Amphetamine: Difference between revisions

Addiction and dependence glossary^[78]^[84]^[85]
Addiction and dependence glossary
	biopsychosocial disorder characterized by persistent use of drugs (including alcohol) despite substantial harm and adverse consequences; addictive drug – psychoactive substances that with repeated use are associated with significantly higher rates of substance use disorders, due in large part to the drug's effect on brain reward systems; dependence – an adaptive state associated with a withdrawal syndrome upon cessation of repeated exposure to a stimulus (e.g., drug intake); drug sensitization or reverse tolerance – the escalating effect of a drug resulting from repeated administration at a given dose; drug withdrawal – symptoms that occur upon cessation of repeated drug use; physical dependence – dependence that involves persistent physical–somatic withdrawal symptoms (e.g., fatigue and delirium tremens); psychological dependence – dependence socially seen as being extremely mild compared to physical dependence (e.g., with enough willpower it could be overcome); reinforcing stimuli – stimuli that increase the probability of repeating behaviors paired with them; rewarding stimuli – stimuli that the brain interprets as intrinsically positive and desirable or as something to approach; sensitization – an amplified response to a stimulus resulting from repeated exposure to it; substance use disorder – a condition in which the use of substances leads to clinically and functionally significant impairment or distress; tolerance – the diminishing effect of a drug resulting from repeated administration at a given dose;
	v; t; e;

Amphetamine
Clinical data
Other names	α-methylphenethylamine
AHFS/Drugs.com	amphetamine
License data	US FDA: Adderall;
intravenous
ATC code	N06BA01 (WHO) ;
Legal status
Legal status	AU: S8 (Controlled drug); CA: Schedule I; UK: Class B; US: WARNINGSchedule II; UN: Schedule II; In general: ℞ (Prescription only);
Renal; pH-dependent range: 1–75%
Identifiers
	IUPAC name (RS)-1-phenylpropan-2-amine; (RS)-1-phenyl-2-aminopropane;
JSmol)	Interactive image;
Density	0.9±0.1 g/cm3
Melting point	11.3 °C (52.3 °F)
Boiling point	203 °C (397 °F)
	SMILES NC(CC1=CC=CC=C1)C;
	InChI InChI=1S/C9H13N/c1-8(10)7-9-5-3-2-4-6-9/h2-6,8H,7,10H2,1H3 ; Key:KWTSXDURSIMDCE-UHFFFAOYSA-N ;
	(verify)

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Amphetamine

euphoriant. It is a prescription medication in many countries, and unauthorized possession and distribution of amphetamine is often tightly controlled due to the significant health risks associated with uncontrolled or heavy use.^{[sources 1]}

The first pharmaceutical amphetamine was

cognitive control. It induces physical effects such as decreased reaction time, fatigue resistance, and increased muscle strength.^{[sources 2]}

Much larger doses of amphetamine are likely to impair cognitive function and induce rapid muscle breakdown. Drug addiction is a serious risk of high dose recreational amphetamine use, 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 effects.^{[sources 3]}

Amphetamine is also the parent compound of its own structural class, the

constitutional isomer that differs only in the placement of the methyl group.^{[sources 4]}

Uses

Medical

Amphetamine is used to treat

off-label for its past medical indications, such as depression, obesity, and nasal congestion.^[5]^[28] 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, 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]

Reviews of clinical stimulant research have established the safety and effectiveness of long-term amphetamine use for ADHD.[44]^[45] Controlled trials spanning two years have demonstrated treatment effectiveness and safety.^[45]^[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.^[46]

Current models of ADHD suggest that it is associated with functional impairments in some of the brain's

Cochrane Collaboration's review^{[note 6]} on the treatment of adult ADHD with amphetamines stated that while amphetamines improve short-term symptoms, they have higher discontinuation rates than non-stimulant medications due to their adverse side effects.^[52]

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.^[53] 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 confirm this.^[54]^[55]^[56]

Enhancing performance

Therapeutic doses of amphetamine improve cortical network efficiency, resulting in higher performance on

cognitive control.^[25]^[58]

Amphetamine is used by some athletes for its psychological and performance-enhancing effects, such as increased stamina and alertness;

effluxion of dopamine in the central nervous system.^[64]^[65]^[66] At therapeutic doses, the adverse effects of amphetamine do not impede athletic performance;^[24]^[64]^[65] however, at much higher doses, amphetamine can induce effects that severely impair performance, such as rapid muscle breakdown and elevated body temperature.^[23]^[32]^[64]

Contraindications

According to the

teratogen), but amphetamine abuse does pose risks to the fetus.^[68] Amphetamine has also been shown to pass into breast milk, so the IPCS and USFDA advise mothers to avoid breastfeeding when using it.^[67]^[68] Due to the potential for reversible growth impairments,^{[note 8]} the USFDA advises monitoring the height and weight of children and adolescents prescribed amphetamines.^[67]

Side effects

The

side effects of amphetamine are varied, and the amount of amphetamine used is the primary factor in determining the likelihood and severity of side effects.^[23]^[32]^[36] Amphetamine products such as Adderall, Dexedrine, and their generic equivalents are currently approved by the USFDA for long-term therapeutic use.^[30]^[32] Recreational use of amphetamine generally involves much larger doses, which have a greater risk of serious side effects than dosages used for therapeutic reasons.^[36]

Physical

At normal therapeutic doses, the physical side effects of amphetamine vary widely by age and from person to person.

tics (a type of movement disorder).^[32]^[36]^[69] Dangerous physical side effects are rare at typical pharmaceutical doses.^[36]

Amphetamine stimulates the

opiates.^[36]

USFDA commissioned studies from 2011 indicate that in children, young adults, and adults there is no association between serious adverse cardiovascular events (

sudden death, heart attack, and stroke) and the medical use of amphetamine or other ADHD stimulants.^{[sources 5]}

Psychological

Common psychological effects of therapeutic doses can include increased

Amphetamine psychosis (e.g., delusions and paranoia) can occur in heavy users.^[23]^[32]^[33] Although very rare, this psychosis can also occur at therapeutic doses during long-term therapy.^[23]^[32]^[34] According to the USFDA, "there is no systematic evidence" that stimulants produce aggressive behavior or hostility.^[32]

Overdose

An amphetamine overdose can lead to many different symptoms, but is rarely fatal with appropriate care.[68]^[75] The severity of overdose symptoms increases with dosage and decreases with drug tolerance to amphetamine.^[36]^[68] Tolerant individuals have been known to take as much as 5 grams of amphetamine in a day, which is roughly 100 times the maximum daily therapeutic dose.^[68] Symptoms of a moderate and extremely large overdose are listed below; fatal amphetamine poisoning usually also involves convulsions and coma.^[23]^[36]

Pathological overactivation of the

ΔFosB, a "master control protein" for addiction;^[78]^[79]^[76] once nucleus accumbens ΔFosB is sufficiently overexpressed, it begins to directly modulate the severity of addictive behavior (e.g., compulsive drug-seeking).^[80]^[81] While there are currently no effective drugs for treating amphetamine addiction, regularly engaging in sustained aerobic exercise appears to reduce the risk of developing such an addiction.^[82] Sustained aerobic exercise on a regular basis also appears to be an effective treatment for amphetamine addiction;^[80]^[82] exercise therapy improves clinical treatment outcomes and may be used as a combination therapy with cognitive behavioral therapy, which is currently the best clinical treatment available.^[82]^[83]

Template:Amphetamine overdose

Addiction

Signaling cascade in the nucleus accumbens that results in amphetamine addiction

Note: colored text contains article links.

Nuclear pore

Nuclear membrane

Plasma membrane

Ca_v1.2

G_s

cAMP

DARPP-32

PP2B

CREB

ΔFosB

JunD

c-Fos

SIRT1

HDAC1

^{[Color legend 1]}

This diagram depicts the signaling events in the

nuclear factor kappa B), it induces an addictive state.^[79]^[88]

Addiction is a serious risk with heavy recreational amphetamine use but is unlikely to arise from typical medical use at therapeutic doses.^[23]^[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 effect.^[90]^[91]

Biomolecular mechanisms

Current models of addiction from chronic drug use involve alterations in

substituted amphetamines.^[80]^[93]^[96]

sex addictions, which are compulsive sexual behaviors that result from excessive amphetamine use.^[80]^[98] These sex addictions are caused by dopamine dysregulation syndrome, an addictive disorder which has been observed in some patients taking dopaminergic drugs, like amphetamine, for an extended period.^[80]^[97]^[98]

The effects of amphetamine on gene regulation are both dose- and route-dependent.[94] Most of the research on gene regulation and addiction is based upon animal studies with intravenous amphetamine administration at very high doses.^[94] 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.^[94]

Pharmacological treatments

A

monotherapy for amphetamine addiction.^[99] A corroborating review indicated that amphetamine addiction is mediated through increased activation of dopamine receptors and co-localized NMDA receptors in the mesolimbic pathway (i.e., the nucleus accumbens).^[77] This review also noted that magnesium ions and serotonin inhibit NMDA receptors and that the magnesium ions do so by blocking the receptor's calcium channels.^[77] It also suggested that, based upon animal testing, pathological (addiction-inducing) amphetamine use significantly reduces the level of intracellular magnesium throughout the brain.^[77] Supplemental magnesium,^{[note 13]} like fluoxetine treatment, has been shown to reduce amphetamine self-administration (doses given to oneself) in both humans and lab animals.^[99]^[77]

Behavioral treatments

reinstatement (i.e., relapse) of drug-seeking, and induces increased dopamine receptor D₂ (DRD2) density in the striatum. This is the opposite of pathological stimulant use, which induces decreased striatal DRD2 density.^[80]

Withdrawal

According to another Cochrane Collaboration review on

increased appetite, increased movement or decreased movement, lack of motivation, sleeplessness or sleepiness, and lucid dreams.^[100] The review indicated that withdrawal symptoms are associated with the degree of dependence, suggesting that therapeutic use would result in far milder discontinuation symptoms.^[100] Manufacturer prescribing information does not indicate the presence of withdrawal symptoms following discontinuation of amphetamine use after an extended period at therapeutic doses.^[101]^[102]^[103]

Toxicity and psychosis

In rodents and primates, sufficiently high doses of amphetamine cause dopaminergic neurotoxicity, or damage to dopamine neurons, which is characterized by reduced transporter and receptor function.^[104] There is no evidence that amphetamine is directly neurotoxic in humans.^[105]^[106] 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]^[107]^[108]

A severe amphetamine overdose can result in a stimulant psychosis that may involve a variety of symptoms, such as paranoia and delusions.^[33] A Cochrane Collaboration review on treatment for amphetamine, dextroamphetamine, and methamphetamine psychosis states that about 5–15% of users fail to recover completely.^[33]^[109] According to the same review, there is at least one trial that shows antipsychotic medications effectively resolve the symptoms of acute amphetamine psychosis.^[33] Psychosis very rarely arises from therapeutic use.^[34]^[67]

Interactions

Many types of substances are known to

H₂ antihistamines, which increase gastrointestinal pH (i.e., make it less acidic).^[110]

Pharmacology

Pharmacodynamics

Pharmacodynamics of amphetamine in a dopamine neuron

via AADC

Amphetamine enters the presynaptic neuron across the neuronal membrane or through DAT.^{CAMKIIα-dependent pathway, in turn producing dopamine efflux.^[115]^[116]}

Amphetamine exerts its behavioral effects by altering the use of monoamines as neuronal signals in the brain, primarily in

mesocorticolimbic projection.^[31]^[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 effects on monoamine transporters.^[31]^[48]^[111] The reinforcing and task saliency effects of amphetamine are mostly due to enhanced dopaminergic activity in the mesolimbic pathway.^[25]

Amphetamine has been identified as a potent

presynaptic 5-HT_1A) have the opposite effect of TAAR1, and together these receptors provide a regulatory system for monoamines.^[31] Notably, amphetamine and trace amines bind to TAAR1, but not monoamine autoreceptors.^[31] Imaging studies indicate that monoamine reuptake inhibition by amphetamine and trace amines is site specific and depends upon the presence of TAAR1 co-localization in the associated monoamine neurons.^[31] 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 transporter (NET) and the serotonin transporter (SERT) has only been evidenced by messenger RNA (mRNA) expression.^[31]

In addition to the neuronal monoamine

cocaine- and amphetamine-regulated transcript (CART) gene expression,^[123] a neuropeptide involved in feeding behavior, stress, and reward, which induces observable increases in neuronal development and survival in vitro.^[124]^[125]^[126] The CART receptor has yet to be identified, but there is significant evidence that CART binds to a unique G_i/G_o-coupled GPCR.^[126]^[127] Amphetamine also inhibits monoamine oxidase at very high doses, resulting in less dopamine and phenethylamine metabolism and consequently higher concentrations of synaptic monoamines.^[15]^[128]

The full profile of amphetamine's short-term drug effects is derived through increased cellular communication or

glutamate,^[131]^[132] which it effects through interactions with CART, EAAT3, TAAR1, and VMAT2.^{[sources 8]}

Dextroamphetamine is a more potent agonist of TAAR1 than levoamphetamine.[133] Consequently, dextroamphetamine produces greater CNS stimulation than levoamphetamine, roughly three to four times more, but levoamphetamine has slightly stronger cardiovascular and peripheral effects.^[36]^[133]

Dopamine

In certain brain regions, amphetamine increases the concentration of dopamine in the

G protein-coupled inwardly-rectifying potassium channels and increased dopamine release, TAAR1 reduces the firing rate of postsynaptic dopamine receptors, preventing a hyper-dopaminergic state.^[135]^[113]^[114]

Amphetamine is also a substrate for the presynaptic vesicular monoamine transporter, VMAT2.[111] Following amphetamine uptake at VMAT2, the synaptic vesicle releases dopamine molecules into the cytosol in exchange.^[111] Subsequently, the cytosolic dopamine molecules exit the presynaptic neuron via reverse transport at DAT.^[31]^[111]

Norepinephrine

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 affect norepinephrine analogously to dopamine.^[31]^[111]^[134] In other words, amphetamine induces TAAR1-mediated efflux and non-competitive reuptake inhibition at phosphorylated NET, competitive NET reuptake inhibition, and norepinephrine release from VMAT2.^[31]^[111]

Serotonin

Amphetamine exerts analogous, yet less pronounced, effects on serotonin as on dopamine and norepinephrine.[31]^[48] Amphetamine affects serotonin via VMAT2 and, like norepinephrine, is thought to phosphorylate SERT via TAAR1.^[31]^[111]

Other neurotransmitters

Amphetamine has no direct effect on

nicotinic receptor activation in the CNS, a factor which likely contributes to the nootropic effects of amphetamine.^[136]

Extracellular levels of

cotransmission effect was found in the mesolimbic pathway, an area of the brain implicated in reward, where amphetamine is known to affect dopamine neurotransmission.^[131]^[132] Amphetamine also induces effluxion of histamine from synaptic vesicles in CNS mast cells and histaminergic neurons through VMAT2.^[111]

Pharmacokinetics

The oral

cationic (salt) form, and less is absorbed.^[4] Approximately 15–40% of amphetamine circulating in the bloodstream is bound to plasma proteins.^[3]

The half-life of amphetamine enantiomers differ and vary with urine pH.^[4] At normal urine pH, the half-lives of dextroamphetamine and levoamphetamine are 9–11 hours and 11–14 hours, respectively.^[4] An acidic diet will reduce the enantiomer half-lives to 8–11 hours; an alkaline diet will increase the range to 16–31 hours.^[137]^[138] The immediate-release and extended release variants of salts of both isomers reach peak plasma concentrations at 3 hours and 7 hours post-dose respectively.^[4] Amphetamine is eliminated via the kidneys, with 30–40% of the drug being excreted unchanged at normal urinary pH.^[4] When the urinary pH is basic, amphetamine is in its free base form, so less is excreted.^[4] When urine pH is abnormal, the urinary recovery of amphetamine may range from a low of 1% to a high of 75%, depending mostly upon whether urine is too basic or acidic, respectively.^[4] Amphetamine is usually eliminated within two days of the last oral dose.^[137] Apparent half-life and duration of effect increase with repeated use and accumulation of the drug.^[139]

The prodrug lisdexamfetamine is not as sensitive to pH as amphetamine when being absorbed in the gastrointestinal tract;^[140] following absorption into the blood stream, it is converted by red blood cell-associated enzymes to dextroamphetamine via hydrolysis.^[140] The elimination half-life of lisdexamfetamine is generally less than one hour.^[140]

sympathomimetics are 4‑hydroxyamphetamine,^[142] 4‑hydroxynorephedrine,^[143] and norephedrine.^[144] The main metabolic pathways involve aromatic para-hydroxylation, aliphatic alpha- and beta-hydroxylation, N-oxidation, N-dealkylation, and deamination.^[4]^[137] The known pathways and detectable metabolites in humans include the following:^[4]^[9]^[141]

Metabolic pathways of amphetamine in humans^{[sources 10]}

4-Hydroxyphenylacetone

4-Hydroxynorephedrine

DBH
^{[note 14]}

Oxidative
Deamination

The primary active metabolites of amphetamine are 4-hydroxyamphetamine and norephedrine;^[141] at normal urine pH, about 30–40% of amphetamine is excreted unchanged and roughly 50% is excreted as the inactive metabolites (bottom row).^[4] The remaining 10–20% is excreted as the active metabolites.^[4] Benzoic acid is metabolized by butyrate-CoA ligase into an intermediate product, benzoyl-CoA,^[11] which is then metabolized by glycine N-acyltransferase into hippuric acid.^[12]

Related endogenous compounds

Amphetamine has a very similar structure and function to the

aromatic amino acid decarboxylase (AADC) enzyme, which converts L-DOPA into dopamine as well.^[38]^[150] In turn, N‑methylphenethylamine is metabolized from phenethylamine by phenylethanolamine N-methyltransferase, the same enzyme that metabolizes norepinephrine into epinephrine.^[38]^[150] Like amphetamine, both phenethylamine and N‑methylphenethylamine regulate monoamine neurotransmission via TAAR1;^[31]^[150] unlike amphetamine, both of these substances are broken down by monoamine oxidase B, and therefore have a shorter half-life than amphetamine.^[38]^[150]

Physical and chemical properties

skeletal structures of L-amph and D-amph

Amphetamine hydrochloride (left bowl)
Phenyl-2-nitropropene

(right cups)

Amphetamine is a

1,1'-bi-2-naphthol.^[154]

Derivatives

Amphetamine derivatives, often referred to as "amphetamines" or "substituted amphetamines", are a broad range of chemicals that contain amphetamine as a "backbone".

empathogens like MDMA (ecstasy), and decongestants like ephedrine, among other subgroups.^[155]^[156] This class of chemicals is sometimes referred to collectively as the "amphetamine family."^[157]

Synthesis

Template:Details3 Since the first preparation was reported in 1887,

methyl iodide followed by benzyl chloride can be converted into 2-methyl-3-phenyl-propanoic acid. This synthetic intermediate can be transformed into amphetamine using either a Hofmann or Curtius rearrangement (method 3).^[164]

A significant number of amphetamine syntheses feature a

nitro, imine, oxime or other nitrogen-containing functional group.^[159] 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).^[165]^[166] 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).^[166]

The most common route of both legal and illicit amphetamine synthesis employs a non-metal reduction known as the

N-formylamphetamine. This intermediate is then hydrolyzed using hydrochloric acid, and subsequently basified, 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.^[166]^[167]

A number of

benzylic amine bond by hydrogenation yields optically pure dextroamphetamine.^[169]

Amphetamine synthetic routes

Method 1: Synthesis by Friedel–Crafts alkylation

Method 2: Ritter synthesis

Method 3: Synthesis via Hofmann and Curtius rearrangements

Method 4: Synthesis by Knoevenagel condensation

Method 5: Synthesis using phenylacetone and ammonia

Method 6: Synthesis by the Leuckart reaction

Top: Chiral resolution of amphetamine
Bottom: Stereoselective synthesis of amphetamine

Detection in body fluids

Amphetamine is frequently measured in urine or blood as part of a

Vicks VapoInhaler, which contains levomethamphetamine) or illicitly obtained substituted amphetamines.^[174]^[175]^[176] Several prescription drugs produce amphetamine as a metabolite, including benzphetamine, clobenzorex, famprofazone, fenproporex, lisdexamfetamine, mesocarb, methamphetamine, prenylamine, and selegiline, among others.^[28]^[177]^[178] These compounds may produce positive results for amphetamine on drug tests.^[177]^[178] 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.^[173]

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 chromatography–tandem mass spectrometry.^[175] Gas chromatography–mass spectrometry (GC–MS) of amphetamine and methamphetamine with the derivatizing agent (S)-(−)-trifluoroacetylprolyl chloride allows for the detection of methamphetamine in urine.^[174] GC–MS of amphetamine and methamphetamine with the chiral derivatizing agent Mosher's acid chloride allows for the detection of both dextroamphetamine and dextromethamphetamine in urine.^[174] 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.^[174]

History, society, and culture

Global estimates of illicit drug users in 2012
(in millions of users)^[179]
Substance	Mean estimate	Low estimate	High estimate
Cannabis	177.63	125.30	227.27
Cocaine	17.24	13.99	20.92
MDMA	18.75	9.4	28.24
Opiates	16.37	12.80	20.23
Opioids	33.04	28.63	38.16
Substituted amphetamines	34.40	13.94	54.81

Amphetamine was first synthesized in 1887 in Germany by Romanian chemist

Benzedrine as a decongestant.^[29] During World War II, amphetamines and methamphetamine were used extensively by both the Allied and Axis forces for their stimulant and performance-enhancing effects.^[158]^[182]^[183] As the addictive properties of the drug became known, governments began to place strict controls on the sale of amphetamine.^[158] For example, during the early 1970s in the United States, amphetamine became a schedule II controlled substance under the Controlled Substances Act.^[184] In spite of strict government controls, amphetamine has been used legally or illicitly by people from a variety of backgrounds, including authors,^[185] musicians,^[186] mathematicians,^[187] and athletes.^[24]

Amphetamine is still illegally synthesized today in

metric tons of illicit amphetamine were seized within EU member states;^[188] the "street price" of illicit amphetamine within the EU ranged from €6–38 per gram during the same period.^[188] Outside Europe, the illicit market for amphetamine is much smaller than the market for methamphetamine and MDMA.^[179]

Legal status

As a result of the United Nations 1971 Convention on Psychotropic Substances, amphetamine became a schedule II controlled substance, as defined in the treaty, in all (183) state parties.^[22] Consequently, it is heavily regulated in most countries.^[189]^[190] Some countries, such as South Korea and Japan, have banned substituted amphetamines even for medical use.^[191]^[192] In other nations, such as Canada (schedule I drug),^[193] the United States (schedule II drug),^[23] Thailand (category 1 narcotic),^[194] and United Kingdom (class B drug),^[195] amphetamine is in a restrictive national drug schedule that allows for its use as a medical treatment.^[27]^[179]

Pharmaceutical products

The only currently prescribed amphetamine formulation that contains both enantiomers is Adderall.^{[note 3]}^[16]^[28] Amphetamine is also prescribed in enantiopure and prodrug form as dextroamphetamine and lisdexamfetamine respectively.^[30]^[196] Lisdexamfetamine is structurally different from amphetamine, and is inactive until it metabolizes into dextroamphetamine.^[196] The free base of racemic amphetamine was previously available as Benzedrine, Psychedrine, and Sympatedrine.^[16]^[28] Levoamphetamine was previously available as Cydril.^[28] All current amphetamine pharmaceuticals are salts due to the comparatively high volatility of the free base.^[28]^[30]^[37] Some of the current brands and their generic equivalents are listed below.

