract;[153] following absorption into the blood stream,it is converted by red blood cell-associated enzymes todextroamphetamine via hydrolysis.[153] The eliminationhalf-life of lisdexamfetamine is generally less than onehour.[153]

CYP2D6, dopamine β-hydroxylase, flavin-containingmonooxygenase 3, butyrate-CoA ligase, and glycineN-acyltransferase are the enzymes known to metabolizeamphetamine or its metabolites in humans.[sources 10]

6.3 Related endogenous compounds

For more details on related compounds, see Traceamines.

Amphetamine has a very similar structure and function tothe endogenous trace amines, which are naturally occur-ring neurotransmitter molecules produced in the humanbody and brain.[30][38] Among this group, themost closelyrelated compounds are phenethylamine, the parent com-pound of amphetamine, and N-methylphenethylamine,an isomer of amphetamine (i.e., it has an identical molec-ular formula).[30][38][158] In humans, phenethylamine isproduced directly from L-phenylalanine by the aromaticamino acid decarboxylase (AADC) enzyme, whichconverts L-DOPA into dopamine as well.[38][158] In turn,N‑methylphenethylamine is metabolized from phenethy-lamine by phenylethanolamine N-methyltransferase,the same enzyme that metabolizes norepinephrine

into epinephrine.[38][158] Like amphetamine, bothphenethylamine and N‑methylphenethylamine regulatemonoamine neurotransmission via TAAR1;[30][158]unlike amphetamine, both of these substances are brokendown by monoamine oxidase B, and therefore have ashorter half-life than amphetamine.[38][158]

7 Physical and chemical properties

Racemic amphetamine

LevoamphetamineDextroamphetamine

The skeletal structures of L-amph and D-amph

A vial of the colorless amphetamine free base

Amphetamine hydrochloride (left bowl)Phenyl-2-nitropropene (right cups)

Amphetamine is a methyl homolog of the mammalian

7.3 Detection in body fluids 9

neurotransmitter phenethylamine with the chemical for-mula C9H13N. The carbon atom adjacent to the primaryamine is a stereogenic center, and amphetamine is com-posed of a racemic 1:1 mixture of two enantiomericmirror images.[15] This racemic mixture can be sepa-rated into its optical isomers:[note 14] levoamphetamineand dextroamphetamine.[15] Physically, at room tem-perature, the pure free base of amphetamine is amobile, colorless, and volatile liquid with a char-acteristically strong amine odor, and acrid, burningtaste.[14] Frequently prepared solid salts of amphetamineinclude amphetamine aspartate,[22] hydrochloride,[159]phosphate,[160] saccharate,[22] and sulfate,[22] the last ofwhich is the most common amphetamine salt.[37] Am-phetamine is also the parent compound of its own struc-tural class, which includes a number of psychoactivederivatives.[15] In organic chemistry, amphetamine is anexcellent chiral ligand for the stereoselective synthesis of1,1'-bi-2-naphthol.[161]

7.1 Derivatives

For a more comprehensive list, see Substituted am-phetamine.

Amphetamine derivatives, often referred to as “am-phetamines” or “substituted amphetamines”, are abroad range of chemicals that contain amphetamineas a “backbone”.[162][163] The class includes stimulantslike methamphetamine, serotonergic empathogens likeMDMA, and decongestants like ephedrine, among othersubgroups.[162][163] This class of chemicals is sometimesreferred to collectively as the “amphetamine family.”[164]

7.2 Synthesis

For more details on illicit amphetamine synthesis, seeIllegal synthesis of substituted amphetamines.

Since the first preparation was reported in 1887,[165]numerous synthetic routes to amphetamine have beendeveloped.[166][167] Many of these syntheses are basedon classic organic reactions. One such example is theFriedel–Crafts alkylation of chlorobenzene by allyl chlo-ride to yield beta chloropropylbenzene which is then re-acted with ammonia to produce racemic amphetamine(method 1).[168] Another example employs the Ritter re-action (method 2). In this route, allylbenzene is re-acted acetonitrile in sulfuric acid to yield an organosulfatewhich in turn is treated with sodium hydroxide togive amphetamine via an acetamide intermediate.[169][170]A third route starts with ethyl 3-oxobutanoate whichthrough a double alkylation with methyl iodide followedby benzyl chloride can be converted into 2-methyl-3-phenyl-propanoic acid. This synthetic intermediatecan be transformed into amphetamine using either a

Hofmann or Curtius rearrangement (method 3).[171]