Amphetamine pharmaceuticals
Brand name	United States Adopted Name	(D:L) ratio of salts	Dosage form	Source
Adderall	–	3:1	tablet	^[28]^[30]
Adderall XR	–	3:1	capsule	^[28]^[30]
Dexedrine	dextroamphetamine sulfate	1:0	capsule	^[28]^[30]
ProCentra	dextroamphetamine sulfate	1:0	liquid	^[30]
Vyvanse	lisdexamfetamine dimesylate	1:0	capsule	^[28]^[196]
Zenzedi	dextroamphetamine sulfate	1:0	tablet	^[30]


The skeletal structure of lisdexamfetamine

Notes

International Nonproprietary Name [INN]), β-phenylisopropylamine, desoxynorephedrine, and speed.^[15]^[16]^[17]

INN) and D-amph or dexamfetamine (INN) respectively.^[15]

^
brand name as opposed to a nonproprietary name; because the latter ("dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine sulfate, and amphetamine aspartate"^[30]
) is excessively long, this article exclusively refers to this amphetamine mixture by the brand name.

^ 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.

^ 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.

^ Cochrane Collaboration reviews are high quality meta-analytic systematic reviews of randomized controlled trials.^[51]

^ The statements supported by the USFDA come from prescribing information, which is the copyrighted intellectual property of the manufacturer and approved by the USFDA.

^ In individuals who experience sub-normal height and weight gains, a rebound to normal levels is expected to occur if stimulant therapy is briefly interrupted.^[45]^[46]^[69] The average reduction in final adult height from continuous stimulant therapy over a 3 year period is 2 cm.^[69]

^ Transcription factors are proteins that increase or decrease the expression of specific genes.^[95]

^ In simpler terms, this necessary and sufficient relationship means that ΔFosB overexpression in the nucleus accumbens and addiction-related behavioral and neural adaptations always simultaneously occur together and never occur alone.

^ During short-term treatment, fluoxetine may decrease drug craving.^[99]

^ During "medium-term treatment," imipramine may extend the duration of adherence to addiction treatment.^[99]

^ The review indicated that magnesium L-aspartate and magnesium chloride produce significant changes in addictive behavior;^[77] other forms of magnesium were not mentioned.

^ 4-Hydroxyamphetamine has been shown to be metabolized into 4-hydroxynorephedrine by dopamine beta-hydroxylase (DBH) in vitro and it is presumed to be metabolized similarly in vivo.^[145]^[146] Evidence from studies that measured the effect of serum DBH concentrations on 4-hydroxyamphetamine metabolism in humans suggests that a different enzyme may mediate the conversion of 4-hydroxyamphetamine to 4-hydroxynorephedrine;^[146]^[8] however, other evidence from animal studies suggests that this reaction is catalyzed by DBH in synaptic vesicles within noradrenergic neurons in the brain.^[148]^[149]

^ Enantiomers are molecules that are mirror images of one another; they are structurally identical, but of the opposite orientation.^[18]

Image legend

G proteins & linked receptors
(Text color) Transcription factors

Reference notes

^ ^[19]^[20]^[21]^[22]^[23]^[24]^[25]^[26]^[27]^[28]^[29]

^ ^[5]^[24]^[25]^[26]^[28]^[29]^[31]^[32]

^ ^[23]^[25]^[33]^[34]^[35]^[36]

^ ^[37]^[38]

^ ^[70]^[71]^[72]^[73]

^ ^[26]^[32]^[36]^[74]

^ ^a ^b ^[111]^[115]^[119]^[120]^[121]^[122]

^ ^[31]^[111]^[119]^[123]

^ ^[4]^[6]^[7]^[8]^[9]^[10]^[11]^[12]

^ ^[4]^[145]^[7]^[9]^[10]^[141]^[146]^[147]

^ ^[24]^[170]^[171]^[172]

References

FDA
. Retrieved 22 October 2023.

^ ^a ^b "Pharmacology". Dextroamphetamine. University of Alberta. 8 February 2013. Retrieved 5 November 2013. {{cite encyclopedia}}: |work= ignored (help)

^ ^a ^b "Pharmacology". Amphetamine. University of Alberta. 8 February 2013. Retrieved 5 November 2013. {{cite encyclopedia}}: |work= ignored (help)

^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ ^o ^p ^q ^r ^s ^t ^u "Adderall XR Prescribing Information" (PDF). United States Food and Drug Administration. Shire US Inc. December 2013. pp. 12–13. Retrieved 30 December 2013. Cite error: The named reference "FDA Pharmacokinetics" was defined multiple times with different content (see the help page).

^ ^a ^b ^c ^d "Adderall IR Prescribing Information" (PDF). United States Food and Drug Administration. Barr Laboratories, Inc. March 2007. pp. 4–5. Retrieved 2 November 2013.

^
ISBN 9781609133450. Alternatively, direct oxidation of amphetamine by DA β-hydroxylase can afford norephedrine.{{cite book}}: CS1 maint: multiple names: authors list (link
)

^
PMID 4809526. Retrieved 6 November 2014. Dopamine-β-hydroxylase catalyzed the removal of the pro-R hydrogen atom and the production of 1-norephedrine, (2S,1R)-2-amino-1-hydroxyl-1-phenylpropane, from d-amphetamine. Cite error: The named reference "DBH amph primary" was defined multiple times with different content (see the help page
).

^
PMID 4713201. Subjects with exceptionally low levels of serum dopamine-β-hydroxylase activity showed normal cardiovascular function and normal β-hydroxylation of an administered synthetic substrate, hydroxyamphetamine.{{cite journal}}: CS1 maint: multiple names: authors list (link) Cite error: The named reference "DBH 4-HA primary" was defined multiple times with different content (see the help page
).

^
PMID 15922018. Cite error: The named reference "FMO" was defined multiple times with different content (see the help page
).

^
PMID 10027866.{{cite journal}}: CS1 maint: multiple names: authors list (link) Cite error: The named reference "FMO3-Primary" was defined multiple times with different content (see the help page
).

^ ^a ^b ^c "Substrate/Product". butyrate-CoA ligase. Technische Universität Braunschweig. Retrieved 7 May 2014. {{cite encyclopedia}}: |work= ignored (help)

^ ^a ^b ^c "Substrate/Product". glycine N-acyltransferase. Technische Universität Braunschweig. Retrieved 7 May 2014. {{cite encyclopedia}}: |work= ignored (help)

^ "Properties: Predicted – EP|Suite". Amphetamine. Retrieved 6 November 2013. {{cite encyclopedia}}: |work= ignored (help)

^ "Chemical and Physical Properties". Amphetamine. National Center for Biotechnology Information. Retrieved 5 November 2013. {{cite encyclopedia}}: |work= ignored (help)

^ ^a ^b ^c "Compound Summary". Amphetamine. National Center for Biotechnology Information. Retrieved 13 October 2013. {{cite encyclopedia}}: |work= ignored (help)

^ ^a ^b ^c ^d ^e ^f "Identification". Amphetamine. University of Alberta. 8 February 2013. Retrieved 13 October 2013. {{cite encyclopedia}}: |work= ignored (help)

^ Cite error: The named reference Acute amph toxicity was invoked but never defined (see the help page).

^
doi:10.1351/goldbook.E02069. Archived from the original
on 17 March 2013. Retrieved 14 March 2014. One of a pair of molecular entities which are mirror images of each other and non-superposable.

^ "Amphetamine". Medical Subject Headings. National Institutes of Health, National Library of Medicine. Retrieved 16 December 2013.

^ "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 different salts or esters of the same active substance should differ only with regard to the inactive moiety of the molecule. ... The latter are called modified INNs (INNMs).

ISBN 9789057020810
. Retrieved 1 December 2014. Amphetamine, in the singular form, properly applies to the racemate of 2-amino-1-phenylpropane. ... In its broadest context, however, the term can even embrace a large number of structurally and pharmacologically related substances.

^ ^a ^b "Convention on psychotropic substances". United Nations Treaty Collection. United Nations. Retrieved 11 November 2013.

^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l "Adderall XR Prescribing Information" (PDF). United States Food and Drug Administration. Shire US Inc. December 2013. p. 11. Retrieved 30 December 2013.

^
PMID 23668655
. Amphetamines and caffeine 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 effects
• 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

^
ISBN 9780071481274. Therapeutic (relatively low) doses of psychostimulants, such as methylphenidate and amphetamine, improve performance on working memory tasks both in in normal subjects and those with ADHD. Positron emission tomography (PET) demonstrates that methylphenidate decreases regional cerebral blood flow in the doroslateral prefrontal cortex and posterior parietal cortex while improving performance of a spacial working memory task. This suggests that cortical networks that normally process spatial working memory become more efficient in response to the drug. ... [It] is now believed that dopamine and norepinephrine, but not serotonin, produce the beneficial effects of stimulants on working memory. At abused (relatively high) doses, stimulants can interfere with working memory and cognitive control ... stimulants act not only on working memory function, but also on general levels of arousal and, within the nucleus accumbens, improve the saliency of tasks. Thus, stimulants improve performance on effortful but tedious tasks ... through indirect stimulation of dopamine and norepinephrine receptors.{{cite book}}: CS1 maint: multiple names: authors list (link
)

^
PMID 19727285
.

^
PMID 18174822. Stimulant misuse appears to occur both for performance enhancement and their euphorogenic effects, the latter being related to the intrinsic properties of the stimulants (e.g., IR versus ER profile) ...

Although useful in the treatment of ADHD, stimulants are controlled II substances with a history of preclinical and human studies showing potential abuse liability.{{cite journal}}: CS1 maint: multiple names: authors list (link
)

^
PMID 23539642.{{cite journal}}: CS1 maint: multiple names: authors list (link
)

^
PMID 16492800
.

^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ "National Drug Code Amphetamine Search Results". National Drug Code Directory. United States Food and Drug Administration. Archived from the original on 7 February 2014. Retrieved 16 December 2013. {{cite web}}: |archive-date= / |archive-url= timestamp mismatch; 16 December 2013 suggested (help)

^
PMID 21073468
.

^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ "Adderall XR Prescribing Information" (PDF). United States Food and Drug Administration. Shire US Inc. December 2013. pp. 4–8. Retrieved 30 December 2013.

^
PMID 19160215. A minority of individuals who use amphetamines develop full-blown psychosis requiring care at emergency departments or psychiatric hospitals. In such cases, symptoms of amphetamine psychosis commonly include paranoid and persecutory delusions as well as auditory and visual hallucinations in the presence of extreme agitation. More common (about 18%) is for frequent amphetamine users to report psychotic symptoms that are sub-clinical and that do not require high-intensity intervention ...
About 5–15% of the users who develop an amphetamine psychosis fail to recover completely (Hofmann 1983) ...
Findings from one trial indicate use of antipsychotic medications effectively resolves symptoms of acute amphetamine psychosis.{{cite journal}}: CS1 maint: multiple names: authors list (link
)

^ ^a ^b ^c Greydanus D. "Stimulant Misuse: Strategies to Manage a Growing Problem" (PDF). American College Health Association (Review Article). ACHA Professional Development Program. p. 20. Retrieved 2 November 2013.

^
ISBN 9783540686989
.

^
ISBN 9780071624428. {{cite book}}: External link in |sectionurl= (help); Unknown parameter |sectionurl= ignored (|section-url= suggested) (help)CS1 maint: multiple names: editors list (link
)

^ ^a ^b ^c ^d "Amphetamine". European Monitoring Centre for Drugs and Drug Addiction. Retrieved 19 October 2013.

^
PMID 19948186
. Fig. 2. Synthetic and metabolic pathways for endogenous and exogenously administered trace amines and sympathomimetic amines ...
Trace amines are metabolized in the mammalian body via monoamine oxidase (MAO; EC 1.4.3.4) (Berry, 2004) (Fig. 2) ... It deaminates primary and secondary amines that are free in the neuronal cytoplasm but not those bound in storage vesicles of the sympathetic neurone ...
Thus, MAO inhibitors potentiate the peripheral effects of indirectly acting sympathomimetic amines ... this potentiation occurs irrespective of whether the amine is a substrate for MAO. An α-methyl group on the side chain, as in amphetamine and ephedrine, renders the amine immune to deamination so that they are not metabolized in the gut. Similarly, β-PEA would not be deaminated in the gut as it is a selective substrate for MAO-B which is not found in the gut ...
Brain levels of endogenous trace amines are several hundred-fold below those for the classical neurotransmitters noradrenaline, dopamine and serotonin but their rates of synthesis are equivalent to those of noradrenaline and dopamine and they have a very rapid turnover rate (Berry, 2004). Endogenous extracellular tissue levels of trace amines measured in the brain are in the low nanomolar range. These low concentrations arise because of their very short half-life ...

^
PMID 22392347.{{cite journal}}: CS1 maint: multiple names: authors list (link
)

PMID 18991959.{{cite journal}}: CS1 maint: multiple names: authors list (link
)

^
PMID 23247506.{{cite journal}}: CS1 maint: multiple names: authors list (link
)

^
PMID 24107764.{{cite journal}}: CS1 maint: multiple names: authors list (link
)

^
PMID 22118249
. Basal ganglia regions like the right globus pallidus, the right putamen, and the nucleus caudatus are structurally affected in children with ADHD. These changes and alterations in limbic regions like ACC and amygdala are more pronounced in non-treated populations and seem to diminish over time from child to adulthood. Treatment seems to have positive effects on brain structure.

^
ISBN 9781441913968
.

^
PMID 21699268
.

^
ISBN 9781441913968
.

^
ISBN 9780071481274.{{cite book}}: CS1 maint: multiple names: authors list (link
)

^
PMID 21596055.{{cite journal}}: CS1 maint: multiple names: authors list (link
)

^ ^a ^b "Stimulants for Attention Deficit Hyperactivity Disorder". WebMD. Healthwise. 12 April 2010. Retrieved 12 November 2013.

PMID 11833633.{{cite journal}}: CS1 maint: multiple names: authors list (link
)

PMID 16052183.{{cite journal}}: CS1 maint: multiple names: authors list (link
)

PMID 21678370.{{cite journal}}: CS1 maint: multiple names: authors list (link
)

PMID 21491404
.

PMID 17253474.{{cite journal}}: CS1 maint: multiple names: authors list (link
)

PMID 17054192.{{cite journal}}: CS1 maint: multiple names: authors list (link
)

PMID 21386667.{{cite journal}}: CS1 maint: multiple names: authors list (link
)

PMID 11337538.{{cite journal}}: CS1 maint: multiple names: authors list (link
)

^
PMID 24344115.{{cite journal}}: CS1 maint: multiple names: authors list (link
)

ISBN 9780071481274. Dopamine acts in the nucleus accumbens to attach motivational significance to stimuli associated with reward.{{cite book}}: CS1 maint: multiple names: authors list (link
)

^ Twohey M (26 March 2006). "Pills become an addictive study aid". JS Online. Archived from the original on 15 August 2007. Retrieved 2 December 2007.

PMID 16999660.{{cite journal}}: CS1 maint: multiple names: authors list (link
)

^ Bracken NM (January 2012). "National Study of Substance Use Trends Among NCAA College Student-Athletes" (PDF). NCAA Publications. National Collegiate Athletic Association. Retrieved 8 October 2013.

PMID 18500382
.

^
PMID 21658550
.

^
PMID 23456493.{{cite journal}}: CS1 maint: multiple names: authors list (link
)

PMID 24198770. The neurotransmitter dopamine is released from projections originating in the midbrain. Manipulations of dopaminergic signaling profoundly influence interval timing, leading to the hypothesis that dopamine influences internal pacemaker, or "clock," activity (Maricq and Church, 1983; Buhusi and Meck, 2005, 2009; Lake and Meck, 2013). For instance, amphetamine, which increases concentrations of dopamine at the synaptic cleft (Maricq and Church, 1983; Zetterström et al., 1983) advances the start of responding during interval timing (Taylor et al., 2007), whereas antagonists of D2 type dopamine receptors typically slow timing (Drew et al., 2003; Lake and Meck, 2013). ... Depletion of dopamine in healthy volunteers impairs timing (Coull et al., 2012), while amphetamine releases synaptic dopamine and speeds up timing (Taylor et al., 2007).{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link
)

^ ^a ^b ^c ^d ^e ^f ^g "Adderall XR Prescribing Information" (PDF). United States Food and Drug Administration. Shire US Inc. December 2013. pp. 4–6. Retrieved 30 December 2013.

^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ Heedes G; Ailakis J. "Amphetamine (PIM 934)". INCHEM. International Programme on Chemical Safety. Retrieved 24 June 2014.{{cite web}}: CS1 maint: multiple names: authors list (link)

^
PMID 18295156
.

^ "FDA Drug Safety Communication: Safety Review Update of Medications used to treat Attention-Deficit/Hyperactivity Disorder (ADHD) in children and young adults". United States Food and Drug Administration. 20 December 2011. Retrieved 4 November 2013.

PMID 22043968.{{cite journal}}: CS1 maint: multiple names: authors list (link
)

^ "FDA Drug Safety Communication: Safety Review Update of Medications used to treat Attention-Deficit/Hyperactivity Disorder (ADHD) in adults". United States Food and Drug Administration. 15 December 2011. Retrieved 4 November 2013.

PMID 22161946.{{cite journal}}: CS1 maint: multiple names: authors list (link
)

^ O'Connor PG (February 2012). "Amphetamines". Merck Manual for Health Care Professionals. Merck. Retrieved 8 May 2012.

PMID 23757186. Amphetamine, dextroamphetamine, and methylphenidate act as substrates for the cellular monoamine transporter, especially the dopamine transporter (DAT) and less so the norepinephrine (NET) and serotonin transporter. The mechanism of toxicity is primarily related to excessive extracellular dopamine, norepinephrine, and serotonin.{{cite journal}}: CS1 maint: multiple names: authors list (link
)

^ ^a ^b ^c Kanehisa Laboratories (10 October 2014). "Amphetamine – Homo sapiens (human)". KEGG Pathway. Retrieved 31 October 2014. Most addictive drugs increase extracellular concentrations of dopamine (DA) in nucleus accumbens (NAc) and medial prefrontal cortex (mPFC), projection areas of mesocorticolimbic DA neurons and key components of the "brain reward circuit". Amphetamine achieves this elevation in extracellular levels of DA by promoting efflux from synaptic terminals. ... Chronic exposure to amphetamine induces a unique transcription factor delta FosB, which plays an essential role in long-term adaptive changes in the brain.

^
PMID 18557129
.

^
PMID 24459410. DESPITE THE IMPORTANCE OF NUMEROUS PSYCHOSOCIAL FACTORS, AT ITS CORE, DRUG ADDICTION INVOLVES A BIOLOGICAL PROCESS: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. ... A large body of literature has demonstrated that such ΔFosB induction in D1-type NAc neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement Cite error: The named reference "Cellular basis" was defined multiple times with different content (see the help page
).

^
PMID 21989194. ΔFosB serves as one of the master control proteins governing this structural plasticity. ... ΔFosB also represses G9a expression, leading to reduced repressive histone methylation at the cdk5 gene. The net result is gene activation and increased CDK5 expression. ... In contrast, ΔFosB binds to the c-fos gene and recruits several co-repressors, including HDAC1 (histone deacetylase 1) and SIRT 1 (sirtuin 1). ... The net result is c-fos gene repression.
Figure 4: Epigenetic basis of drug regulation of gene expression

^
PMID 21459101
. Similar to environmental enrichment, studies have found that exercise reduces self-administration and relapse to drugs of abuse (Cosgrove et al., 2002; Zlebnik et al., 2010). There is also some evidence that these preclinical findings translate to human populations, as exercise reduces withdrawal symptoms and relapse in abstinent smokers (Daniel et al., 2006; Prochaska et al., 2008), and one drug recovery program has seen success in participants that train for and compete in a marathon as part of the program (Butler, 2005). ... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some patients taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al., 2006; Aiken, 2007; Lader, 2008).

^
PMID 25083822
.
ΔFosB as a therapeutic biomarker
The strong correlation between chronic drug exposure and ΔFosB provides novel opportunities for targeted therapies in addiction (118), and suggests methods to analyze their efficacy (119). Over the past two decades, research has progressed from identifying ΔFosB induction to investigating its subsequent action (38). It is likely that ΔFosB research will now progress into a new era – the use of ΔFosB as a biomarker. If ΔFosB detection is indicative of chronic drug exposure (and is at least partly responsible for dependence of the substance), then its monitoring for therapeutic efficacy in interventional studies is a suitable biomarker (Figure 2). Examples of therapeutic avenues are discussed herein. ...

Conclusions
ΔFosB is an essential transcription factor implicated in the molecular and behavioral pathways of addiction following repeated drug exposure. The formation of ΔFosB in multiple brain regions, and the molecular pathway leading to the formation of AP-1 complexes is well understood. The establishment of a functional purpose for ΔFosB has allowed further determination as to some of the key aspects of its molecular cascades, involving effectors such as GluR2 (87,88), Cdk5 (93) and NFkB (100). Moreover, many of these molecular changes identified are now directly linked to the structural, physiological and behavioral changes observed following chronic drug exposure (60,95,97,102). New frontiers of research investigating the molecular roles of ΔFosB have been opened by epigenetic studies, and recent advances have illustrated the role of ΔFosB acting on DNA and histones, truly as a molecular switch (34). As a consequence of our improved understanding of ΔFosB in addiction, it is possible to evaluate the addictive potential of current medications (119), as well as use it as a biomarker for assessing the efficacy of therapeutic interventions (121,122,124). Some of these proposed interventions have limitations (125) or are in their infancy (75). However, it is hoped that some of these preliminary findings may lead to innovative treatments, which are much needed in addiction.

^
PMID 23806439. these data show that exercise can affect dopaminergic signaling at many different levels, which may underlie its ability to modify vulnerability during drug use initiation. Exercise also produces neuroadaptations that may influence an individual's vulnerability to initiate drug use. Consistent with this idea, chronic moderate levels of forced treadmill running blocks not only subsequent methamphetamine-induced conditioned place preference, but also stimulant-induced increases in dopamine release in the NAc (Chen et al., 2008) and striatum (Marques et al., 2008). ... [These] findings indicate the efficacy of exercise at reducing drug intake in drug-dependent individuals ... wheel running [reduces] methamphetamine self-administration under extended access conditions (Engelmann et al., 2013) ... These findings suggest that exercise may "magnitude"-dependently prevent the development of an addicted phenotype possibly by blocking/reversing behavioral and neuro-adaptive changes that develop during and following extended access to the drug. ... Exercise has been proposed as a treatment for drug addiction that may reduce drug craving and risk of relapse. Although few clinical studies have investigated the efficacy of exercise for preventing relapse, the few studies that have been conducted generally report a reduction in drug craving and better treatment outcomes (see Table 4). ... Taken together, these data suggest that the potential benefits of exercise during relapse, particularly for relapse to psychostimulants, may be mediated via chromatin remodeling and possibly lead to greater treatment outcomes.{{cite journal}}: CS1 maint: multiple names: authors list (link
)

^
ISBN 9780071481274. Currently, cognitive–behavioral therapies are the most successful treatment available for preventing the relapse of psychostimulant use.{{cite book}}: CS1 maint: multiple names: authors list (link
)

ISBN 978-0-07-148127-4
.

PMID 26816013
. Substance-use disorder: A diagnostic term in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) referring to recurrent use of alcohol or other drugs that causes clinically and functionally significant impairment, such as health problems, disability, and failure to meet major responsibilities at work, school, or home. Depending on the level of severity, this disorder is classified as mild, moderate, or severe.
Addiction: A term used to indicate the most severe, chronic stage of substance-use disorder, in which there is a substantial loss of self-control, as indicated by compulsive drug taking despite the desire to stop taking the drug. In the DSM-5, the term addiction is synonymous with the classification of severe substance-use disorder.

^
PMID 19877494. [Psychostimulants] increase cAMP levels in striatum, which activates protein kinase A (PKA) and leads to phosphorylation of its targets. This includes the cAMP response element binding protein (CREB), the phosphorylation of which induces its association with the histone acetyltransferase, CREB binding protein (CBP) to acetylate histones and facilitate gene activation. This is known to occur on many genes including fosB and c-fos in response to psychostimulant exposure. ΔFosB is also upregulated by chronic psychostimulant treatments, and is known to activate certain genes (eg, cdk5) and repress others (eg, c-fos) where it recruits HDAC1 as a corepressor. ... Chronic exposure to psychostimulants increases glutamatergic [signaling] from the prefrontal cortex to the NAc. Glutamatergic signaling elevates Ca2+ levels in NAc postsynaptic elements where it activates CaMK (calcium/calmodulin protein kinases) signaling, which, in addition to phosphorylating CREB, also phosphorylates HDAC5.
Figure 2: Psychostimulant-induced signaling events

PMID 22200950
. Coincident and convergent input often induces plasticity on a postsynaptic neuron. The NAc integrates processed information about the environment from basolateral amygdala, hippocampus, and prefrontal cortex (PFC), as well as projections from midbrain dopamine neurons. Previous studies have demonstrated how dopamine modulates this integrative process. For example, high frequency stimulation potentiates hippocampal inputs to the NAc while simultaneously depressing PFC synapses (Goto and Grace, 2005). The converse was also shown to be true; stimulation at PFC potentiates PFC–NAc synapses but depresses hippocampal–NAc synapses. In light of the new functional evidence of midbrain dopamine/glutamate co-transmission (references above), new experiments of NAc function will have to test whether midbrain glutamatergic inputs bias or filter either limbic or cortical inputs to guide goal-directed behavior.

^
PMID 23430970
. The 35-37 kD ΔFosB isoforms accumulate with chronic drug exposure due to their extraordinarily long half-lives. ... As a result of its stability, the ΔFosB protein persists in neurons for at least several weeks after cessation of drug exposure. ... ΔFosB overexpression in nucleus accumbens induces NFκB ... In contrast, the ability of ΔFosB to repress the c-Fos gene occurs in concert with the recruitment of a histone deacetylase and presumably several other repressive proteins such as a repressive histone methyltransferase

PMID 18640924
. Recent evidence has shown that ΔFosB also represses the c-fos gene that helps create the molecular switch—from the induction of several short-lived Fos family proteins after acute drug exposure to the predominant accumulation of ΔFosB after chronic drug exposure

^ "Amphetamines: Drug Use and Abuse". Merck Manual Home Edition. Merck. February 2003. Archived from the original on 17 February 2007. Retrieved 28 February 2007.

PMID 23996457.{{cite journal}}: CS1 maint: multiple names: authors list (link
)

PMID 16776597.{{cite journal}}: CS1 maint: multiple names: authors list (link
)

^
PMID 21989194
. ΔFosB has been linked directly to several addiction-related behaviors ... Importantly, genetic or viral overexpression of ΔJunD, a dominant negative mutant of JunD which antagonizes ΔFosB- and other AP-1-mediated transcriptional activity, in the NAc or OFC blocks these key effects of drug exposure^14,22–24. This indicates that ΔFosB is both necessary and sufficient for many of the changes wrought in the brain by chronic drug exposure. ΔFosB is also induced in D1-type NAc MSNs by chronic consumption of several natural rewards, including sucrose, high fat food, sex, wheel running, where it promotes that consumption^14,26–30. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states.

^
PMID 23085425
.

ISBN 9780071481274. All living cells depend on the regulation of gene expression by extracellular signals for their development, homeostasis, and adaptation to the environment. Indeed, many signal transduction pathways function primarily to modify transcription factors that alter the expression of specific genes. Thus, neurotransmitters, growth factors, and drugs change patterns of gene expression in cells and in turn affect many aspects of nervous system functioning, including the formation of long-term memories. Many drugs that require prolonged administration, such as antidepressants and antipsychotics, trigger changes in gene expression that are thought to be therapeutic adaptations to the initial action of the drug.{{cite book}}: CS1 maint: multiple names: authors list (link
)

^ Kanehisa Laboratories (29 October 2014). "Alcoholism – Homo sapiens (human)". KEGG Pathway. Retrieved 31 October 2014.

^
PMID 22641964. It has been found that deltaFosB gene in the NAc is critical for reinforcing effects of sexual reward. Pitchers and colleagues (2010) reported that sexual experience was shown to cause DeltaFosB accumulation in several limbic brain regions including the NAc, medial pre-frontal cortex, VTA, caudate, and putamen, but not the medial preoptic nucleus. ... these findings support a critical role for DeltaFosB expression in the NAc in the reinforcing effects of sexual behavior and sexual experience-induced facilitation of sexual performance. ... both drug addiction and sexual addiction represent pathological forms of neuroplasticity along with the emergence of aberrant behaviors involving a cascade of neurochemical changes mainly in the brain's rewarding circuitry.{{cite journal}}: CS1 maint: multiple names: authors list (link
)

^
PMID 23426671. Drugs of abuse induce neuroplasticity in the natural reward pathway, specifically the nucleus accumbens (NAc), thereby causing development and expression of addictive behavior. ... Together, these findings demonstrate that drugs of abuse and natural reward behaviors act on common molecular and cellular mechanisms of plasticity that control vulnerability to drug addiction, and that this increased vulnerability is mediated by ΔFosB and its downstream transcriptional targets. ... Sexual behavior is highly rewarding (Tenk et al., 2009), and sexual experience causes sensitized drug-related behaviors, including cross-sensitization to amphetamine (Amph)-induced locomotor activity (Bradley and Meisel, 2001; Pitchers et al., 2010a) and enhanced Amph reward (Pitchers et al., 2010a). Moreover, sexual experience induces neural plasticity in the NAc similar to that induced by psychostimulant exposure, including increased dendritic spine density (Meisel and Mullins, 2006; Pitchers et al., 2010a), altered glutamate receptor trafficking, and decreased synaptic strength in prefrontal cortex-responding NAc shell neurons (Pitchers et al., 2012). Finally, periods of abstinence from sexual experience were found to be critical for enhanced Amph reward, NAc spinogenesis (Pitchers et al., 2010a), and glutamate receptor trafficking (Pitchers et al., 2012). These findings suggest that natural and drug reward experiences share common mechanisms of neural plasticity{{cite journal}}: CS1 maint: multiple names: authors list (link
)

^
PMID 11687171. Although there are a variety of amphetamines and amphetamine derivatives, the word "amphetamines" in this review stands for amphetamine, dextroamphetamine and methamphetamine only.{{cite journal}}: CS1 maint: multiple names: authors list (link
)

^
PMID 19370579. The prevalence of this withdrawal syndrome is extremely common (Cantwell 1998; Gossop 1982) with 87.6% of 647 individuals with amphetamine dependence reporting six or more signs of amphetamine withdrawal listed in the DSM when the drug is not available (Schuckit 1999) ... The severity of withdrawal symptoms is greater in amphetamine dependent individuals who are older and who have more extensive amphetamine use disorders (McGregor 2005). Withdrawal symptoms typically present within 24 hours of the last use of amphetamine, with a withdrawal syndrome involving two general phases that can last 3 weeks or more. The first phase of this syndrome is the initial "crash" that resolves within about a week (Gossop 1982;McGregor 2005) ...{{cite journal}}: CS1 maint: multiple names: authors list (link
)

^ "Adderall IR Prescribing Information" (PDF). United States Food and Drug Administration. Barr Laboratories, Inc. March 2007. Retrieved 4 November 2013.

^ "Dexedrine Medication Guide" (PDF). United States Food and Drug Administration. Amedra Pharmaceuticals LLC. May 2013. Retrieved 4 November 2013.

^ "Adderall XR Prescribing Information" (PDF). United States Food and Drug Administration. Shire US Inc. December 2013. Retrieved 30 December 2013.

PMID 17606768
.

^ "Amphetamine". Hazardous Substances Data Bank. National Library of Medicine. Retrieved 26 February 2014. Direct toxic damage to vessels seems unlikely because of the dilution that occurs before the drug reaches the cerebral circulation.

ISBN 9780071481274. Unlike cocaine and amphetamine, methamphetamine is directly toxic to midbrain dopamine neurons.{{cite book}}: CS1 maint: multiple names: authors list (link
)

PMID 12835101
.

PMID 18596830
.

ISBN 9780195030570
.

^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j "Adderall XR Prescribing Information" (PDF). United States Food and Drug Administration. Shire US Inc. December 2013. pp. 8–10. Retrieved 30 December 2013.

^
PMID 21272013
. VMAT2 is the CNS vesicular transporter for not only the biogenic amines DA, NE, EPI, 5-HT, and HIS, but likely also for the trace amines TYR, PEA, and thyronamine (THYR) ... [Trace aminergic] neurons in mammalian CNS would be identiﬁable as neurons expressing VMAT2 for storage, and the biosynthetic enzyme aromatic amino acid decarboxylase (AADC).

^ Cite error: The named reference Amphetamine VMAT2 pH gradient was invoked but never defined (see the help page).

^
PMID 21772817. inhibition of firing due to increased release of dopamine; (b) reduction of D2 and GABAB receptor-mediated inhibitory responses (excitatory effects due to disinhibition); and (c) a direct TA1 receptor-mediated activation of GIRK channels which produce cell membrane hyperpolarization.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link
)

^ ^a ^b mct (28 January 2012). "TAAR1". GenAtlas. University of Paris. Retrieved 29 May 2014.
• tonically activates inwardly rectifying K(+) channels, which reduces the basal firing frequency of dopamine (DA) neurons of the ventral tegmental area (VTA)

^
PMID 25033183. AMPH also increases intracellular calcium (Gnegy et al., 2004) that is associated with calmodulin/CamKII activation (Wei et al., 2007) and modulation and trafficking of the DAT (Fog et al., 2006; Sakrikar et al., 2012).{{cite journal}}: CS1 maint: multiple names: authors list (link
)

^
PMID 23968642
. AMPH and METH also stimulate DA efflux, which is thought to be a crucial element in their addictive properties [80], although the mechanisms do not appear to be identical for each drug [81]. These processes are PKCβ– and CaMK–dependent [72, 82], and PKCβ knock-out mice display decreased AMPH-induced efflux that correlates with reduced AMPH-induced locomotion [72].

^ ^a ^b Maguire JJ, Davenport AP (2 December 2014). "TA₁ receptor". IUPHAR database. International Union of Basic and Clinical Pharmacology. Retrieved 8 December 2014. Comments: Tyramine causes an increase in intracellular cAMP in HEK293 or COS-7 cells expressing the TA1 receptor in vitro [4,6,18]. In addition, coupling to a promiscuous Gαq has been observed, resulting in increased intracellular calcium concentration [24].

PMID 11459929.{{cite journal}}: CS1 maint: multiple names: authors list (link
)

^ ^a ^b "SLC1A1 solute carrier family 1 (neuronal/epithelial high affinity glutamate transporter, system Xag), member 1 [ Homo sapiens (human) ]". NCBI Gene. National Center for Biotechnology Information. Retrieved 11 November 2014. Amphetamine modulates excitatory neurotransmission through endocytosis of the glutamate transporter EAAT3 in dopamine neurons. ... internalization of EAAT3 triggered by amphetamine increases glutamatergic signaling and thus contributes to the effects of amphetamine on neurotransmission.

PMID 20402963.{{cite journal}}: CS1 maint: multiple names: authors list (link
)

PMID 15316089
.

PMID 13677912.{{cite journal}}: CS1 maint: multiple names: authors list (link
)

^
PMID 16840648
. The physiological importance of CART was further substantiated in numerous human studies demonstrating a role of CART in both feeding and psychostimulant addiction. ... Colocalization studies also support a role for CART in the actions of psychostimulants. ... CART and DA receptor transcripts colocalize (Beaudry et al., 2004). Second, dopaminergic nerve terminals in the NAc synapse on CART-containing neurons (Koylu et al., 1999), hence providing the proximity required for neurotransmitter signaling. These studies suggest that DA plays a role in regulating CART gene expression possibly via the activation of CREB. Indeed, CART gene expression is regulated via cAMP signaling and pCREB in vivo as centrally administered forskolin activated cAMP, phosphorylated CREB, and increased CART mRNA and peptide levels (Jones and Kuhar, 2006).

PMID 22077697. Numerous studies have established the role of CART in food intake, maintenance of bodyweight, stress control, reward and pain transmission. Recently, it was demonstrated that CART, as a neurotrophic peptide, had a cerebroprotective against focal ischaemic stroke and inhibited the neurotoxicity of β-amyloid protein, which focused attention on the role of CART in the central nervous system (CNS) and neurological diseases. 3. In fact, little is known about the way in which CART peptide interacts with its receptors, initiates downstream cascades and finally exerts its neuroprotective effect under normal or pathological conditions. The literature indicates that there are many factors, such as regulation of the immunological system and protection against energy failure, that may be involved in the cerebroprotection afforded by CART{{cite journal}}: CS1 maint: multiple names: authors list (link
)

^ "Biomolecular Interactions and Pathways". Amphetamine. National Center for Biotechnology Information. Retrieved 13 October 2013. {{cite encyclopedia}}: |work= ignored (help)

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PMID 20943895
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^
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^ ^a ^b ^c ^d "Biomedical Effects and Toxicity". Amphetamine. National Center for Biotechnology Information. Retrieved 12 October 2013. {{cite encyclopedia}}: |work= ignored (help)

^ "Biological Half-Life". AMPHETAMINE. Hazardous Substances Data Bank. Retrieved 5 January 2014. Concentrations of (14)C-amphetamine declined less rapidly in the plasma of human subjects maintained on an alkaline diet (urinary pH > 7.5) than those on an acid diet (urinary pH < 6). Plasma half-lives of amphetamine ranged between 16-31 hr & 8-11 hr, respectively, & the excretion of (14)C in 24 hr urine was 45 & 70%. {{cite encyclopedia}}: |work= ignored (help)

^ Richard RA (1999). "Route of Administration". Chapter 5—Medical Aspects of Stimulant Use Disorders. Treatment Improvement Protocol 33. Substance Abuse and Mental Health Services Administration. {{cite encyclopedia}}: |work= ignored (help)

^ ^a ^b ^c "Vyvanse Prescribing Information" (PDF). United States Food and Drug Administration. Shire US Inc. December 2013. pp. 12–13. Retrieved 25 February 2013.

^
PMID 12191709.{{cite journal}}: CS1 maint: multiple names: authors list (link) Cite error: The named reference "Metabolites" was defined multiple times with different content (see the help page
).

^ "Compound Summary". p-Hydroxyamphetamine. National Center for Biotechnology Information. Retrieved 15 October 2013. {{cite encyclopedia}}: |work= ignored (help)

^ "Compound Summary". p-Hydroxynorephedrine. National Center for Biotechnology Information. Retrieved 15 October 2013. {{cite encyclopedia}}: |work= ignored (help)

^ "Compound Summary". Phenylpropanolamine. National Center for Biotechnology Information. Retrieved 15 October 2013. {{cite encyclopedia}}: |work= ignored (help)

^
ISBN 9781609133450
. The simplest unsubstituted phenylisopropylamine, 1-phenyl-2-aminopropane, or amphetamine, serves as a common structural template for hallucinogens and psychostimulants. Amphetamine produces central stimulant, anorectic, and sympathomimetic actions, and it is the prototype member of this class (39). ... The phase 1 metabolism of amphetamine analogs is catalyzed by two systems: cytochrome P450 and flavin monooxygenase. ... Amphetamine can also undergo aromatic hydroxylation to p-hydroxyamphetamine. ... Subsequent oxidation at the benzylic position by DA β-hydroxylase affords p-hydroxynorephedrine. Alternatively, direct oxidation of amphetamine by DA β-hydroxylase can afford norephedrine.