A significant number of amphetamine syntheses featurea reduction of a nitro, imine, oxime or other nitrogen-containing functional groups.[166] In one such exam-ple, a Knoevenagel condensation of benzaldehyde withnitroethane yields phenyl-2-nitropropene. The doublebond and nitro group of this intermediate is reduced us-ing either catalytic hydrogenation or by treatment withlithium aluminium hydride (method 4).[172][173] Anothermethod is the reaction of phenylacetone with ammonia,producing an imine intermediate that is reduced to theprimary amine using hydrogen over a palladium catalystor lithium aluminum hydride (method 5).[173]

The most common route of both legal and illicit am-phetamine synthesis employs a non-metal reductionknown as the Leuckart reaction (method 6).[37][173]In the first step, a reaction between phenylacetoneand formamide, either using additional formic acidor formamide itself as a reducing agent, yields N-formylamphetamine. This intermediate is then hy-drolyzed using hydrochloric acid, and subsequently basi-fied, extracted with organic solvent, concentrated, anddistilled to yield the free base. The free base is then dis-solved in an organic solvent, sulfuric acid added, and am-phetamine precipitates out as the sulfate salt.[173][174]

A number of chiral resolutions have been developed toseparate the two enantiomers of amphetamine.[167] Forexample, racemic amphetamine can be treated with d-tartaric acid to form a diastereoisomeric salt which isfractionally crystallized to yield dextroamphetamine.[175]Chiral resolution remains the most economical methodfor obtaining optically pure amphetamine on a largescale.[176] In addition, several enantioselective synthe-ses of amphetamine have been developed. In one ex-ample, optically pure (R)−1-phenyl-ethanamine is con-densed with phenylacetone to yield a chiral Schiff base.In the key step, this intermediate is reduced by catalytichydrogenation with a transfer of chirality to the car-bon atom alpha to the amino group. Cleavage of thebenzylic amine bond by hydrogenation yields opticallypure dextroamphetamine.[176]

7.3 Detection in body fluids

Amphetamine is frequently measured in urine or bloodas part of a drug test for sports, employment, poisoningdiagnostics, and forensics.[sources 11] Techniques suchas immunoassay, which is the most common formof amphetamine test, may cross-react with a numberof sympathomimetic drugs.[180] Chromatographicmethods specific for amphetamine are employed toprevent false positive results.[181] Chiral separationtechniques may be employed to help distinguish thesource of the drug, whether prescription amphetamine,prescription amphetamine prodrugs, (e.g., selegiline),over-the-counter drug products (e.g., the American

10 9 NOTES

version of Vicks VapoInhaler,[182] which containslevomethamphetamine) or illicitly obtained substi-tuted amphetamines.[181][183][184] Several prescriptiondrugs produce amphetamine as a metabolite, in-cluding benzphetamine, clobenzorex, famprofazone,fenproporex, lisdexamfetamine, mesocarb, metham-phetamine, prenylamine, and selegiline, amongothers.[27][185][186] These compounds may producepositive results for amphetamine on drug tests.[185][186]Amphetamine is generally only detectable by a standarddrug test for approximately 24 hours, although a highdose may be detectable for two to four days.[180]

For the assays, a study noted that an enzyme mul-tiplied immunoassay technique (EMIT) assay for am-phetamine and methamphetamine may produce morefalse positives than liquid chromatography–tandem massspectrometry.[183] Gas chromatography–mass spectrom-etry (GC–MS) of amphetamine and methamphetaminewith the derivatizing agent (S)-(−)-trifluoroacetylprolylchloride allows for the detection of methamphetaminein urine.[181] GC–MS of amphetamine and metham-phetamine with the chiral derivatizing agent Mosher’sacid chloride allows for the detection of both dextroam-phetamine and dextromethamphetamine in urine.[181]Hence, the latter method may be used on samples thattest positive using other methods to help distinguish be-tween the various sources of the drug.[181]

8 History, society, and culture

Main article: History and culture of substituted am-phetamines

Amphetamine was first synthesized in 1887 in Ger-many by Romanian chemist Lazăr Edeleanu who namedit phenylisopropylamine;[165][188][189] its stimulant effectsremained unknown until 1927, when it was independentlyresynthesized by Gordon Alles and reported to havesympathomimetic properties.[189] Amphetamine had nopharmacological use until 1934, when Smith, Kline andFrench began selling it as an inhaler under the trade nameBenzedrine as a decongestant.[28] During World War II,amphetamine and methamphetamine were used exten-sively by both the Allied and Axis forces for their stim-ulant and performance-enhancing effects.[165][190][191] Asthe addictive properties of the drug became known, gov-ernments began to place strict controls on the sale ofamphetamine.[165] For example, during the early 1970sin the United States, amphetamine became a scheduleII controlled substance under the Controlled SubstancesAct.[192] In spite of strict government controls, am-phetamine has been used legally or illicitly by peoplefrom a variety of backgrounds, including authors,[193]musicians,[194] mathematicians,[195] and athletes.[23]