^
PMID 13977820
. Hydroxyamphetamine was administered orally to five human subjects ... Since conversion of hydroxyamphetamine to hydroxynorephedrine occurs in vitro by the action of dopamine-β-oxidase, a simple method is suggested for measuring the activity of this enzyme and the effect of its inhibitors in man. ... The lack of effect of administration of neomycin to one patient indicates that the hydroxylation occurs in body tissues. ... a major portion of the β-hydroxylation of hydroxyamphetamine occurs in non-adrenal tissue. Unfortunately, at the present time one cannot be completely certain that the hydroxylation of hydroxyamphetamine in vivo is accomplished by the same enzyme which converts dopamine to noradrenaline.

S2CID 23738007
. Figure 1. Glycine conjugation of benzoic acid. The glycine conjugation pathway consists of two steps. First benzoate is ligated to CoASH to form the high-energy benzoyl-CoA thioester. This reaction is catalyzed by the HXM-A and HXM-B medium-chain acid:CoA ligases and requires energy in the form of ATP. ... The benzoyl-CoA is then conjugated to glycine by GLYAT to form hippuric acid, releasing CoASH. In addition to the factors listed in the boxes, the levels of ATP, CoASH, and glycine may influence the overall rate of the glycine conjugation pathway.

PMID 4457764
. In species where aromatic hydroxylation of amphetamine is the major metabolic pathway, p-hydroxyamphetamine (POH) and p-hydroxynorephedrine (PHN) may contribute to the pharmacological profile of the parent drug. ... The location of the p-hydroxylation and β-hydroxylation reactions is important in species where aromatic hydroxylation of amphetamine is the predominant pathway of metabolism. Following systemic administration of amphetamine to rats, POH has been found in urine and in plasma.
The observed lack of a significant accumulation of PHN in brain following the intraventricular administration of (+)-amphetamine and the formation of appreciable amounts of PHN from (+)-POH in brain tissue in vivo supports the view that the aromatic hydroxylation of amphetamine following its systemic administration occurs predominantly in the periphery, and that POH is then transported through the blood-brain barrier, taken up by noradrenergic neurones in brain where (+)-POH is converted in the storage vesicles by dopamine β-hydroxylase to PHN.

PMID 2600821
. The metabolism of p-OHA to p-OHNor is well documented and dopamine-β hydroxylase present in noradrenergic neurons could easily convert p-OHA to p-OHNor after intraventricular administration.

^
PMID 15860375
. In addition to the main metabolic pathway, TAs can also be converted by nonspecific N-methyltransferase (NMT) [22] and phenylethanolamine N-methyltransferase (PNMT) [23] to the corresponding secondary amines (e.g. synephrine [14], N-methylphenylethylamine and N-methyltyramine [15]), which display similar activities on TAAR1 (TA1) as their primary amine precursors.

^ "Chemical and Physical Properties". Amphetamine. National Center for Biotechnology Information. Retrieved 13 October 2013. {{cite encyclopedia}}: |work= ignored (help)

^ Amphetamine Hydrochloride. National Center for Biotechnology Information. Retrieved 8 November 2013. {{cite encyclopedia}}: |work= ignored (help)

^ Amphetamine Phosphate. National Center for Biotechnology Information. Retrieved 8 November 2013. {{cite encyclopedia}}: |work= ignored (help)

doi:10.1016/S0040-4039(00)88151-4
.

^ ^a ^b "Compound Summary". Amphetamine. University of Alberta. 8 February 2013. Retrieved 30 September 2013. {{cite encyclopedia}}: |work= ignored (help)

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PMID 20849327.{{cite journal}}: CS1 maint: multiple names: authors list (link
)

^ "Amphetamine, Methamphetamine, & Cystal Meth". Addiction Prevention Centre. Retrieved 10 October 2013.

^ ^a ^b ^c ^d "Historical overview of methamphetamine". Vermont Department of Health. Government of Vermont. Retrieved 29 January 2012.

^
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.

^ ^a ^b Allen A, Ely R (2009). "Review: Synthetic Methods for Amphetamine" (PDF). Crime Scene. 37 (2). Northwest Association of Forensic Scientists: 15–25. Retrieved 6 December 2014.

PMID 20985610.{{cite journal}}: CS1 maint: multiple names: authors list (link
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PMID 18105933
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doi:10.1002/0471264180.or017.03. {{cite journal}}: Missing or empty |title= (help
)

^ US patent 2413493, Bitler WP, Flisik AC, Leonard N, "Synthesis of isomer-free benzyl methyl acetoacetic methyl ester", published 31 December 1946, assigned to Kay Fries Chemicals Inc

PMID 20486262.{{cite journal}}: CS1 maint: multiple names: authors list (link
)

^ ^a ^b ^c ^d "Recommended methods of the identification and analysis of amphetamine, methamphetamine, and their ring-substituted analogues in seized materials" (PDF). United Nations Office on Drugs and Crime. United Nations. 2006. pp. 9–12. Retrieved 14 October 2013.

doi:10.1021/jo01145a001
.

^ US patent 2276508, Nabenhauer FP, "Method for the separation of optically active alpha-methylphenethylamine", published 17 March 1942, assigned to Smith Kline French

^
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PMID 9700558
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PMID 17468860
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PMID 8075776
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^ ^a ^b "Clinical Drug Testing in Primary Care" (PDF). Substance Abuse and Mental Health Services Administration. Technical Assistance Publication Series 32. United States Department of Health and Human Services. 2012. Retrieved 31 October 2013.

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ISBN 9780962652387
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^ ^a ^b ^c ^d Mohan J, ed. (June 2014). "World Drug Report 2014" (PDF). United Nations Office on Drugs and Crime. pp. 3, 123–152. Retrieved 18 August 2014.

ISBN 9780203871171
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^ "Controlled Substances Act". United States Food and Drug Administration. 11 June 2009. Retrieved 4 November 2013.

^ Gyenis A. "Forty Years of On the Road 1957–1997". wordsareimportant.com. DHARMA beat. Archived from the original on 14 February 2008. Retrieved 18 March 2008.

^ Wilson A (2008). "Mixing the Medicine: The unintended consequence of amphetamine control on the Northern Soul Scene" (PDF). Internet Journal of Criminology. Retrieved 25 May 2013.

^ Hill J (4 June 2004). "Paul Erdos, Mathematical Genius, Human (In That Order)" (PDF). untruth.org. Retrieved 2 November 2013.

^
ISSN 2314-9086. Retrieved 18 August 2014. 1.2 million or 0.9% of young adults (15–34) used amphetamines in the last year {{cite journal}}: Cite journal requires |journal= (help
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ISBN 9789211482232
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^ "List of psychotropic substances under international control" (PDF). International Narcotics Control Board. United Nations. August 2003. Archived from the original (PDF) on 5 December 2005. Retrieved 19 November 2005.

^ Park Jin-seng (25 May 2012). "Moving to Korea brings medical, social changes". The Korean Times. Retrieved 14 November 2013.

^ "Importing or Bringing Medication into Japan for Personal Use". Japanese Ministry of Health, Labour and Welfare. 1 April 2004. Retrieved 3 November 2013.

^ "Controlled Drugs and Substances Act". Canadian Justice Laws Website. Government of Canada. 11 November 2013. Retrieved 11 November 2013.

^ "Table of controlled Narcotic Drugs under the Thai Narcotics Act" (PDF). Thailand Food and Drug Administration. 22 May 2013. Retrieved 11 November 2013.

^ "Class A, B and C drugs". Home Office, Government of the United Kingdom. Archived from the original on 4 August 2007. Retrieved 23 July 2007.

^ ^a ^b ^c "Identification". Lisdexamfetamine. University of Alberta. 8 February 2013. Retrieved 13 October 2013. {{cite encyclopedia}}: |work= ignored (help)

External links

Wikimedia Commons has media related to amphetamine.

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

v
t
e
Amphetamine
Main articles
and
pharmaceuticals
Amphetamine

Adzenys ER

Adzenys XR-ODT

Dyanavel XR

Evekeo

Evekeo ODT

Mixed amphetamine salts
Adderall

Adderall XR

Mydayis

Levoamphetamine
N/A
Dextroamphetamine

Dexedrine

ProCentra

Zenzedi

Lisdexamfetamine

Vyvanse

Neuropharmacology
Biomolecular targets

TAAR1 (full agonist)

CART (mRNATooltip messenger RNA inducer)

5-HT1A receptor (low affinity ligand)

MAO (weak competitive inhibitor)

hCA5B, hCA7, hCA12, hCA13, and hCA14 (enzyme activator
)

Inhibited transporters

DAT

NET

SERT

VMAT1

VMAT2

EAAT3

SLC22A3

SLC22A5

Active metabolites

4-Hydroxyamphetamine

4-Hydroxynorephedrine

Norephedrine

Related articles

ADHD

ADHD management

Amphetamine psychosis

Benzedrine in popular culture

Dopamine

Doping in sport

Executive functions

Formetorex

ΔFosB

History and culture of substituted amphetamines

Methamphetamine

Methylphenidate

N-Methylphenethylamine

Motivational salience
Incentive salience

Narcolepsy

Neurobiological effects of physical exercise § Attention deficit hyperactivity disorder

Nootropic

Norepinephrine

Obesity

Performance-enhancing substance

Phenethylamine

Phentermine

Phenylacetone

Recreational drug use

Serotonin

Substituted amphetamine

Trace amine

Category

v
t
e
Methamphetamine
Enantiomers

Dextromethamphetamine

Levomethamphetamine

Neuropharmacology
Biomolecular targets

TAAR1 (agonist)

σ1R (agonist)

σ2R (agonist)

α_2A adrenoceptor (agonist)

α_2B adrenoceptor (agonist)

α_2C adrenoceptor (agonist)

competitive inhibitor
)

Inhibited transporters

DAT

NET

SERT

VMAT1

VMAT2

EAAT1

EAAT2

SLC22A3

SLC22A5

Health

Amphetamine dependence

Meth mouth

History and culture

Amphetamine

Crystal Darkness

Crystal Meth Anonymous

Faces of Meth

History and culture of amphetamines

Montana Meth Project

No More Sunsets

Party and play

Rolling meth lab

Ya ba

Law

Legal status

Combat Methamphetamine Epidemic Act of 2005

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Illinois Methamphetamine Precursor Control Act

Ethnicity and nationality

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stimulants

Amphetamine (
Mixed amphetamine salts, Levoamphetamine, Dextroamphetamine, Lisdexamfetamine
)

Methamphetamine

Methylphenidate

Dexmethylphenidate

Serdexmethylphenidate (+dexmethylphenidate)

Non-classical
CNS
stimulants

Armodafinil

Atomoxetine

Modafinil

Viloxazine

α₂-adrenoceptor
agonists

Clonidine

Guanfacine

Antidepressants

Amitriptyline

Bupropion

Buspirone

Desipramine

Duloxetine

Imipramine

Milnacipran

Moclobemide

Nortriptyline

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Venlafaxine

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Amantadine

Carbamazepine

Related articles

Attention deficit hyperactivity disorder (ADHD)

Attention deficit hyperactivity disorder management

Hypokalemic sensory overstimulation

Monoamine releasing agent

Dopamine (DA)

Dopamine transporter (DAT)

Dopamine reuptake inhibitor (DRI)

Norepinephrine (NE)

Norepinephrine transporter (NET)

Norepinephrine reuptake inhibitor (NRI)

Serotonin (5-HT)

Serotonin transporter (SERT)

Selective serotonin reuptake inhibitor (SSRI)

Serotonin-norepinephrine reuptake inhibitor
(SNRI)

Norepinephrine-dopamine reuptake inhibitor
(NDRI)

Serotonin-norepinephrine-dopamine reuptake inhibitor
(SNDRI)

Template:Catecholaminergics

v
t
e
Phenethylamines
Phenethylamines

Psychedelics: 25B-NBOMe

25C-NBOMe

25D-NBOMe

25I-NBOMe

25N-NBOMe

2C-B

2C-B-AN

2C-Bn

2C-Bu

2C-C

2C-CN

2C-CP

2C-D

2C-E

2C-EF

2C-F

2C-G

2C-G-1

2C-G-2

2C-G-3

2C-G-4

2C-G-5

2C-G-6

2C-G-N

2C-H

2C-I

2C-iP

2C-N

2C-NH2

2C-O

2C-O-4

2C-P

2C-Ph

2C-SE

2C-T

2C-T-2

2C-T-3

2C-T-4

2C-T-5

2C-T-6

2C-T-7

2C-T-8

2C-T-9

2C-T-10

2C-T-11

2C-T-12

2C-T-13

2C-T-14

2C-T-15

2C-T-16

2C-T-17

2C-T-18

2C-T-19

2C-T-20

2C-T-21

2C-T-22

2C-T-22.5

2C-T-23

2C-T-24

2C-T-25

2C-T-27

2C-T-28

2C-T-30

2C-T-31

2C-T-32

2C-T-33

2C-TFE

2C-TFM

2C-YN

2C-V

Allylescaline

DESOXY

Escaline

Isoproscaline

Jimscaline

Macromerine

MEPEA

Mescaline

Metaescaline

Methallylescaline

Proscaline

Psi-2C-T-4

TCB-2

Stimulants: Phenylethanolamine

Hordenine

Phenethylamine

Phenpromethamine

α-Methylphenethylamine (amphetamine)

β-Methylphenethylamine

m-Methylphenethylamine

N-Methylphenethylamine

o-Methylphenethylamine

p-Methylphenethylamine

Methylphenidate

Entactogens: Lophophine

MDPEA

MDMPEA
Others: BOH

DMPEA

Amphetamines

Psychedelics: 3C-AL

3C-BZ

3C-E

3C-MAL

3C-P

Aleph

Beatrice

Bromo-DragonFLY

D-Deprenyl

DMA

DMCPA

DMMDA

DOB

DOC

DOEF

DOET

DOI

DOM

DON

DOPR

DOTFM

Ganesha

MMDA

MMDA-2

Psi-DOM

TMA

TeMA

ZDCM-04
Stimulants: 2-FA

2-FMA

3-FA

3-FMA

Acridorex

Alfetamine

Amfecloral

Amfepentorex

Amphetamine (Dextroamphetamine, Levoamphetamine)

Amphetaminil

Benfluorex

Benzphetamine

Cathine

Clobenzorex

Dimethylamphetamine

Ephedrine

Etilamfetamine

Fencamfamin

Fencamine

Fenethylline

Fenfluramine (Dexfenfluramine, Levofenfluramine)

Fenproporex

Flucetorex

Fludorex

Formetorex

Furfenorex

Gepefrine

4-Hydroxyamphetamine

Iofetamine

Isopropylamphetamine

Lefetamine

Lisdexamfetamine

Mefenorex

Metaraminol

Methamphetamine (Dextromethamphetamine, Levomethamphetamine)

Methoxyphenamine

MMA

Morforex

Norfenfluramine

L-Norpseudoephedrine

N,alpha-Diethylphenylethylamine

Oxifentorex

Oxilofrine

Ortetamine

PBA

PCA

PFA

PFMA

PIA

PMA

PMEA

PMMA

Phenylpropanolamine

Pholedrine

Prenylamine

Propylamphetamine

Pseudoephedrine

Sibutramine

Tiflorex

Tranylcypromine

Xylopropamine

Zylofuramine
Entactogens: 4-FA

4-FMA

4-MA

4-MMA

4-MTA

5-APB

5-APDB

5-EAPB

5-IT

5-MAPB

5-MAPDB

6-APB

6-APDB

6-Chloro-MDMA

6-EAPB

6-IT

6-MAPB

6-MAPDB

EDA

IAP

2,3-MDA

3,4-MDA (tenamfetamine)

MDEA

MDHMA

MDMA (midomafetamine)

MDOH

Methamnetamine

MMDMA

Naphthylaminopropane

TAP
Others: 3,4-DCA

Amiflamine

DiFMDA

Selegiline (also D-Deprenyl)

Phentermines

Stimulants: Chlorphentermine

Cloforex

Clortermine

Etolorex

Mephentermine

Pentorex

MDPH

MDMPH
Others: Cericlamine

Cathinones

Stimulants: 3-FMC

4-MC

4-BMC

4-CMC

4-EMC

4-FMC

4-MEC

4-MeMABP

4-MPD

Amfepramone

Benzedrone

Brephedrone

Buphedrone

Bupropion

Cathinone

Dimethylcathinone

Ethcathinone

Eutylone

Hydroxybupropion

Methcathinone

Methedrone

NEB

N-Ethylhexedrone

N-Ethylpentedrone

Pentedrone

Pentylone

Radafaxine
Entactogens: 3,4-DMMC

3-MMC

Butylone

Ethylone

Methylone

Methylenedioxycathinone

Mephedrone

Phenylisobutylamines

Entactogens: 4-CAB

4-MAB

Ariadne

BDB

Butylone

EBDB

Eutylone

MBDB
Stimulants: Phenylisobutylamine

Phenylalkylpyrrolidines

Stimulants: α-PBP

α-PHP

α-PPP

α-PVP

MDPBP

MDPPP

MDPV

4-MePBP

4-MePHP

4-MePPP

MOPPP

MOPVP

MPBP

MPHP

MPPP

Naphyrone

PEP

Prolintane

Pyrovalerone

Catecholamines
(and close relatives)

6-FNE

6-OHDA

a-Me-DA

a-Me-TRA

Adrenochrome

Ciladopa

D-DOPA (Dextrodopa)

Dimetofrine

Dopamine

Epinephrine

Epinine

Etilefrine

Ethylnorepinephrine

Fenclonine

Ibopamine

Isoprenaline

Isoetarine

L-DOPA (Levodopa)

L-DOPS
(Droxidopa)

L-Phenylalanine

L-Tyrosine

m-Tyramine

Metanephrine

Metaraminol

Metaterol

Metirosine

Methyldopa

N,N-Dimethyldopamine

Levonordefrin
)

Norepinephrine

Norfenefrine (m-Octopamine)

Normetanephrine

Orciprenaline

p-Octopamine

p-Tyramine

Phenylephrine

Synephrine

Miscellaneous

AL-LAD

Amidephrine

Arbutamine

Cafedrine

Denopamine

Desvenlafaxine

Diphenidine

Dizocilpine

Dobutamine

Dopexamine

Ephenidine

Etafedrine

ETH-LAD

Famprofazone

Fluorolintane

Hexapradol

IP-LAD

Lysergic acid amide

Lysergic acid 2-butyl amide

Lysergic acid 2,4-dimethylazetidide

Lysergic acid diethylamide

Methoxamine

Methoxphenidine

MT-45

PARGY-LAD

Phenibut

PRO-LAD

Pronethalol

Salbutamol (Levosalbutamol)

Solriamfetol

Theodrenaline

Thiamphenicol

UWA-101

Venlafaxine

Human trace amine-associated receptor ligands
TAAR1
Agonists
Endogenous^†

Classical monoamine neurotransmitters
Dopamine

Histamine

Norepinephrine

Serotonin

Trace amines
3-Iodothyronamine

3-Methoxytyramine

N-Methylphenethylamine

N-Methyltyramine

m-Octopamine

p-Octopamine

Phenethylamine

Phenylethanolamine

Synephrine

Tryptamine

m-Tyramine

p-Tyramine

Synthetic^‡

Amphetamine

DOB

DOET

4-Hydroxyamphetamine

Isoprenaline

MDA (tenamfetamine)

MDMA (midomafetamine)

2-Methylphenethylamine

3-Methylphenethylamine

4-Methylphenethylamine

β-Methylphenethylamine

Methamphetamine

3-MMA

Norfenfluramine

Phentermine

o-PIT

Propylhexedrine

Ralmitaront (RG-7906, RO-6889450)

RO5166017

N,N-Dimethylphenethylamine

Ulotaront (SEP-363856)

Neutral antagonists

Inverse agonists

EPPTB (RO5212773)

TAAR2
Agonists^‡

Neutral antagonists

TAAR5
Agonists^‡

N,N-Dimethylethylamine

Trimethylamine

Neutral antagonists

Inverse agonists^‡

3-Iodothyronamine

^† References for all endogenous human TAAR1 ligands are provided at List of trace amines

^‡ References for synthetic TAAR1 agonists can be found at TAAR1 or in the associated compound articles. For TAAR2 and TAAR5 agonists and inverse agonists, see TAAR for references.

See also: Receptor/signaling modulators

[18] International Nonproprietary Name [INN]), β-phenylisopropylamine, desoxynorephedrine, and speed.^[15]^[16]^[17]

[20] INN) and D-amph or dexamfetamine (INN) respectively.^[15]

[Adderall-34] 
brand name as opposed to a nonproprietary name; because the latter ("dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine sulfate, and amphetamine aspartate"^[30]
) is excessively long, this article exclusively refers to this amphetamine mixture by the brand name.

[43] 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.

[44] 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.

[61] Cochrane Collaboration reviews are high quality meta-analytic systematic reviews of randomized controlled trials.^[51]

[77] The statements supported by the USFDA come from prescribing information, which is the copyrighted intellectual property of the manufacturer and approved by the USFDA.