Amphetamine is still illegally synthesized today in

clandestine labs and sold on the black market, primar-ily in European countries.[187] Among European Union(EU) member states, 1.2 million young adults used illicitamphetamine or methamphetamine in 2013.[196] Dur-ing 2012, approximately 5.9 metric tons of illicit am-phetamine were seized within EU member states;[196]the “street price” of illicit amphetamine within the EUranged from€6–38 per gram during the same period.[196]Outside Europe, the illicit market for amphetamine ismuch smaller than the market for methamphetamine andMDMA.[187]

8.1 Legal status

As a result of the United Nations 1971 Convention onPsychotropic Substances, amphetamine became a sched-ule II controlled substance, as defined in the treaty,in all (183) state parties.[21] Consequently, it is heav-ily regulated in most countries.[197][198] Some countries,such as South Korea and Japan, have banned substi-tuted amphetamines even for medical use.[199][200] Inother nations, such as Canada (schedule I drug),[201] theNetherlands (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 isin a restrictive national drug schedule that allows for itsuse as a medical treatment.[26][187]

8.2 Pharmaceutical products

The only currently prescribed amphetamine formulationthat contains both enantiomers is Adderall.[note 3][15][27]Amphetamine is also prescribed in enantiopure andprodrug form as dextroamphetamine and lisdexamfe-tamine respectively.[29][205] Lisdexamfetamine is struc-turally different from amphetamine, and is inactive un-til it metabolizes into dextroamphetamine.[205] The freebase of racemic amphetamine was previously availableas Benzedrine, Psychedrine, and Sympatedrine.[15][27]Levoamphetamine was previously available as Cydril.[27]All current amphetamine pharmaceuticals are saltsdue to the comparatively high volatility of the freebase.[27][29][37] Some of the current brands and theirgeneric equivalents are listed below.

9 Notes[1] Synonyms and alternate spellings include: 1-

phenylpropan-2-amine (IUPAC name), α-methylbenzeneethanamine, α-methylphenethylamine,amfetamine (International Nonproprietary Name [INN]),β-phenylisopropylamine, desoxynorephedrine, andspeed.[12][15][16]

[2] Enantiomers are molecules that are mirror images of oneanother; they are structurally identical, but of the opposite

9.1 Dependence and withdrawal 11

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

[3] “Adderall” is a brand name as opposed to a nonproprietaryname; because the latter ("dextroamphetamine sulfate,dextroamphetamine saccharate, amphetamine sulfate, andamphetamine aspartate"[29]) is excessively long, this arti-cle exclusively refers to this amphetamine mixture by thebrand name.

[4] Due to confusion that may arise from use of the pluralform, this article will only use the terms “amphetamine”and “amphetamines” to refer to racemic amphetamine,levoamphetamine, and dextroamphetamine and reservethe term “substituted amphetamines” for the class.

[5] Again, due to confusion that may arise from use of the plu-ral form, this article will only use “phenethylamine” and“phenethylamines” to refer to the compound itself and re-serve the term “substituted phenethylamines” for the class.

[6] Cochrane Collaboration reviews are high quality meta-analytic systematic reviews of randomized controlledtrials.[52]

[7] The statements supported by the USFDA come from pre-scribing information, which is the copyrighted intellec-tual property of the manufacturer and approved by theUSFDA.

[8] In individuals who experience sub-normal height andweight gains, a rebound to normal levels is expected tooccur if stimulant therapy is briefly interrupted.[44][46][71]The average reduction in final adult height from continu-ous stimulant therapy over a 3 year period is 2 cm.[71]

[9] The 95% confidence interval indicates that there is a 95%probability that the true number of deaths lies between3,425 and 4,145.

[10] Transcription factors are proteins that increase or decreasethe expression of specific genes.[102]

[11] In simpler terms, this necessary and sufficient relationshipmeans that ΔFosB overexpression in the nucleus accum-bens and addiction-related behavioral and neural adapta-tions always occur together and never occur alone.

[12] NMDA receptors are voltage-dependent ligand-gated ionchannels that requires simultaneous binding of glutamateand a co-agonist (D-serine or glycine) to open the ionchannel.[110]

[13] The review indicated that magnesium L-aspartate andmagnesium chloride produce significant changes in ad-dictive behavior;[82] other forms of magnesium werenot mentioned.xiety] and fluoxetine treatment have beenshown to reduce amphetamine self-administration (dosesgiven to oneself) in humans, but neither is an effectivemonotherapy for amphetamine addiction.[82][111]

9.0.1 Behavioral treatments

Cognitive behavioral therapy is currently the most effec-tive clinical treatment for psychostimulant addiction.[89]Additionally, research on the neurobiological effects ofphysical exercise suggests that daily aerobic exercise, es-pecially endurance exercise (e.g., marathon running), pre-vents the development of drug addiction and is an effec-tive adjunct (supplemental) treatment for amphetamineaddiction.[86][87][88] Exercise leads to better treatment out-comes when used as an adjunct treatment, particularly forpsychostimulant addictions.[87][88] In particular, aerobicexercise 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 patholog-ical stimulant use, which induces decreased striatal DRD2density.[86]

9.1 Dependence and withdrawalAccording to another Cochrane Collaboration reviewon withdrawal in individuals who compulsively use am-phetamine and methamphetamine, “when chronic heavyusers abruptly discontinue amphetamine use, many reporta time-limited withdrawal syndrome that occurs within24 hours of their last dose.”[112] This review noted thatwithdrawal symptoms in chronic, high-dose users are fre-quent, occurring in up to 87.6% of cases, and persist forthree to four weeks with a marked “crash” phase occur-ring during the first week.[112] Amphetamine withdrawalsymptoms can include anxiety, drug craving, depressedmood, fatigue, increased appetite, increased movementor decreased movement, lack of motivation, sleeplessnessor sleepiness, and lucid dreams.[112] The review indicatedthat withdrawal symptoms are associated with the degreeof dependence, suggesting that therapeutic use would re-sult in far milder discontinuation symptoms.[112] Manufac-turer prescribing information does not indicate the pres-ence of withdrawal symptoms following discontinuationof amphetamine use after an extended period at therapeu-tic doses.[113][114][115]

9.2 Toxicity and psychosisSee also: Stimulant psychosisIn rodents and primates, sufficiently high doses of am-phetamine cause dopaminergic neurotoxicity, or dam-age to dopamine neurons, which is characterized by re-duced transporter and receptor function.[116] There isno evidence that amphetamine is directly neurotoxic inhumans.[117][118] However, large doses of amphetaminemay cause indirect neurotoxicity as a result of in-creased oxidative stress from reactive oxygen speciesand autoxidation of dopamine.[39][119][120] A severe am-phetamine overdose can result in a stimulant psychosisthat may involve a variety of symptoms, such as paranoiaand delusions.[32] A Cochrane Collaboration review ontreatment for amphetamine, dextroamphetamine, andmethamphetamine psychosis states that about 5–15%

12 10 REFERENCE NOTES

of users fail to recover completely.[32][121] According tothe same review, there is at least one trial that showsantipsychotic medications effectively resolve the symp-toms of acute amphetamine psychosis.[32] Psychosis veryrarely arises from therapeutic use.[33]sms | journal =J. Psychoactive “Adderall XR Prescribing Information”(PDF).United States Food andDrug Administration. ShireUS Inc. December 2013. pp. 4–6. Retrieved 30 Decem-ber 2013.

[14] Enantiomers are molecules that are mirror images of oneanother; they are structurally identical, but of the oppositeorientation.[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 va-riety of excreted metabolic products, including4-hydroxyamfetamine, 4-hydroxynorephedrine, 4-hydroxyphenylacetone, benzoic acid, hippuric acid,norephedrine, and phenylacetone.[3][150][154] Amongthese metabolites, the active sympathomimetics are4‑hydroxyamphetamine,[155] 4‑hydroxynorephedrine,[156]and norephedrine.[157] The main metabolic pathwaysinvolve aromatic para-hydroxylation, aliphatic alpha- andbeta-hydroxylation, N-oxidation, N-dealkylation, anddeamination.[3][150] The known pathways and detectablemetabolites in humans include the following:[3][7][154]Metabolic pathways of amphetamine

4-HydroxyphenylacetonePhenylacetoneBenzoic acidHippuric acidAmphetamineNorephedrine4-Hydroxyamphetamine4-HydroxynorephedrinePara-HydroxylationPara-HydroxylationPara-HydroxylationBeta-HydroxylationBeta-HydroxylationOxidativeDeaminationOxidationGlycineConjugationThe primary active metabolites of amphetamine are4-hydroxyamphetamine and norephedrine;[154] at normalurine pH, about 30–40% of amphetamine is excretedunchanged and roughly 50% is excreted as the inactivemetabolites (bottom row).[3] The remaining 10–20%is excreted as the active metabolites.[3] Benzoic acid ismetabolized by butyrate-CoA ligase into an intermediateproduct, benzoyl-CoA,[9] which is then metabolized byglycine N-acyltransferase into hippuric acid.cit hyperac-tivity dis“Substrate/Product”. glycine N-acyltransferase.BRENDA. Technische Universität Braunschweig. Re-trieved 7 May 2014.