[81] In individuals who experience sub-normal height and weight gains, a rebound to normal levels is expected to occur if stimulant therapy is briefly interrupted.^[45]^[46]^[69] The average reduction in final adult height from continuous stimulant therapy over a 3 year period is 2 cm.^[69]

[111] Transcription factors are proteins that increase or decrease the expression of specific genes.^[95]

[112] In simpler terms, this necessary and sufficient relationship means that ΔFosB overexpression in the nucleus accumbens and addiction-related behavioral and neural adaptations always simultaneously occur together and never occur alone.

[117] During short-term treatment, fluoxetine may decrease drug craving.^[99]

[118] During "medium-term treatment," imipramine may extend the duration of adherence to addiction treatment.^[99]

[119] The review indicated that magnesium L-aspartate and magnesium chloride produce significant changes in addictive behavior;^[77] other forms of magnesium were not mentioned.

[174] 4-Hydroxyamphetamine has been shown to be metabolized into 4-hydroxynorephedrine by dopamine beta-hydroxylase (DBH) in vitro and it is presumed to be metabolized similarly in vivo.^[145]^[146] Evidence from studies that measured the effect of serum DBH concentrations on 4-hydroxyamphetamine metabolism in humans suggests that a different enzyme may mediate the conversion of 4-hydroxyamphetamine to 4-hydroxynorephedrine;^[146]^[8] however, other evidence from animal studies suggests that this reaction is catalyzed by DBH in synaptic vesicles within noradrenergic neurons in the brain.^[148]^[149]

[176] Enantiomers are molecules that are mirror images of one another; they are structurally identical, but of the opposite orientation.^[18]

[100] G proteins & linked receptors
(Text color) Transcription factors

[32] [19]^[20]^[21]^[22]^[23]^[24]^[25]^[26]^[27]^[28]^[29]

[37] [5]^[24]^[25]^[26]^[28]^[29]^[31]^[32]

[42] [23]^[25]^[33]^[34]^[35]^[36]

[47] [37]^[38]

[86] [70]^[71]^[72]^[73]

[88] [26]^[32]^[36]^[74]

[Reuptake_inhibition-143] [111]^[115]^[119]^[120]^[121]^[122]

[154] [31]^[111]^[119]^[123]

[163] [4]^[6]^[7]^[8]^[9]^[10]^[11]^[12]

[amphetamine_metabolism-171] [4]^[145]^[7]^[9]^[10]^[141]^[146]^[147]

[199] [24]^[170]^[171]^[172]

[FDA-AllBoxedWarnings-1] FDA
. Retrieved 22 October 2023.

[Drugbank-dexamph-2] "Pharmacology". Dextroamphetamine. University of Alberta. 8 February 2013. Retrieved 5 November 2013. {{cite encyclopedia}}: |work= ignored (help)

[Drugbank-amph-3] "Pharmacology". Amphetamine. University of Alberta. 8 February 2013. Retrieved 5 November 2013. {{cite encyclopedia}}: |work= ignored (help)

[FDA_Pharmacokinetics-4] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ ^o ^p ^q ^r ^s ^t ^u "Adderall XR Prescribing Information" (PDF). United States Food and Drug Administration. Shire US Inc. December 2013. pp. 12–13. Retrieved 30 December 2013. Cite error: The named reference "FDA Pharmacokinetics" was defined multiple times with different content (see the help page).

[Adderall_IR-5] "Adderall IR Prescribing Information" (PDF). United States Food and Drug Administration. Barr Laboratories, Inc. March 2007. pp. 4–5. Retrieved 2 November 2013.

[DBH_ref-6] 
ISBN 9781609133450. Alternatively, direct oxidation of amphetamine by DA β-hydroxylase can afford norephedrine.{{cite book}}: CS1 maint: multiple names: authors list (link
)

[DBH_amph_primary-7] 
PMID 4809526. Retrieved 6 November 2014. Dopamine-β-hydroxylase catalyzed the removal of the pro-R hydrogen atom and the production of 1-norephedrine, (2S,1R)-2-amino-1-hydroxyl-1-phenylpropane, from d-amphetamine. Cite error: The named reference "DBH amph primary" was defined multiple times with different content (see the help page
).

[DBH_4-HA_primary-8] 
PMID 4713201. Subjects with exceptionally low levels of serum dopamine-β-hydroxylase activity showed normal cardiovascular function and normal β-hydroxylation of an administered synthetic substrate, hydroxyamphetamine.{{cite journal}}: CS1 maint: multiple names: authors list (link) Cite error: The named reference "DBH 4-HA primary" was defined multiple times with different content (see the help page
).

[FMO-9] 
PMID 15922018. Cite error: The named reference "FMO" was defined multiple times with different content (see the help page
).

[FMO3-Primary-10] 
PMID 10027866.{{cite journal}}: CS1 maint: multiple names: authors list (link) Cite error: The named reference "FMO3-Primary" was defined multiple times with different content (see the help page
).

[Benzoic1-11] "Substrate/Product". butyrate-CoA ligase. Technische Universität Braunschweig. Retrieved 7 May 2014. {{cite encyclopedia}}: |work= ignored (help)

[Benzoic2-12] "Substrate/Product". glycine N-acyltransferase. Technische Universität Braunschweig. Retrieved 7 May 2014. {{cite encyclopedia}}: |work= ignored (help)

[Chemspider-13] "Properties: Predicted – EP|Suite". Amphetamine. Retrieved 6 November 2013. {{cite encyclopedia}}: |work= ignored (help)

[14] "Chemical and Physical Properties". Amphetamine. National Center for Biotechnology Information. Retrieved 5 November 2013. {{cite encyclopedia}}: |work= ignored (help)

[PubChem_Header-15] "Compound Summary". Amphetamine. National Center for Biotechnology Information. Retrieved 13 October 2013. {{cite encyclopedia}}: |work= ignored (help)

[DrugBank1-16] ^ ^a ^b ^c ^d ^e ^f "Identification". Amphetamine. University of Alberta. 8 February 2013. Retrieved 13 October 2013. {{cite encyclopedia}}: |work= ignored (help)

[Acute_amph_toxicity-17] Cite error: The named reference Acute amph toxicity was invoked but never defined (see the help page).

[Enantiomers-19] 
doi:10.1351/goldbook.E02069. Archived from the original
on 17 March 2013. Retrieved 14 March 2014. One of a pair of molecular entities which are mirror images of each other and non-superposable.

[MeSHAmphetamine-21] "Amphetamine". Medical Subject Headings. National Institutes of Health, National Library of Medicine. Retrieved 16 December 2013.

[WHO_INN_active_moiety-22] "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 different salts or esters of the same active substance should differ only with regard to the inactive moiety of the molecule. ... The latter are called modified INNs (INNMs).

[Proper_definition-23] ISBN 9789057020810
. Retrieved 1 December 2014. Amphetamine, in the singular form, properly applies to the racemate of 2-amino-1-phenylpropane. ... In its broadest context, however, the term can even embrace a large number of structurally and pharmacologically related substances.

[UN_Convention-24] "Convention on psychotropic substances". United Nations Treaty Collection. United Nations. Retrieved 11 November 2013.

[FDA_Abuse_&_OD-25] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l "Adderall XR Prescribing Information" (PDF). United States Food and Drug Administration. Shire US Inc. December 2013. p. 11. Retrieved 30 December 2013.

[Ergogenics-26] 
PMID 23668655
. Amphetamines and caffeine 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 effects
• 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

[Malenka_2009-27] 
ISBN 9780071481274. Therapeutic (relatively low) doses of psychostimulants, such as methylphenidate and amphetamine, improve performance on working memory tasks both in in normal subjects and those with ADHD. Positron emission tomography (PET) demonstrates that methylphenidate decreases regional cerebral blood flow in the doroslateral prefrontal cortex and posterior parietal cortex while improving performance of a spacial working memory task. This suggests that cortical networks that normally process spatial working memory become more efficient in response to the drug. ... [It] is now believed that dopamine and norepinephrine, but not serotonin, produce the beneficial effects of stimulants on working memory. At abused (relatively high) doses, stimulants can interfere with working memory and cognitive control ... stimulants act not only on working memory function, but also on general levels of arousal and, within the nucleus accumbens, improve the saliency of tasks. Thus, stimulants improve performance on effortful but tedious tasks ... through indirect stimulation of dopamine and norepinephrine receptors.{{cite book}}: CS1 maint: multiple names: authors list (link
)

[Libido-28] 
PMID 19727285
.

[Nonmedical-29] 
PMID 18174822. Stimulant misuse appears to occur both for performance enhancement and their euphorogenic effects, the latter being related to the intrinsic properties of the stimulants (e.g., IR versus ER profile) ...

Although useful in the treatment of ADHD, stimulants are controlled II substances with a history of preclinical and human studies showing potential abuse liability.{{cite journal}}: CS1 maint: multiple names: authors list (link
)

[Amph_Uses-30] 
PMID 23539642.{{cite journal}}: CS1 maint: multiple names: authors list (link
)

[Benzedrine-31] 
PMID 16492800
.

[NDCD-33] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ "National Drug Code Amphetamine Search Results". National Drug Code Directory. United States Food and Drug Administration. Archived from the original on 7 February 2014. Retrieved 16 December 2013. {{cite web}}: |archive-date= / |archive-url= timestamp mismatch; 16 December 2013 suggested (help)

[Miller-35] 
PMID 21073468
.

[FDA_Effects-36] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ "Adderall XR Prescribing Information" (PDF). United States Food and Drug Administration. Shire US Inc. December 2013. pp. 4–8. Retrieved 30 December 2013.

[Cochrane-38] 
PMID 19160215. A minority of individuals who use amphetamines develop full-blown psychosis requiring care at emergency departments or psychiatric hospitals. In such cases, symptoms of amphetamine psychosis commonly include paranoid and persecutory delusions as well as auditory and visual hallucinations in the presence of extreme agitation. More common (about 18%) is for frequent amphetamine users to report psychotic symptoms that are sub-clinical and that do not require high-intensity intervention ...
About 5–15% of the users who develop an amphetamine psychosis fail to recover completely (Hofmann 1983) ...
Findings from one trial indicate use of antipsychotic medications effectively resolves symptoms of acute amphetamine psychosis.{{cite journal}}: CS1 maint: multiple names: authors list (link
)

[Stimulant_Misuse-39] Greydanus D. "Stimulant Misuse: Strategies to Manage a Growing Problem" (PDF). American College Health Association (Review Article). ACHA Professional Development Program. p. 20. Retrieved 2 November 2013.

[EncycOfPsychopharm-40] 
ISBN 9783540686989
.

[Westfall-41] 
ISBN 9780071624428. {{cite book}}: External link in |sectionurl= (help); Unknown parameter |sectionurl= ignored (|section-url= suggested) (help)CS1 maint: multiple names: editors list (link
)

[EMC-45] "Amphetamine". European Monitoring Centre for Drugs and Drug Addiction. Retrieved 19 October 2013.

[Trace_Amines-46] 
PMID 19948186
. Fig. 2. Synthetic and metabolic pathways for endogenous and exogenously administered trace amines and sympathomimetic amines ...
Trace amines are metabolized in the mammalian body via monoamine oxidase (MAO; EC 1.4.3.4) (Berry, 2004) (Fig. 2) ... It deaminates primary and secondary amines that are free in the neuronal cytoplasm but not those bound in storage vesicles of the sympathetic neurone ...
Thus, MAO inhibitors potentiate the peripheral effects of indirectly acting sympathomimetic amines ... this potentiation occurs irrespective of whether the amine is a substrate for MAO. An α-methyl group on the side chain, as in amphetamine and ephedrine, renders the amine immune to deamination so that they are not metabolized in the gut. Similarly, β-PEA would not be deaminated in the gut as it is a selective substrate for MAO-B which is not found in the gut ...
Brain levels of endogenous trace amines are several hundred-fold below those for the classical neurotransmitters noradrenaline, dopamine and serotonin but their rates of synthesis are equivalent to those of noradrenaline and dopamine and they have a very rapid turnover rate (Berry, 2004). Endogenous extracellular tissue levels of trace amines measured in the brain are in the low nanomolar range. These low concentrations arise because of their very short half-life ...

[pmid22392347-48] 
PMID 22392347.{{cite journal}}: CS1 maint: multiple names: authors list (link
)

[AbuseAndAbnormalities-49] PMID 18991959.{{cite journal}}: CS1 maint: multiple names: authors list (link
)

[Neuroplasticity_1-50] 
PMID 23247506.{{cite journal}}: CS1 maint: multiple names: authors list (link
)

[Neuroplasticity_2-51] 
PMID 24107764.{{cite journal}}: CS1 maint: multiple names: authors list (link
)

[Neuroplasticity_3-52] 
PMID 22118249
. Basal ganglia regions like the right globus pallidus, the right putamen, and the nucleus caudatus are structurally affected in children with ADHD. These changes and alterations in limbic regions like ACC and amygdala are more pronounced in non-treated populations and seem to diminish over time from child to adulthood. Treatment seems to have positive effects on brain structure.

[Millichap_3-53] 
ISBN 9781441913968
.

[Long-Term_Outcomes_Medications-54] 
PMID 21699268
.

[Millichap-55] 
ISBN 9781441913968
.

[Malenka_2009_03-56] 
ISBN 9780071481274.{{cite book}}: CS1 maint: multiple names: authors list (link
)

[cognition_enhancers-57] 
PMID 21596055.{{cite journal}}: CS1 maint: multiple names: authors list (link
)

[ADHD-58] "Stimulants for Attention Deficit Hyperactivity Disorder". WebMD. Healthwise. 12 April 2010. Retrieved 12 November 2013.

[WebMds_Review-59] PMID 11833633.{{cite journal}}: CS1 maint: multiple names: authors list (link
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[pmid16052183-60] PMID 16052183.{{cite journal}}: CS1 maint: multiple names: authors list (link
)

[Cochrane_Amphetamines_ADHD-62] PMID 21678370.{{cite journal}}: CS1 maint: multiple names: authors list (link
)

[63] PMID 21491404
.

[64] PMID 17253474.{{cite journal}}: CS1 maint: multiple names: authors list (link
)

[65] PMID 17054192.{{cite journal}}: CS1 maint: multiple names: authors list (link
)

[SpeedyRecovery-66] PMID 21386667.{{cite journal}}: CS1 maint: multiple names: authors list (link
)

[pmid11337538-67] PMID 11337538.{{cite journal}}: CS1 maint: multiple names: authors list (link
)

[Continuum-68] 
PMID 24344115.{{cite journal}}: CS1 maint: multiple names: authors list (link
)

[Malenka_NAcc-69] ISBN 9780071481274. Dopamine acts in the nucleus accumbens to attach motivational significance to stimuli associated with reward.{{cite book}}: CS1 maint: multiple names: authors list (link
)

[70] Twohey M (26 March 2006). "Pills become an addictive study aid". JS Online. Archived from the original on 15 August 2007. Retrieved 2 December 2007.

[pmid16999660-71] PMID 16999660.{{cite journal}}: CS1 maint: multiple names: authors list (link
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[NCAA-72] Bracken NM (January 2012). "National Study of Substance Use Trends Among NCAA College Student-Athletes" (PDF). NCAA Publications. National Collegiate Athletic Association. Retrieved 8 October 2013.

[WADA_&_AD_regulation-73] PMID 18500382
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[Ergogenics2-74] 
PMID 21658550
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[Roelands_2013-75] 
PMID 23456493.{{cite journal}}: CS1 maint: multiple names: authors list (link
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[Amph-DA_reaction_time-76] PMID 24198770. The neurotransmitter dopamine is released from projections originating in the midbrain. Manipulations of dopaminergic signaling profoundly influence interval timing, leading to the hypothesis that dopamine influences internal pacemaker, or "clock," activity (Maricq and Church, 1983; Buhusi and Meck, 2005, 2009; Lake and Meck, 2013). For instance, amphetamine, which increases concentrations of dopamine at the synaptic cleft (Maricq and Church, 1983; Zetterström et al., 1983) advances the start of responding during interval timing (Taylor et al., 2007), whereas antagonists of D2 type dopamine receptors typically slow timing (Drew et al., 2003; Lake and Meck, 2013). ... Depletion of dopamine in healthy volunteers impairs timing (Coull et al., 2012), while amphetamine releases synaptic dopamine and speeds up timing (Taylor et al., 2007).{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link
)

[FDA_Contra_Warnings-78] ^ ^a ^b ^c ^d ^e ^f ^g "Adderall XR Prescribing Information" (PDF). United States Food and Drug Administration. Shire US Inc. December 2013. pp. 4–6. Retrieved 30 December 2013.

[International-79] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ Heedes G; Ailakis J. "Amphetamine (PIM 934)". INCHEM. International Programme on Chemical Safety. Retrieved 24 June 2014.{{cite web}}: CS1 maint: multiple names: authors list (link)

[pmid18295156-80] 
PMID 18295156
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[82] "FDA Drug Safety Communication: Safety Review Update of Medications used to treat Attention-Deficit/Hyperactivity Disorder (ADHD) in children and young adults". United States Food and Drug Administration. 20 December 2011. Retrieved 4 November 2013.

[pmid22043968-83] PMID 22043968.{{cite journal}}: CS1 maint: multiple names: authors list (link
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[84] "FDA Drug Safety Communication: Safety Review Update of Medications used to treat Attention-Deficit/Hyperactivity Disorder (ADHD) in adults". United States Food and Drug Administration. 15 December 2011. Retrieved 4 November 2013.

[pmid22161946-85] PMID 22161946.{{cite journal}}: CS1 maint: multiple names: authors list (link
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[Merck_Manual_Amphetamines-87] O'Connor PG (February 2012). "Amphetamines". Merck Manual for Health Care Professionals. Merck. Retrieved 8 May 2012.

[Amphetamine_toxidrome-89] PMID 23757186. Amphetamine, dextroamphetamine, and methylphenidate act as substrates for the cellular monoamine transporter, especially the dopamine transporter (DAT) and less so the norepinephrine (NET) and serotonin transporter. The mechanism of toxicity is primarily related to excessive extracellular dopamine, norepinephrine, and serotonin.{{cite journal}}: CS1 maint: multiple names: authors list (link
)

[Amphetamine_KEGG_ΔFosB-90] Kanehisa Laboratories (10 October 2014). "Amphetamine – Homo sapiens (human)". KEGG Pathway. Retrieved 31 October 2014. Most addictive drugs increase extracellular concentrations of dopamine (DA) in nucleus accumbens (NAc) and medial prefrontal cortex (mPFC), projection areas of mesocorticolimbic DA neurons and key components of the "brain reward circuit". Amphetamine achieves this elevation in extracellular levels of DA by promoting efflux from synaptic terminals. ... Chronic exposure to amphetamine induces a unique transcription factor delta FosB, which plays an essential role in long-term adaptive changes in the brain.

[Magnesium-91] 
PMID 18557129
.

[Cellular_basis-92] 
PMID 24459410. DESPITE THE IMPORTANCE OF NUMEROUS PSYCHOSOCIAL FACTORS, AT ITS CORE, DRUG ADDICTION INVOLVES A BIOLOGICAL PROCESS: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. ... A large body of literature has demonstrated that such ΔFosB induction in D1-type NAc neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement Cite error: The named reference "Cellular basis" was defined multiple times with different content (see the help page
).

[Nestler1-93] 
PMID 21989194. ΔFosB serves as one of the master control proteins governing this structural plasticity. ... ΔFosB also represses G9a expression, leading to reduced repressive histone methylation at the cdk5 gene. The net result is gene activation and increased CDK5 expression. ... In contrast, ΔFosB binds to the c-fos gene and recruits several co-repressors, including HDAC1 (histone deacetylase 1) and SIRT 1 (sirtuin 1). ... The net result is c-fos gene repression.
Figure 4: Epigenetic basis of drug regulation of gene expression

[Natural_and_drug_addictions-94] 
PMID 21459101
. Similar to environmental enrichment, studies have found that exercise reduces self-administration and relapse to drugs of abuse (Cosgrove et al., 2002; Zlebnik et al., 2010). There is also some evidence that these preclinical findings translate to human populations, as exercise reduces withdrawal symptoms and relapse in abstinent smokers (Daniel et al., 2006; Prochaska et al., 2008), and one drug recovery program has seen success in participants that train for and compete in a marathon as part of the program (Butler, 2005). ... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some patients taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al., 2006; Aiken, 2007; Lader, 2008).

[What_the_ΔFosB?-95] 
PMID 25083822
.
ΔFosB as a therapeutic biomarker
The strong correlation between chronic drug exposure and ΔFosB provides novel opportunities for targeted therapies in addiction (118), and suggests methods to analyze their efficacy (119). Over the past two decades, research has progressed from identifying ΔFosB induction to investigating its subsequent action (38). It is likely that ΔFosB research will now progress into a new era – the use of ΔFosB as a biomarker. If ΔFosB detection is indicative of chronic drug exposure (and is at least partly responsible for dependence of the substance), then its monitoring for therapeutic efficacy in interventional studies is a suitable biomarker (Figure 2). Examples of therapeutic avenues are discussed herein. ...