13

[11] [23][177][178][179]

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[3] “Adderall XR Prescribing Information” (PDF). UnitedStates Food and Drug Administration. Shire US Inc. De-cember 2013. pp. 12–13. Retrieved 30 December 2013.

[4] Lemke TL, Williams DA, Roche VF, Zito W (2013).Foye’s Principles of Medicinal Chemistry (7th ed.).Philadelphia, USA: Wolters Kluwer Health/LippincottWilliams & Wilkins. p. 648. ISBN 9781609133450.Alternatively, direct oxidation of amphetamine by DA β-hydroxylase can afford norephedrine.

[5] Taylor KB (January 1974). “Dopamine-beta-hydroxylase. Stereochemical course of the reaction”(PDF). J. Biol. Chem. 249 (2): 454–458. PMID4809526. Retrieved 6 November 2014. Dopamine-β-hydroxylase catalyzed the removal of the pro-Rhydrogen atom and the production of 1-norephedrine,(2S,1R)−2-amino-1-hydroxyl-1-phenylpropane, fromd-amphetamine.

[6] Horwitz D, Alexander RW, Lovenberg W, KeiserHR (May 1973). “Human serum dopamine-β-hydroxylase. Relationship to hypertension andsympathetic activity”. Circ. Res. 32 (5): 594–599.doi:10.1161/01.RES.32.5.594. PMID 4713201. Sub-jects with exceptionally low levels of serum dopamine-β-hydroxylase activity showed normal cardiovascularfunction and normal β-hydroxylation of an administeredsynthetic substrate, hydroxyamphetamine.

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12 External links• CID 5826 from PubChem (dextroamphetamine)

• CID 3007 from PubChem (racemic amphetamine)

• CID 32893 from PubChem (levoamphetamine)

• Comparative Toxicogenomics Database entry: Am-phetamine

• Comparative Toxicogenomics Database entry:CARTPT

• U.S. National Library of Medicine: Drug Informa-tion Portal – Amphetamine

23

13 Text and image sources, contributors, and licenses

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

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Kasey1123, Woodmand0809, Citation bot, Jobo123, ArthurBot, Me86532,Bronckobuster, IllusionalFate, S h i v a (Visnu), RickyTheJanitor, Δζ, Pontificalibus, Jü, Br77rino, البط علي ,حسن Harbinary, Maddie!,AbigailAbernathy, Nasa-verve, GrouchoBot, DriverDan, Richard.decal, Bohemian Arcade, Euanmacdermid, Magicandmyth, 11bje11,Ajax151, Editor182, Jimebob, MikeCU2008, Al Wiseman, BoomerAB, FrescoBot, TinyHero55, Jatlas, Lonaowna, Mert91, Benwards1,SpunkySkunk347, D'ohBot, PasswordUsername, BenzolBot, PigFlu Oink, Nirmos, Trusslars, Chezulvena, Fuzbaby, NattoMaki, Dylancat-low, Yeliabrecneps, LittleWink, Onthegogo, MastiBot, Fentlehan, Piandcompany, Tea with toast, Spaceboss, David51387, BogBot, WayneRiddock, Trappist the monk, Dcs002, David Hedlund, Chal09, DARTH SIDIOUS 2, RjwilmsiBot, Bento00, DASHBot, Mr. Anon515,John of Reading, Stryn, Dadaist6174, Rbaselt, Lilypopluiy, GoingBatty, Kassem23, Elmozo, Woodywoodpeckerthe3rd, Strattgr, Ebe123,Wikipelli, Everything Else Is Taken, ZéroBot, Manicjedi, John Cline, Traxs7, Joejello, Betohaku, Hkazmi, Mediatiger838, Bustermyth-monger, Ebrambot, Bamyers99, H3llBot, Fsdadssghfd, Joshlepaknpsa, Wayne Slam, Addicted2l, MaxErdwien, Brandmeister~enwiki,L Kensington, DFerret, Allethrin, Lawstubes, Peteb4, Carmichael, Chris857, Noodles32236, DASHBotAV, Spicemix, Louisajb, WillBeback Auto, ClueBot NG, Jack Greenmaven, Gilderien, Pashihiko, Chester Markel, Bped1985, Diogenes2000, SubDural12, Frietjes,

24 13 TEXT AND IMAGE SOURCES, CONTRIBUTORS, AND LICENSES

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