Conclusions
ΔFosB is an essential transcription factor implicated in the molecular and behavioral pathways of addiction following repeated drug exposure. The formation of ΔFosB in multiple brain regions, and the molecular pathway leading to the formation of AP-1 complexes is well understood. The establishment of a functional purpose for ΔFosB has allowed further determination as to some of the key aspects of its molecular cascades, involving effectors such as GluR2 (87,88), Cdk5 (93) and NFkB (100). Moreover, many of these molecular changes identified are now directly linked to the structural, physiological and behavioral changes observed following chronic drug exposure (60,95,97,102). New frontiers of research investigating the molecular roles of ΔFosB have been opened by epigenetic studies, and recent advances have illustrated the role of ΔFosB acting on DNA and histones, truly as a molecular switch (34). As a consequence of our improved understanding of ΔFosB in addiction, it is possible to evaluate the addictive potential of current medications (119), as well as use it as a biomarker for assessing the efficacy of therapeutic interventions (121,122,124). Some of these proposed interventions have limitations (125) or are in their infancy (75). However, it is hoped that some of these preliminary findings may lead to innovative treatments, which are much needed in addiction.

[Running_vs_addiction-96] 
PMID 23806439. these data show that exercise can affect dopaminergic signaling at many different levels, which may underlie its ability to modify vulnerability during drug use initiation. Exercise also produces neuroadaptations that may influence an individual's vulnerability to initiate drug use. Consistent with this idea, chronic moderate levels of forced treadmill running blocks not only subsequent methamphetamine-induced conditioned place preference, but also stimulant-induced increases in dopamine release in the NAc (Chen et al., 2008) and striatum (Marques et al., 2008). ... [These] findings indicate the efficacy of exercise at reducing drug intake in drug-dependent individuals ... wheel running [reduces] methamphetamine self-administration under extended access conditions (Engelmann et al., 2013) ... These findings suggest that exercise may "magnitude"-dependently prevent the development of an addicted phenotype possibly by blocking/reversing behavioral and neuro-adaptive changes that develop during and following extended access to the drug. ... Exercise has been proposed as a treatment for drug addiction that may reduce drug craving and risk of relapse. Although few clinical studies have investigated the efficacy of exercise for preventing relapse, the few studies that have been conducted generally report a reduction in drug craving and better treatment outcomes (see Table 4). ... Taken together, these data suggest that the potential benefits of exercise during relapse, particularly for relapse to psychostimulants, may be mediated via chromatin remodeling and possibly lead to greater treatment outcomes.{{cite journal}}: CS1 maint: multiple names: authors list (link
)

[Nestler_CBT-97] 
ISBN 9780071481274. Currently, cognitive–behavioral therapies are the most successful treatment available for preventing the relapse of psychostimulant use.{{cite book}}: CS1 maint: multiple names: authors list (link
)

[Addiction_glossary-98] ISBN 978-0-07-148127-4
.

[Brain_disease-99] PMID 26816013
. Substance-use disorder: A diagnostic term in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) referring to recurrent use of alcohol or other drugs that causes clinically and functionally significant impairment, such as health problems, disability, and failure to meet major responsibilities at work, school, or home. Depending on the level of severity, this disorder is classified as mild, moderate, or severe.
Addiction: A term used to indicate the most severe, chronic stage of substance-use disorder, in which there is a substantial loss of self-control, as indicated by compulsive drug taking despite the desire to stop taking the drug. In the DSM-5, the term addiction is synonymous with the classification of severe substance-use disorder.

[Nestler-Renthal_Figure_2-101] 
PMID 19877494. [Psychostimulants] increase cAMP levels in striatum, which activates protein kinase A (PKA) and leads to phosphorylation of its targets. This includes the cAMP response element binding protein (CREB), the phosphorylation of which induces its association with the histone acetyltransferase, CREB binding protein (CBP) to acetylate histones and facilitate gene activation. This is known to occur on many genes including fosB and c-fos in response to psychostimulant exposure. ΔFosB is also upregulated by chronic psychostimulant treatments, and is known to activate certain genes (eg, cdk5) and repress others (eg, c-fos) where it recruits HDAC1 as a corepressor. ... Chronic exposure to psychostimulants increases glutamatergic [signaling] from the prefrontal cortex to the NAc. Glutamatergic signaling elevates Ca2+ levels in NAc postsynaptic elements where it activates CaMK (calcium/calmodulin protein kinases) signaling, which, in addition to phosphorylating CREB, also phosphorylates HDAC5.
Figure 2: Psychostimulant-induced signaling events

[Glutamate-dopamine_cotransmission_review-102] PMID 22200950
. Coincident and convergent input often induces plasticity on a postsynaptic neuron. The NAc integrates processed information about the environment from basolateral amygdala, hippocampus, and prefrontal cortex (PFC), as well as projections from midbrain dopamine neurons. Previous studies have demonstrated how dopamine modulates this integrative process. For example, high frequency stimulation potentiates hippocampal inputs to the NAc while simultaneously depressing PFC synapses (Goto and Grace, 2005). The converse was also shown to be true; stimulation at PFC potentiates PFC–NAc synapses but depresses hippocampal–NAc synapses. In light of the new functional evidence of midbrain dopamine/glutamate co-transmission (references above), new experiments of NAc function will have to test whether midbrain glutamatergic inputs bias or filter either limbic or cortical inputs to guide goal-directed behavior.

[Nestler2-103] 
PMID 23430970
. The 35-37 kD ΔFosB isoforms accumulate with chronic drug exposure due to their extraordinarily long half-lives. ... As a result of its stability, the ΔFosB protein persists in neurons for at least several weeks after cessation of drug exposure. ... ΔFosB overexpression in nucleus accumbens induces NFκB ... In contrast, the ability of ΔFosB to repress the c-Fos gene occurs in concert with the recruitment of a histone deacetylase and presumably several other repressive proteins such as a repressive histone methyltransferase

[c-Fos_repression-104] PMID 18640924
. Recent evidence has shown that ΔFosB also represses the c-fos gene that helps create the molecular switch—from the induction of several short-lived Fos family proteins after acute drug exposure to the predominant accumulation of ΔFosB after chronic drug exposure

[105] "Amphetamines: Drug Use and Abuse". Merck Manual Home Edition. Merck. February 2003. Archived from the original on 17 February 2007. Retrieved 28 February 2007.

[106] PMID 23996457.{{cite journal}}: CS1 maint: multiple names: authors list (link
)

[Nestler,_Hyman,_and_Malenka_2-107] PMID 16776597.{{cite journal}}: CS1 maint: multiple names: authors list (link
)

[Nestler-108] 
PMID 21989194
. ΔFosB has been linked directly to several addiction-related behaviors ... Importantly, genetic or viral overexpression of ΔJunD, a dominant negative mutant of JunD which antagonizes ΔFosB- and other AP-1-mediated transcriptional activity, in the NAc or OFC blocks these key effects of drug exposure^14,22–24. This indicates that ΔFosB is both necessary and sufficient for many of the changes wrought in the brain by chronic drug exposure. ΔFosB is also induced in D1-type NAc MSNs by chronic consumption of several natural rewards, including sucrose, high fat food, sex, wheel running, where it promotes that consumption^14,26–30. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states.

[Addiction_genetics-109] 
PMID 23085425
.

[NHM-Transcription_factor-110] ISBN 9780071481274. All living cells depend on the regulation of gene expression by extracellular signals for their development, homeostasis, and adaptation to the environment. Indeed, many signal transduction pathways function primarily to modify transcription factors that alter the expression of specific genes. Thus, neurotransmitters, growth factors, and drugs change patterns of gene expression in cells and in turn affect many aspects of nervous system functioning, including the formation of long-term memories. Many drugs that require prolonged administration, such as antidepressants and antipsychotics, trigger changes in gene expression that are thought to be therapeutic adaptations to the initial action of the drug.{{cite book}}: CS1 maint: multiple names: authors list (link
)

[Alcoholism_ΔFosB-113] Kanehisa Laboratories (29 October 2014). "Alcoholism – Homo sapiens (human)". KEGG Pathway. Retrieved 31 October 2014.

[ΔFosB_reward-114] 
PMID 22641964. It has been found that deltaFosB gene in the NAc is critical for reinforcing effects of sexual reward. Pitchers and colleagues (2010) reported that sexual experience was shown to cause DeltaFosB accumulation in several limbic brain regions including the NAc, medial pre-frontal cortex, VTA, caudate, and putamen, but not the medial preoptic nucleus. ... these findings support a critical role for DeltaFosB expression in the NAc in the reinforcing effects of sexual behavior and sexual experience-induced facilitation of sexual performance. ... both drug addiction and sexual addiction represent pathological forms of neuroplasticity along with the emergence of aberrant behaviors involving a cascade of neurochemical changes mainly in the brain's rewarding circuitry.{{cite journal}}: CS1 maint: multiple names: authors list (link
)

[Amph_and_sex_addiction-115] 
PMID 23426671. Drugs of abuse induce neuroplasticity in the natural reward pathway, specifically the nucleus accumbens (NAc), thereby causing development and expression of addictive behavior. ... Together, these findings demonstrate that drugs of abuse and natural reward behaviors act on common molecular and cellular mechanisms of plasticity that control vulnerability to drug addiction, and that this increased vulnerability is mediated by ΔFosB and its downstream transcriptional targets. ... Sexual behavior is highly rewarding (Tenk et al., 2009), and sexual experience causes sensitized drug-related behaviors, including cross-sensitization to amphetamine (Amph)-induced locomotor activity (Bradley and Meisel, 2001; Pitchers et al., 2010a) and enhanced Amph reward (Pitchers et al., 2010a). Moreover, sexual experience induces neural plasticity in the NAc similar to that induced by psychostimulant exposure, including increased dendritic spine density (Meisel and Mullins, 2006; Pitchers et al., 2010a), altered glutamate receptor trafficking, and decreased synaptic strength in prefrontal cortex-responding NAc shell neurons (Pitchers et al., 2012). Finally, periods of abstinence from sexual experience were found to be critical for enhanced Amph reward, NAc spinogenesis (Pitchers et al., 2010a), and glutamate receptor trafficking (Pitchers et al., 2012). These findings suggest that natural and drug reward experiences share common mechanisms of neural plasticity{{cite journal}}: CS1 maint: multiple names: authors list (link
)

[Cochrane_Addiction-116] 
PMID 11687171. Although there are a variety of amphetamines and amphetamine derivatives, the word "amphetamines" in this review stands for amphetamine, dextroamphetamine and methamphetamine only.{{cite journal}}: CS1 maint: multiple names: authors list (link
)

[Cochrane_Withdrawal-120] 
PMID 19370579. The prevalence of this withdrawal syndrome is extremely common (Cantwell 1998; Gossop 1982) with 87.6% of 647 individuals with amphetamine dependence reporting six or more signs of amphetamine withdrawal listed in the DSM when the drug is not available (Schuckit 1999) ... The severity of withdrawal symptoms is greater in amphetamine dependent individuals who are older and who have more extensive amphetamine use disorders (McGregor 2005). Withdrawal symptoms typically present within 24 hours of the last use of amphetamine, with a withdrawal syndrome involving two general phases that can last 3 weeks or more. The first phase of this syndrome is the initial "crash" that resolves within about a week (Gossop 1982;McGregor 2005) ...{{cite journal}}: CS1 maint: multiple names: authors list (link
)

[121] "Adderall IR Prescribing Information" (PDF). United States Food and Drug Administration. Barr Laboratories, Inc. March 2007. Retrieved 4 November 2013.

[122] "Dexedrine Medication Guide" (PDF). United States Food and Drug Administration. Amedra Pharmaceuticals LLC. May 2013. Retrieved 4 November 2013.

[123] "Adderall XR Prescribing Information" (PDF). United States Food and Drug Administration. Shire US Inc. December 2013. Retrieved 30 December 2013.

[Humans&Animals-124] PMID 17606768
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[125] "Amphetamine". Hazardous Substances Data Bank. National Library of Medicine. Retrieved 26 February 2014. Direct toxic damage to vessels seems unlikely because of the dilution that occurs before the drug reaches the cerebral circulation.

[Malenka_2009_02-126] ISBN 9780071481274. Unlike cocaine and amphetamine, methamphetamine is directly toxic to midbrain dopamine neurons.{{cite book}}: CS1 maint: multiple names: authors list (link
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[Autoxidation1-127] PMID 12835101
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[Autoxidation2-128] PMID 18596830
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[Hofmann-129] ISBN 9780195030570
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[FDA_Interactions-130] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j "Adderall XR Prescribing Information" (PDF). United States Food and Drug Administration. Shire US Inc. December 2013. pp. 8–10. Retrieved 30 December 2013.

[E_Weihe-131] 
PMID 21272013
. VMAT2 is the CNS vesicular transporter for not only the biogenic amines DA, NE, EPI, 5-HT, and HIS, but likely also for the trace amines TYR, PEA, and thyronamine (THYR) ... [Trace aminergic] neurons in mammalian CNS would be identiﬁable as neurons expressing VMAT2 for storage, and the biosynthetic enzyme aromatic amino acid decarboxylase (AADC).

[Amphetamine_VMAT2_pH_gradient-132] Cite error: The named reference Amphetamine VMAT2 pH gradient was invoked but never defined (see the help page).

[GIRK-133] 
PMID 21772817. inhibition of firing due to increased release of dopamine; (b) reduction of D2 and GABAB receptor-mediated inhibitory responses (excitatory effects due to disinhibition); and (c) a direct TA1 receptor-mediated activation of GIRK channels which produce cell membrane hyperpolarization.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link
)

[Genatlas_TAAR1-134] t (28 January 2012). "TAAR1". GenAtlas. University of Paris. Retrieved 29 May 2014.
• tonically activates inwardly rectifying K(+) channels, which reduces the basal firing frequency of dopamine (DA) neurons of the ventral tegmental area (VTA)

[EAAT3-135] 
PMID 25033183. AMPH also increases intracellular calcium (Gnegy et al., 2004) that is associated with calmodulin/CamKII activation (Wei et al., 2007) and modulation and trafficking of the DAT (Fog et al., 2006; Sakrikar et al., 2012).{{cite journal}}: CS1 maint: multiple names: authors list (link
)

[DAT_regulation_review-136] 
PMID 23968642
. AMPH and METH also stimulate DA efflux, which is thought to be a crucial element in their addictive properties [80], although the mechanisms do not appear to be identical for each drug [81]. These processes are PKCβ– and CaMK–dependent [72, 82], and PKCβ knock-out mice display decreased AMPH-induced efflux that correlates with reduced AMPH-induced locomotion [72].

[TAAR1_IUPHAR-137] Maguire JJ, Davenport AP (2 December 2014). "TA₁ receptor". IUPHAR database. International Union of Basic and Clinical Pharmacology. Retrieved 8 December 2014. Comments: Tyramine causes an increase in intracellular cAMP in HEK293 or COS-7 cells expressing the TA1 receptor in vitro [4,6,18]. In addition, coupling to a promiscuous Gαq has been observed, resulting in increased intracellular calcium concentration [24].

[pmid11459929-138] PMID 11459929.{{cite journal}}: CS1 maint: multiple names: authors list (link
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[SLC1A1-139] "SLC1A1 solute carrier family 1 (neuronal/epithelial high affinity glutamate transporter, system Xag), member 1 [ Homo sapiens (human) ]". NCBI Gene. National Center for Biotechnology Information. Retrieved 11 November 2014. Amphetamine modulates excitatory neurotransmission through endocytosis of the glutamate transporter EAAT3 in dopamine neurons. ... internalization of EAAT3 triggered by amphetamine increases glutamatergic signaling and thus contributes to the effects of amphetamine on neurotransmission.

[SLC22A3-140] PMID 20402963.{{cite journal}}: CS1 maint: multiple names: authors list (link
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[SLC22A5-141] PMID 15316089
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[pmid13677912-142] PMID 13677912.{{cite journal}}: CS1 maint: multiple names: authors list (link
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[CART_NAcc-144] 
PMID 16840648
. The physiological importance of CART was further substantiated in numerous human studies demonstrating a role of CART in both feeding and psychostimulant addiction. ... Colocalization studies also support a role for CART in the actions of psychostimulants. ... CART and DA receptor transcripts colocalize (Beaudry et al., 2004). Second, dopaminergic nerve terminals in the NAc synapse on CART-containing neurons (Koylu et al., 1999), hence providing the proximity required for neurotransmitter signaling. These studies suggest that DA plays a role in regulating CART gene expression possibly via the activation of CREB. Indeed, CART gene expression is regulated via cAMP signaling and pCREB in vivo as centrally administered forskolin activated cAMP, phosphorylated CREB, and increased CART mRNA and peptide levels (Jones and Kuhar, 2006).

[CART_functions-145] PMID 22077697. Numerous studies have established the role of CART in food intake, maintenance of bodyweight, stress control, reward and pain transmission. Recently, it was demonstrated that CART, as a neurotrophic peptide, had a cerebroprotective against focal ischaemic stroke and inhibited the neurotoxicity of β-amyloid protein, which focused attention on the role of CART in the central nervous system (CNS) and neurological diseases. 3. In fact, little is known about the way in which CART peptide interacts with its receptors, initiates downstream cascades and finally exerts its neuroprotective effect under normal or pathological conditions. The literature indicates that there are many factors, such as regulation of the immunological system and protection against energy failure, that may be involved in the cerebroprotection afforded by CART{{cite journal}}: CS1 maint: multiple names: authors list (link
)

[PubChem_Targets-146] "Biomolecular Interactions and Pathways". Amphetamine. National Center for Biotechnology Information. Retrieved 13 October 2013. {{cite encyclopedia}}: |work= ignored (help)

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[Pubchem_Kinetics-159] "Biomedical Effects and Toxicity". Amphetamine. National Center for Biotechnology Information. Retrieved 12 October 2013. {{cite encyclopedia}}: |work= ignored (help)

[160] "Biological Half-Life". AMPHETAMINE. Hazardous Substances Data Bank. Retrieved 5 January 2014. Concentrations of (14)C-amphetamine declined less rapidly in the plasma of human subjects maintained on an alkaline diet (urinary pH > 7.5) than those on an acid diet (urinary pH < 6). Plasma half-lives of amphetamine ranged between 16-31 hr & 8-11 hr, respectively, & the excretion of (14)C in 24 hr urine was 45 & 70%. {{cite encyclopedia}}: |work= ignored (help)

[Flomenbaum_2006-161] Richard RA (1999). "Route of Administration". Chapter 5—Medical Aspects of Stimulant Use Disorders. Treatment Improvement Protocol 33. Substance Abuse and Mental Health Services Administration. {{cite encyclopedia}}: |work= ignored (help)

[FDA_Vyvanse-162] "Vyvanse Prescribing Information" (PDF). United States Food and Drug Administration. Shire US Inc. December 2013. pp. 12–13. Retrieved 25 February 2013.

[Metabolites-164] 
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[166] "Compound Summary". p-Hydroxynorephedrine. National Center for Biotechnology Information. Retrieved 15 October 2013. {{cite encyclopedia}}: |work= ignored (help)

[167] "Compound Summary". Phenylpropanolamine. National Center for Biotechnology Information. Retrieved 15 October 2013. {{cite encyclopedia}}: |work= ignored (help)

[Substituted_amphetamines,_FMO,_and_DBH-168] 
ISBN 9781609133450
. The simplest unsubstituted phenylisopropylamine, 1-phenyl-2-aminopropane, or amphetamine, serves as a common structural template for hallucinogens and psychostimulants. Amphetamine produces central stimulant, anorectic, and sympathomimetic actions, and it is the prototype member of this class (39). ... The phase 1 metabolism of amphetamine analogs is catalyzed by two systems: cytochrome P450 and flavin monooxygenase. ... Amphetamine can also undergo aromatic hydroxylation to p-hydroxyamphetamine. ... Subsequent oxidation at the benzylic position by DA β-hydroxylase affords p-hydroxynorephedrine. Alternatively, direct oxidation of amphetamine by DA β-hydroxylase can afford norephedrine.

[pmid13977820-169] 
PMID 13977820
. Hydroxyamphetamine was administered orally to five human subjects ... Since conversion of hydroxyamphetamine to hydroxynorephedrine occurs in vitro by the action of dopamine-β-oxidase, a simple method is suggested for measuring the activity of this enzyme and the effect of its inhibitors in man. ... The lack of effect of administration of neomycin to one patient indicates that the hydroxylation occurs in body tissues. ... a major portion of the β-hydroxylation of hydroxyamphetamine occurs in non-adrenal tissue. Unfortunately, at the present time one cannot be completely certain that the hydroxylation of hydroxyamphetamine in vivo is accomplished by the same enzyme which converts dopamine to noradrenaline.

[Glycine_conjugation_review-170] S2CID 23738007
. Figure 1. Glycine conjugation of benzoic acid. The glycine conjugation pathway consists of two steps. First benzoate is ligated to CoASH to form the high-energy benzoyl-CoA thioester. This reaction is catalyzed by the HXM-A and HXM-B medium-chain acid:CoA ligases and requires energy in the form of ATP. ... The benzoyl-CoA is then conjugated to glycine by GLYAT to form hippuric acid, releasing CoASH. In addition to the factors listed in the boxes, the levels of ATP, CoASH, and glycine may influence the overall rate of the glycine conjugation pathway.

[pmid4457764-172] PMID 4457764
. In species where aromatic hydroxylation of amphetamine is the major metabolic pathway, p-hydroxyamphetamine (POH) and p-hydroxynorephedrine (PHN) may contribute to the pharmacological profile of the parent drug. ... The location of the p-hydroxylation and β-hydroxylation reactions is important in species where aromatic hydroxylation of amphetamine is the predominant pathway of metabolism. Following systemic administration of amphetamine to rats, POH has been found in urine and in plasma.
The observed lack of a significant accumulation of PHN in brain following the intraventricular administration of (+)-amphetamine and the formation of appreciable amounts of PHN from (+)-POH in brain tissue in vivo supports the view that the aromatic hydroxylation of amphetamine following its systemic administration occurs predominantly in the periphery, and that POH is then transported through the blood-brain barrier, taken up by noradrenergic neurones in brain where (+)-POH is converted in the storage vesicles by dopamine β-hydroxylase to PHN.

[pmid2600821-173] PMID 2600821
. The metabolism of p-OHA to p-OHNor is well documented and dopamine-β hydroxylase present in noradrenergic neurons could easily convert p-OHA to p-OHNor after intraventricular administration.

[Renaissance_GPCR-175] 
PMID 15860375
. In addition to the main metabolic pathway, TAs can also be converted by nonspecific N-methyltransferase (NMT) [22] and phenylethanolamine N-methyltransferase (PNMT) [23] to the corresponding secondary amines (e.g. synephrine [14], N-methylphenylethylamine and N-methyltyramine [15]), which display similar activities on TAAR1 (TA1) as their primary amine precursors.

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[1]

[4]

[13]

[14]

[sources 1]

[sources 2]

[sources 3]

[sources 4]

[5]

[28]

[39]

[40]

[41]

[42]

[43]

[45]

[46]

[note 6]

[52]

[53]

[54]

[55]

[56]

[25]

[58]

[64]

[65]

[66]

[24]

[23]

[32]

[68]

[67]

[note 8]

[36]

[30]

[69]

[sources 5]

[33]

[34]

[75]

[78]

[79]

[76]

[80]

[81]

[82]

[83]

[84]

[85]

[Color legend 1]

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[35]

[90]

[91]

[93]

[96]

[98]

[97]

[94]

[99]

[77]

[note 13]

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[101]

[102]

[103]

[104]

[105]

[106]

[107]

[108]

[109]

[110]

[115]

[116]

[31]

[48]

[111]

[123]

[124]

[125]

[126]

[127]

[15]

[128]

[131]

[132]

[sources 8]

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[135]

[113]

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[38]

[134]

[136]

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[137]

[138]

[139]

@@ Line 8: / Line 8: @@
 | IUPAC_name = (''RS'')-1-phenylpropan-2-amine<br />(''RS'')-1-phenyl-2-aminopropane
 | image = Amphetamine-2D-skeletal.svg
+| width = 250
 | alt = An image of the amphetamine compound
 | image2 = Amphetamine-3d-CPK.png
+| width2 = 250
 | alt2 = A 3d image of the amphetamine compound
 | imagename = 1 : 1 mixture (racemate)
@@ Line 20: / Line 22: @@
 | legal_AU = Schedule 8
 | legal_CA = Schedule I
-| legal_UK = [[Drugs_controlled_by_the_UK_Misuse_of_Drugs_Act#Class B drugs|Class B]]
+| legal_UK = [[Drugs controlled by the UK Misuse of Drugs Act#Class B drugs|Class B]]
 | legal_US = Schedule II
 | legal_UN = [[Convention on Psychotropic Substances#Schedule II|Schedule II]]
@@ Line 79: / Line 81: @@
 The first pharmaceutical amphetamine was [[Benzedrine]], a brand of inhalers used to treat a variety of conditions. Currently, pharmaceutical amphetamine is typically prescribed as [[Adderall]],{{#tag:ref|"Adderall" is a [[brand name]] as opposed to a nonproprietary name; because the latter ("''dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine sulfate, and amphetamine aspartate''"<ref name="NDCD">{{cite web | title = National Drug Code Amphetamine Search Results | url = http://www.accessdata.fda.gov/scripts/cder/ndc/results.cfm?beginrow=1&numberperpage=160&searchfield=amphetamine&searchtype=ActiveIngredient&OrderBy=ProprietaryName | work = National Drug Code Directory|publisher=United States Food and Drug Administration | accessdate = 16 December 2013 | archiveurl = http://web.archive.org/web/20131216080856/http://www.accessdata.fda.gov/scripts/cder/ndc/results.cfm?beginrow=1&numberperpage=160&searchfield=amphetamine&searchtype=ActiveIngredient&OrderBy=ProprietaryName | archivedate = 7 February 2014}}</ref>) is excessively long, this article exclusively refers to this amphetamine mixture by the brand name.|name="Adderall"| group="note"}} dextroamphetamine, or the inactive [[prodrug]] [[lisdexamfetamine]]. Amphetamine, through activation of a [[TAAR1|trace amine receptor]], increases [[biogenic amine]] and [[Neurotransmitter#Excitatory and inhibitory|excitatory neurotransmitter]] activity in the brain, with its most pronounced effects targeting the [[catecholamine]] neurotransmitters norepinephrine and dopamine. At therapeutic doses, this causes emotional and cognitive effects such as euphoria, change in libido, increased wakefulness, and improved [[cognitive control]]. It induces physical effects such as decreased reaction time, fatigue resistance, and increased muscle strength.{{#tag:ref|<ref name="Adderall IR" /><ref name="Ergogenics" /><ref name="Malenka_2009" /><ref name="Libido" /><ref name="Amph Uses" /><ref name="Benzedrine" /><ref name="Miller" /><ref name="FDA Effects" />|group="sources"}}
-Much larger doses of amphetamine are likely to impair cognitive function and induce rapid muscle breakdown. [[Addiction|Drug addiction]] is a serious risk of amphetamine abuse but rarely arises from medical use. Very high doses can result in [[Stimulant psychosis#Amphetamines|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 effects.{{#tag:ref|<ref name="FDA Abuse & OD" /><ref name="Malenka_2009" /><ref name="Cochrane" /><ref name="Stimulant Misuse" /><ref name="EncycOfPsychopharm" /><ref name="Westfall" />|group="sources"}}
+Much larger doses of amphetamine are likely to impair cognitive function and induce rapid muscle breakdown. [[Addiction|Drug addiction]] is a serious risk of high dose recreational amphetamine use, but rarely arises from medical use. Very high doses can result in [[Stimulant psychosis#Amphetamines|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 effects.{{#tag:ref|<ref name="FDA Abuse & OD" /><ref name="Malenka_2009" /><ref name="Cochrane" /><ref name="Stimulant Misuse" /><ref name="EncycOfPsychopharm" /><ref name="Westfall" />|group="sources"}}
 Amphetamine is also the parent compound of its own structural class, the [[substituted amphetamine]]s,{{#tag:ref|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.|group="note"}} which includes prominent substances such as [[bupropion]], [[cathinone]], [[MDMA|MDMA (ecstasy)]], and [[methamphetamine]]. Unlike methamphetamine, amphetamine's salts lack sufficient [[Volatility (chemistry)|volatility]] to be smoked. As a member of the phenethylamine class, amphetamine is also chemically related to the naturally occurring [[trace amine]] neuromodulators, specifically [[phenethylamine]]{{#tag:ref|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.|group="note"}} and {{nowrap|[[N-methylphenethylamine|''N''-methylphenethylamine]]}}, both of which are produced within the human body. Phenethylamine is the parent compound of amphetamine, while ''N''-methylphenethylamine is a [[constitutional isomer]] that differs only in the placement of the methyl group.{{#tag:ref|<ref name="EMC">{{cite web | title = Amphetamine | url = http://www.emcdda.europa.eu/publications/drug-profiles/amphetamine | work = European Monitoring Centre for Drugs and Drug Addiction | accessdate = 19 October 2013}}</ref><ref name="Trace Amines" />|group="sources"}}
@@ Line 90: / Line 92: @@
 <onlyinclude>{{#ifeq:{{{transcludesection|Medical uses}}}|Medical uses|
-{{if pagename| Dextroamphetamine=Dextroamphetamine is used to treat [[attention deficit hyperactivity disorder]] (ADHD) and [[narcolepsy]], an excessive tendency to fall asleep. It is sometimes prescribed [[off-label]] for its past [[Indication (medicine)|medical indications]], such as [[treatment-resistant depression|depression]], [[obesity]], and [[nasal congestion]].<ref name="Amph Uses Dex">{{cite journal | author = Heal DJ, Smith SL, Gosden J, Nutt DJ | title = Amphetamine, past and present – a pharmacological and clinical perspective | journal = J. Psychopharmacol. | volume = 27 | issue = 6 | pages = 479–96 |date=June 2013 | pmid = 23539642 | pmc = 3666194 | doi = 10.1177/0269881113482532}}</ref><ref name = DM2>{{cite web|title=DEXEDRINE (dextroamphetamine sulfate) tablet [Amedra Pharmaceuticals LLC]|work=[[DailyMed]]|publisher=Amedra Pharmaceuticals LLC|date=June 2014|accessdate=18 July 2014|location=Horsham, USA|url=http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=9ee6fd99-88ea-4cea-8370-a8945581325f}}</ref>| Lisdexamfetamine=Lisdexamfetamine is used primarily as a treatment for [[attention deficit hyperactivity disorder]] (ADHD) and has similar [[off-label]] uses as those of other pharmaceutical amphetamines.<ref name="Vyvanse Drug Insert" /><ref name="Amph Uses Lisdex">{{cite journal | author = Heal DJ, Smith SL, Gosden J, Nutt DJ | title = Amphetamine, past and present – a pharmacological and clinical perspective | journal = J. Psychopharmacol. | volume = 27 | issue = 6 | pages = 479–496 |date=June 2013 | pmid = 23539642 | pmc = 3666194 | doi = 10.1177/0269881113482532 |quote=}}</ref>| other={{if pagename|Adderall=Adderall|other=Amphetamine}} is used to treat [[attention deficit hyperactivity disorder]] (ADHD) and [[narcolepsy]]{{if pagename| Adderall=| other=, and is sometimes prescribed [[off-label]] for its past [[Indication (medicine)|medical indications]], such as [[treatment-resistant depression|depression]], [[obesity]], and [[nasal congestion]]}}.<ref name="Adderall IR">{{cite web | title=Adderall IR Prescribing Information | url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/011522s040lbl.pdf | publisher = Barr Laboratories, Inc. | work = United States Food and Drug Administration |date=March 2007 | accessdate=2 November 2013 | pages=4–5}}</ref><ref name="Amph Uses">{{cite journal | author = Heal DJ, Smith SL, Gosden J, Nutt DJ | title = Amphetamine, past and present – a pharmacological and clinical perspective | journal = J. Psychopharmacol. | volume = 27 | issue = 6 | pages = 479–496 |date=June 2013 | pmid = 23539642 | pmc = 3666194 | doi = 10.1177/0269881113482532}}</ref>}} Long-term amphetamine exposure in some animal species is known to produce abnormal [[Dopamine receptor|dopamine system]] development or nerve damage,<ref name="pmid22392347" /><ref name="AbuseAndAbnormalities">{{cite journal| author=Berman S, O'Neill J, Fears S, Bartzokis G, London ED| title=Abuse of amphetamines and structural abnormalities in the brain | journal=Ann. N. Y. Acad. Sci. | year= 2008 | volume= 1141 | issue= | pages= 195–220 | pmid=18991959 | doi=10.1196/annals.1441.031 | pmc=2769923 }}</ref> but, in humans with ADHD, amphetamines appear to improve brain development and nerve growth.<ref name="Neuroplasticity 1">{{cite journal |author=Hart H, Radua J, Nakao T, Mataix-Cols D, Rubia K |title=Meta-analysis of functional magnetic resonance imaging studies of inhibition and attention in attention-deficit/hyperactivity disorder: exploring task-specific, stimulant medication, and age effects |journal=JAMA Psychiatry |volume=70 |issue=2 |pages=185–198 |date=February 2013 |pmid=23247506 |doi=10.1001/jamapsychiatry.2013.277 |url=}}</ref><ref name="Neuroplasticity 2">{{cite journal |author=Spencer TJ, Brown A, Seidman LJ, Valera EM, Makris N, Lomedico A, Faraone SV, Biederman J |title=Effect of psychostimulants on brain structure and function in ADHD: a qualitative literature review of magnetic resonance imaging-based neuroimaging studies |journal=J. Clin. Psychiatry |volume=74 |issue=9 |pages=902–917 |date=September 2013 |pmid=24107764 |doi=10.4088/JCP.12r08287 |url= |pmc=3801446}}</ref><ref name="Neuroplasticity 3">{{cite journal | title=Meta-analysis of structural MRI studies in children and adults with attention deficit hyperactivity disorder indicates treatment effects. | journal=Acta psychiatrica Scand. | date=February 2012 | volume=125 | issue=2 | pages=114–126 | pmid=22118249 | author=Frodl T, Skokauskas N | quote=Basal ganglia regions like the right globus pallidus, the right putamen, and the nucleus caudatus are structurally affected in children with ADHD. These changes and alterations in limbic regions like ACC and amygdala are more pronounced in non-treated populations and seem to diminish over time from child to adulthood. Treatment seems to have positive effects on brain structure. | doi=10.1111/j.1600-0447.2011.01786.x}}</ref> [[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]].<ref name="Neuroplasticity 1" /><ref name="Neuroplasticity 2" /><ref name="Neuroplasticity 3" />
+{{if pagename| Dextroamphetamine=Dextroamphetamine is used to treat [[attention deficit hyperactivity disorder]] (ADHD) and [[narcolepsy]] (a sleep disorder), and is sometimes prescribed [[off-label]] for its past [[Indication (medicine)|medical indications]], such as [[treatment-resistant depression|depression]], [[obesity]], and [[nasal congestion]].<ref name="Amph Uses Dex">{{cite journal | author = Heal DJ, Smith SL, Gosden J, Nutt DJ | title = Amphetamine, past and present – a pharmacological and clinical perspective | journal = J. Psychopharmacol. | volume = 27 | issue = 6 | pages = 479–96 |date=June 2013 | pmid = 23539642 | pmc = 3666194 | doi = 10.1177/0269881113482532}}</ref><ref name = DM2>{{cite web|title=DEXEDRINE (dextroamphetamine sulfate) tablet [Amedra Pharmaceuticals LLC]|work=[[DailyMed]]|publisher=Amedra Pharmaceuticals LLC|date=June 2014|accessdate=18 July 2014|location=Horsham, USA|url=http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=9ee6fd99-88ea-4cea-8370-a8945581325f}}</ref>| Lisdexamfetamine=Lisdexamfetamine is used primarily as a treatment for [[attention deficit hyperactivity disorder]] (ADHD) and has similar [[off-label]] uses as those of other pharmaceutical amphetamines.<ref name="Vyvanse Drug Insert" /><ref name="Amph Uses Lisdex">{{cite journal | author = Heal DJ, Smith SL, Gosden J, Nutt DJ | title = Amphetamine, past and present – a pharmacological and clinical perspective | journal = J. Psychopharmacol. | volume = 27 | issue = 6 | pages = 479–496 |date=June 2013 | pmid = 23539642 | pmc = 3666194 | doi = 10.1177/0269881113482532 |quote=}}</ref>| other={{if pagename|Adderall=Adderall|other=Amphetamine}} is used to treat [[attention deficit hyperactivity disorder]] (ADHD) and [[narcolepsy]] (a sleep disorder){{if pagename| Adderall=| other=, and is sometimes prescribed [[off-label]] for its past [[Indication (medicine)|medical indications]], such as [[treatment-resistant depression|depression]], [[obesity]], and [[nasal congestion]]}}.<ref name="Adderall IR">{{cite web | title=Adderall IR Prescribing Information | url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/011522s040lbl.pdf | publisher = Barr Laboratories, Inc. | work = United States Food and Drug Administration |date=March 2007 | accessdate=2 November 2013 | pages=4–5}}</ref><ref name="Amph Uses">{{cite journal | author = Heal DJ, Smith SL, Gosden J, Nutt DJ | title = Amphetamine, past and present – a pharmacological and clinical perspective | journal = J. Psychopharmacol. | volume = 27 | issue = 6 | pages = 479–496 |date=June 2013 | pmid = 23539642 | pmc = 3666194 | doi = 10.1177/0269881113482532}}</ref>}} Long-term amphetamine exposure in some animal species is known to produce abnormal [[Dopamine receptor|dopamine system]] development or nerve damage,<ref name="pmid22392347" /><ref name="AbuseAndAbnormalities">{{cite journal| author=Berman S, O'Neill J, Fears S, Bartzokis G, London ED| title=Abuse of amphetamines and structural abnormalities in the brain | journal=Ann. N. Y. Acad. Sci. | year= 2008 | volume= 1141 | issue= | pages= 195–220 | pmid=18991959 | doi=10.1196/annals.1441.031 | pmc=2769923 }}</ref> but, in humans with ADHD, amphetamines appear to improve brain development and nerve growth.<ref name="Neuroplasticity 1">{{cite journal |author=Hart H, Radua J, Nakao T, Mataix-Cols D, Rubia K |title=Meta-analysis of functional magnetic resonance imaging studies of inhibition and attention in attention-deficit/hyperactivity disorder: exploring task-specific, stimulant medication, and age effects |journal=JAMA Psychiatry |volume=70 |issue=2 |pages=185–198 |date=February 2013 |pmid=23247506 |doi=10.1001/jamapsychiatry.2013.277 |url=}}</ref><ref name="Neuroplasticity 2">{{cite journal |author=Spencer TJ, Brown A, Seidman LJ, Valera EM, Makris N, Lomedico A, Faraone SV, Biederman J |title=Effect of psychostimulants on brain structure and function in ADHD: a qualitative literature review of magnetic resonance imaging-based neuroimaging studies |journal=J. Clin. Psychiatry |volume=74 |issue=9 |pages=902–917 |date=September 2013 |pmid=24107764 |doi=10.4088/JCP.12r08287 |url= |pmc=3801446}}</ref><ref name="Neuroplasticity 3">{{cite journal | title=Meta-analysis of structural MRI studies in children and adults with attention deficit hyperactivity disorder indicates treatment effects. | journal=Acta psychiatrica Scand. | date=February 2012 | volume=125 | issue=2 | pages=114–126 | pmid=22118249 | author=Frodl T, Skokauskas N | quote=Basal ganglia regions like the right globus pallidus, the right putamen, and the nucleus caudatus are structurally affected in children with ADHD. These changes and alterations in limbic regions like ACC and amygdala are more pronounced in non-treated populations and seem to diminish over time from child to adulthood. Treatment seems to have positive effects on brain structure. | doi=10.1111/j.1600-0447.2011.01786.x}}</ref> [[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]].<ref name="Neuroplasticity 1" /><ref name="Neuroplasticity 2" /><ref name="Neuroplasticity 3" />
 Reviews of clinical stimulant research have established the safety and effectiveness of long-term amphetamine use for ADHD.<ref name="Millichap_3" /><ref name="Long-Term Outcomes Medications">{{cite journal | author = Huang YS, Tsai MH | title = Long-term outcomes with medications for attention-deficit hyperactivity disorder: current status of knowledge | journal = CNS Drugs | volume = 25 | issue = 7 | pages = 539–554 |date=July 2011 | pmid = 21699268 | doi = 10.2165/11589380-000000000-00000 | url = }}</ref> Controlled trials spanning two years have demonstrated treatment effectiveness and safety.<ref name="Long-Term Outcomes Medications" /><ref name="Millichap" /> One review highlighted a nine-month [[randomized controlled trial]] in children with ADHD that found an average increase of&nbsp;4.5 [[intelligence quotient|IQ]] points, continued increases in attention, and continued decreases in disruptive behaviors and hyperactivity.<ref name="Millichap">{{cite book | author = Millichap JG | editor = Millichap JG | title = Attention Deficit Hyperactivity Disorder Handbook: A Physician's Guide to ADHD | year = 2010 | publisher = Springer | location = New York, USA | isbn = 9781441913968 | pages = 121–123, 125–127 | edition = 2nd | chapter = Chapter 3: Medications for ADHD}}</ref>
@@ Line 133: / Line 135: @@
 ==Overdose==
 <onlyinclude>{{#ifeq:{{{transcludesection|Overdose}}}|Overdose|
-An amphetamine overdose can lead to many different symptoms but is rarely fatal with appropriate care.<ref name="International" /><ref name="Amphetamine toxidrome">{{cite journal | author = Spiller HA, Hays HL, Aleguas A | title = Overdose of drugs for attention-deficit hyperactivity disorder: clinical presentation, mechanisms of toxicity, and management | journal = CNS Drugs | volume = 27| issue = 7| pages = 531–543|date=June 2013 | pmid = 23757186 | doi = 10.1007/s40263-013-0084-8 |quote=Amphetamine, dextroamphetamine, and methylphenidate act as substrates for the cellular monoamine transporter, especially the dopamine transporter (DAT) and less so the norepinephrine (NET) and serotonin transporter. The mechanism of toxicity is primarily related to excessive extracellular dopamine, norepinephrine, and serotonin.}}</ref> The severity of overdose symptoms increases with dosage and decreases with [[drug tolerance]] to amphetamine.<ref name="Westfall" /><ref name="International" /> Tolerant individuals have been known to take as much as 5&nbsp;grams of amphetamine in a day, which is roughly 100&nbsp;times the maximum daily therapeutic dose.<ref name="International" /> Symptoms of a moderate and extremely large overdose are listed below; fatal amphetamine poisoning usually also involves convulsions and falling into a [[coma]].<ref name="FDA Abuse & OD" /><ref name="Westfall" />
+An amphetamine overdose can lead to many different symptoms, but is rarely fatal with appropriate care.<ref name="International" /><ref name="Amphetamine toxidrome">{{cite journal | author = Spiller HA, Hays HL, Aleguas A | title = Overdose of drugs for attention-deficit hyperactivity disorder: clinical presentation, mechanisms of toxicity, and management | journal = CNS Drugs | volume = 27| issue = 7| pages = 531–543|date=June 2013 | pmid = 23757186 | doi = 10.1007/s40263-013-0084-8 |quote=Amphetamine, dextroamphetamine, and methylphenidate act as substrates for the cellular monoamine transporter, especially the dopamine transporter (DAT) and less so the norepinephrine (NET) and serotonin transporter. The mechanism of toxicity is primarily related to excessive extracellular dopamine, norepinephrine, and serotonin.}}</ref>  The severity of overdose symptoms increases with dosage and decreases with [[drug tolerance]] to amphetamine.<ref name="Westfall" /><ref name="International" /> Tolerant individuals have been known to take as much as 5&nbsp;grams of amphetamine in a day, which is roughly 100&nbsp;times the maximum daily therapeutic dose.<ref name="International" /> Symptoms of a moderate and extremely large overdose are listed below; fatal amphetamine poisoning usually also involves convulsions and [[coma]].<ref name="FDA Abuse & OD" /><ref name="Westfall" />
+Pathological overactivation of the [[mesolimbic pathway]], a [[dopamine pathway]] that connects the [[ventral tegmental area]] to the [[nucleus accumbens]], plays a central role in amphetamine addiction;<ref name="Amphetamine KEGG ΔFosB" /><ref name="Magnesium" /> Individuals who frequently overdose on amphetamine during recreational use have a high risk of developing an amphetamine addiction, since frequent overdose continually increases the level of [[accumbal]] [[ΔFosB]], a "master control protein" for addiction;{{if pagename| Amphetamine=<ref name="Cellular basis">{{cite journal | author = Nestler EJ | title = Cellular basis of memory for addiction | journal = Dialogues Clin Neurosci | volume = 15 | issue = 4 | pages = 431–443 |date=December 2013 | pmid = 24459410 | pmc = 3898681 | doi = | quote = DESPITE THE IMPORTANCE OF NUMEROUS PSYCHOSOCIAL FACTORS, AT ITS CORE, DRUG ADDICTION INVOLVES A BIOLOGICAL PROCESS: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction.&nbsp;... A large body of literature has demonstrated that such ΔFosB induction in D1-type NAc neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement}}</ref><ref name="Nestler1" /><ref name="Amphetamine KEGG ΔFosB" />| Other=<ref name="Cellular basis" /><ref name="Nestler1">{{cite journal | author = Robison AJ, Nestler EJ | title = Transcriptional and epigenetic mechanisms of addiction | journal = Nat. Rev. Neurosci. | volume = 12 | issue = 11 | pages = 623–637 | date = November 2011 | pmid = 21989194 | pmc = 3272277 | doi = 10.1038/nrn3111 | quote = ΔFosB serves as one of the master control proteins governing this structural plasticity.}}</ref><ref name="Amphetamine KEGG ΔFosB">{{cite web | title=Amphetamine – Homo sapiens (human) | url=http://www.genome.jp/kegg-bin/show_pathway?hsa05031 | work=KEGG Pathway | accessdate=31 October 2014 | author=Kanehisa Laboratories | date=10 October 2014}}</ref>}} once nucleus accumbens ΔFosB is sufficiently overexpressed, it begins to directly modulate the severity of addictive behavior (e.g., compulsive drug-seeking).<ref name="Natural and drug addictions" /><ref name="What the ΔFosB?">{{cite journal | author = Ruffle JK | title = Molecular neurobiology of addiction: what's all the (Δ)FosB about? | journal = Am J Drug Alcohol Abuse | volume = 40 | issue = 6 | pages = 428–437 | date = November 2014 | pmid = 25083822 | doi = 10.3109/00952990.2014.933840 | quote = <br />ΔFosB as a therapeutic biomarker<br />The strong correlation between chronic drug exposure and ΔFosB provides novel opportunities for targeted therapies in addiction (118), and suggests methods to analyze their efficacy (119). Over the past two decades, research has progressed from identifying ΔFosB induction to investigating its subsequent action (38). It is likely that ΔFosB research will now progress into a new era – the use of ΔFosB as a biomarker. If ΔFosB detection is indicative of chronic drug exposure (and is at least partly responsible for dependence of the substance), then its monitoring for therapeutic efficacy in interventional studies is a suitable biomarker (Figure 2). Examples of therapeutic avenues are discussed herein.&nbsp;...<br /><br />Conclusions<br />ΔFosB is an essential transcription factor implicated in the molecular and behavioral pathways of addiction following repeated drug exposure. The formation of ΔFosB in multiple brain regions, and the molecular pathway leading to the formation of AP-1 complexes is well understood. The establishment of a functional purpose for ΔFosB has allowed further determination as to some of the key aspects of its molecular cascades, involving effectors such as GluR2 (87,88), Cdk5 (93) and NFkB (100). Moreover, many of these molecular changes identified are now directly linked to the structural, physiological and behavioral changes observed following chronic drug exposure (60,95,97,102). New frontiers of research investigating the molecular roles of ΔFosB have been opened by epigenetic studies, and recent advances have illustrated the role of ΔFosB acting on DNA and histones, truly as a ‘‘molecular switch’’ (34). As a consequence of our improved understanding of ΔFosB in addiction, it is possible to evaluate the addictive potential of current medications (119), as well as use it as a biomarker for assessing the efficacy of therapeutic interventions (121,122,124). Some of these proposed interventions have limitations (125) or are in their infancy (75). However, it is hoped that some of these preliminary findings may lead to innovative treatments, which are much needed in addiction.}}</ref> While there are currently no effective drugs for treating amphetamine addiction, regularly engaging in sustained aerobic exercise appears to reduce the risk of developing such an addiction.<ref name="Running vs addiction" /> Sustained aerobic exercise on a regular basis also appears to be an effective treatment for amphetamine addiction;<ref name="Natural and drug addictions" /><ref name="Running vs addiction" /> exercise therapy improves [[wikt:clinical|clinical]] treatment outcomes and may be used as a [[combination therapy]] with [[cognitive behavioral therapy]], which is currently the best clinical treatment available.<ref name="Running vs addiction" /><ref name="Nestler CBT"/>
-People who [[Wikt:chronic|chronically]] overdose on amphetamine are at a high risk of becoming addicted to it since high doses result in overexpression of [[ΔFosB]] in the nucleus accumbens<ref name="Nestler" />; ΔFosB is a gene that plays a significant role in drug addiction.{{if pagename| Amphetamine=<ref name="Amphetamine KEGG ΔFosB" />| Other=<ref name="Amphetamine KEGG ΔFosB">{{cite web | title=Amphetamine – Homo sapiens (human) | url=http://www.genome.jp/kegg-bin/show_pathway?hsa05031 | work=KEGG Pathway | accessdate=31 October 2014 | author=Kanehisa Laboratories | date=10 October 2014}}</ref>}} Pathological overactivation of the mesolimbic dopamine pathway is also thought to play a part in drug addiction.<ref name="Magnesium" /> While there are currently no effective drugs for treating amphetamine addiction,<ref name="Cochrane Addiction">{{cite journal |author=Srisurapanont M, Jarusuraisin N, Kittirattanapaiboon P |title=Treatment for amphetamine dependence and abuse |journal=Cochrane Database Syst. Rev. |volume= |issue=4 |pages=CD003022 |year=2001 |pmid=11687171 |doi=10.1002/14651858.CD003022 |quote=Although there are a variety of amphetamines and amphetamine derivatives, the word "amphetamines" in this review stands for amphetamine, dextroamphetamine and methamphetamine only. |editor=Srisurapanont M}}</ref> sustained aerobic exercise appears to reduce the risk of developing such an addiction.<ref name="Running vs addiction" /> Sustained aerobic exercise also seems to work well as a secondary treatment for amphetamine addiction<ref name="Running vs addiction" /> when used together with cognitive behavioral therapy, which is currently the best treatment available.<ref name="Nestler CBT"/>
 {{Amphetamine overdose}}
 ===Addiction===
+<!--The line below contains only affects the transclusions to other amphetamine articles-->
-<noinclude>{{Psychostimulant addiction|Colorcode=yes|align=right|header=[[Signaling cascade]] in the [[nucleus accumbens]] that results in amphetamine addiction}}</noinclude><includeonly>{{Addiction glossary}}</includeonly><!--
+<includeonly>{{Addiction glossary}}</includeonly>
--->[[Substance dependence|Addiction]] is a serious risk with heavy recreational amphetamine use but is unlikely to arise from typical medical use at therapeutic doses.<ref name="FDA Abuse & OD" /><ref name="EncycOfPsychopharm">{{Cite book | author = Stolerman IP | editor = Stolerman IP | title = Encyclopedia of Psychopharmacology | year = 2010 | publisher = Springer | location = Berlin, Germany; London, England | isbn = 9783540686989 | page = 78}}</ref><ref name="Westfall" /> [[Drug tolerance|Tolerance]] develops rapidly in heavy amphetamine use, so periods of extended use require increasingly larger doses of the drug in order to achieve the same effect.<ref>{{cite web| title = Amphetamines: Drug Use and Abuse | work = Merck Manual Home Edition | publisher = Merck | url = http://www.merckmanuals.com/home/special_subjects/drug_use_and_abuse/amphetamines.html | accessdate = 28 February 2007 | archiveurl = http://web.archive.org/web/20070217053619/http://www.merck.com/mmhe/sec07/ch108/ch108g.html |date=February 2003 | archivedate = 17 February 2007}}</ref><ref>{{cite journal |author=Pérez-Mañá C, Castells X, Torrens M, Capellà D, Farre M |title=Efficacy of psychostimulant drugs for amphetamine abuse or dependence |journal=Cochrane Database Syst. Rev. |volume=9 |issue= |pages=CD009695 |year=2013 |pmid=23996457 |doi=10.1002/14651858.CD009695.pub2 |url= |editor=Pérez-Mañá C}}</ref>
+<!--The lines below specifies these templates for use in this article-->
+<noinclude>
+{{Addiction glossary|class="wikitable mw-collapsible mw-collapsed"|width=610|reverse citation order=yes}}
+{{Psychostimulant addiction|Colorcode=yes|align=right|header=[[Signaling cascade]] in the [[nucleus accumbens]] that results in amphetamine addiction}}
+</noinclude><!--
+-->[[Addiction]] is a serious risk with heavy recreational amphetamine use but is unlikely to arise from typical medical use at therapeutic doses.<ref name="FDA Abuse & OD" /><ref name="EncycOfPsychopharm">{{Cite book | author = Stolerman IP | editor = Stolerman IP | title = Encyclopedia of Psychopharmacology | year = 2010 | publisher = Springer | location = Berlin, Germany; London, England | isbn = 9783540686989 | page = 78}}</ref><ref name="Westfall" /> [[Drug tolerance|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 effect.<ref>{{cite web| title = Amphetamines: Drug Use and Abuse | work = Merck Manual Home Edition | publisher = Merck | url = http://www.merckmanuals.com/home/special_subjects/drug_use_and_abuse/amphetamines.html | accessdate = 28 February 2007 | archiveurl = http://web.archive.org/web/20070217053619/http://www.merck.com/mmhe/sec07/ch108/ch108g.html |date=February 2003 | archivedate = 17 February 2007}}</ref><ref>{{cite journal |author=Pérez-Mañá C, Castells X, Torrens M, Capellà D, Farre M |title=Efficacy of psychostimulant drugs for amphetamine abuse or dependence |journal=Cochrane Database Syst. Rev. |volume=9 |issue= |pages=CD009695 |year=2013 |pmid=23996457 |doi=10.1002/14651858.CD009695.pub2 |url= |editor=Pérez-Mañá C}}</ref>
 ====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]].<ref name="Nestler, Hyman, and Malenka 2">{{cite journal |author=Hyman SE, Malenka RC, Nestler EJ |title=Neural mechanisms of addiction: the role of reward-related learning and memory |journal=Annu. Rev. Neurosci. |volume=29 |issue= |pages=565–598 |year=2006 |pmid=16776597 |doi=10.1146/annurev.neuro.29.051605.113009 |url=}}</ref><ref name="Nestler" /><ref name="Addiction genetics" /> The most important [[transcription factor]]s{{#tag:ref|Transcription factors are proteins that increase or decrease the [[gene expression|expression]] of specific genes.<ref name="NHM-Transcription factor">{{cite book | author = Malenka RC, Nestler EJ, Hyman SE | editor = Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York, USA | isbn = 9780071481274 | page = 94 | edition = 2nd | chapter = Chapter 4: Signal Transduction in the Brain | quote= All living cells depend on the regulation of gene expression by extracellular signals for their development, homeostasis, and adaptation to the environment. Indeed, many signal transduction pathways function primarily to modify transcription factors that alter the expression of specific genes. Thus, neurotransmitters, growth factors, and drugs change patterns of gene expression in cells and in turn affect many aspects of nervous system functioning, including the formation of long-term memories. Many drugs that require prolonged administration, such as antidepressants and antipsychotics, trigger changes in gene expression that are thought to be therapeutic adaptations to the initial action of the drug.}}</ref>|group="note"}} that produce these alterations are [[ΔFosB]], [[Cyclic adenosine monophosphate|cAMP]] response element binding protein ([[cAMP response element binding protein|CREB]]), and nuclear factor kappa B ([[nuclear factor kappa B|NFκB]]).<ref name="Nestler" /> ΔFosB is the most significant transcription factor in drug addiction, since its overexpression in the nucleus accumbens is [[necessary and sufficient]] for many of the associated neural adaptations that occur; that is, ΔFosB overexpression (see diagram) always occurs together with the changes in the brain seen in drug addiction.<ref name="Nestler" /> It has been implicated in addictions to [[alcoholism|alcohol]], [[cannabinoid]]s, [[cocaine]], [[nicotine]], [[opiates]], [[phencyclidine]], and [[substituted amphetamines]].<ref name="Nestler" /><ref name="Natural and drug addictions" /><ref name="Alcoholism ΔFosB">{{cite web | title=Alcoholism – Homo sapiens (human) | url=http://www.genome.jp/kegg-bin/show_pathway?hsa05034+2354 | work=KEGG Pathway | accessdate=31 October 2014 | author=Kanehisa Laboratories | date=29 October 2014}}</ref>
+Current models of addiction from chronic drug use involve alterations in [[gene expression]] in certain parts of the brain, particularly the [[nucleus accumbens]].<ref name="Nestler, Hyman, and Malenka 2">{{cite journal |author=Hyman SE, Malenka RC, Nestler EJ |title=Neural mechanisms of addiction: the role of reward-related learning and memory |journal=Annu. Rev. Neurosci. |volume=29 |issue= |pages=565–598 |year=2006 |pmid=16776597 |doi=10.1146/annurev.neuro.29.051605.113009 |url=}}</ref><ref name="Nestler" /><ref name="Addiction genetics" /> The most important [[transcription factor]]s{{#tag:ref|Transcription factors are proteins that increase or decrease the [[gene expression|expression]] of specific genes.<ref name="NHM-Transcription factor">{{cite book | author = Malenka RC, Nestler EJ, Hyman SE | editor = Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York, USA | isbn = 9780071481274 | page = 94 | edition = 2nd | chapter = Chapter 4: Signal Transduction in the Brain | quote= All living cells depend on the regulation of gene expression by extracellular signals for their development, homeostasis, and adaptation to the environment. Indeed, many signal transduction pathways function primarily to modify transcription factors that alter the expression of specific genes. Thus, neurotransmitters, growth factors, and drugs change patterns of gene expression in cells and in turn affect many aspects of nervous system functioning, including the formation of long-term memories. Many drugs that require prolonged administration, such as antidepressants and antipsychotics, trigger changes in gene expression that are thought to be therapeutic adaptations to the initial action of the drug.}}</ref>|group="note"}} that produce these alterations are [[ΔFosB]], [[Cyclic adenosine monophosphate|cAMP]] response element binding protein ([[cAMP response element binding protein|CREB]]), and nuclear factor kappa B ([[nuclear factor kappa B|NFκB]]).<ref name="Nestler" /> ΔFosB plays a crucial role in the development drug addictions, since its overexpression in the nucleus accumbens is [[necessary and sufficient#Definitions|necessary and sufficient]]{{#tag:ref|In simpler terms, this ''necessary and sufficient'' relationship means that ΔFosB overexpression in the nucleus accumbens and addiction-related behavioral and neural adaptations always simultaneously occur together and never occur alone.|group="note"}} for most of the behavioral and neural adaptations that arise from addiction.<ref name="Cellular basis" /><ref name="What the ΔFosB?" /><ref name="Nestler" /> Once ΔFosB is sufficiently overexpressed, it induces an addictive state that becomes increasingly more severe with further increases in ΔFosB expression.<ref name="What the ΔFosB?" /> It has been implicated in addictions to [[alcoholism|alcohol]], [[cannabinoid]]s, [[cocaine]], [[nicotine]], [[opiates]], [[phencyclidine]], and [[substituted amphetamines]].<ref name="Natural and drug addictions" /><ref name="Nestler" /><ref name="Alcoholism ΔFosB">{{cite web | title=Alcoholism – Homo sapiens (human) | url=http://www.genome.jp/kegg-bin/show_pathway?hsa05034+2354 | work=KEGG Pathway | accessdate=31 October 2014 | author=Kanehisa Laboratories | date=29 October 2014}}</ref>
-[[ΔJunD]] is the transcription factor which directly opposes ΔFosB.<ref name="Nestler" /> Increases in nucleus accumbens ΔJunD expression using [[viral vector]]s can reduce many of the neural and behavioral alterations seen in chronic drug abuse (i.e., the changes caused by ΔFosB); large enough increases may block these changes altogether.<ref name="Nestler" /> ΔFosB also plays an important role in regulating behavioral responses to [[natural reward]]s, such as palatable food, sex, and exercise.<ref name="Nestler" /><ref name="Natural and drug addictions" /><ref name="ΔFosB reward">{{cite journal | author = Blum K, Werner T, Carnes S, Carnes P, Bowirrat A, Giordano J, Oscar-Berman M, Gold M | title = Sex, drugs, and rock 'n' roll: hypothesizing common mesolimbic activation as a function of reward gene polymorphisms | journal = J. Psychoactive Drugs | volume = 44 | issue = 1 | pages = 38–55 | year = 2012 | pmid = 22641964 | pmc = 4040958 | doi = 10.1080/02791072.2012.662112| quote = It has been found that deltaFosB gene in the {{abbr|NAc|nucleus accumbens}} is critical for reinforcing effects of sexual reward. Pitchers and colleagues (2010) reported that sexual experience was shown to cause DeltaFosB accumulation in several limbic brain regions including the NAc, medial pre-frontal cortex, {{abbr|VTA|ventral tegmental area}}, caudate, and putamen, but not the medial preoptic nucleus.&nbsp;... these findings support a critical role for DeltaFosB expression in the NAc in the reinforcing effects of sexual behavior and sexual experience-induced facilitation of sexual performance.&nbsp;... both drug addiction and sexual addiction represent pathological forms of neuroplasticity along with the emergence of aberrant behaviors involving a cascade of neurochemical changes mainly in the brain's rewarding circuitry.}}</ref> Since both natural rewards and drugs of abuse [[inducible gene|induce expression]] of ΔFosB (i.e., they cause the brain to make more of it), chronic acquisition of these rewards can result in a similar pathological state of addiction.<ref name="Natural and drug addictions" /><ref name="Nestler">{{cite journal | author = Robison AJ, Nestler EJ | title = Transcriptional and epigenetic mechanisms of addiction | journal = Nat. Rev. Neurosci. | volume = 12 | issue = 11 | pages = 623–637 |date=November 2011 | pmid = 21989194 | pmc = 3272277 | doi = 10.1038/nrn3111 | quote = ΔFosB has been linked directly to several addiction-related behaviors&nbsp;... Importantly, genetic or viral overexpression of ΔJunD, a dominant negative mutant of JunD which antagonizes ΔFosB- and other AP-1-mediated transcriptional activity, in the {{abbr|NAc|nucleus accumbens}} or {{abbr|OFC|orbitofrontal cortex}} blocks these key effects of drug exposure<sup>14,22–24</sup>. This indicates that ΔFosB is both necessary and sufficient for many of the changes wrought in the brain by chronic drug exposure. ΔFosB is also induced in D1-type NAc {{abbr|MSNs|medium spiny neurons}} by chronic consumption of several natural rewards, including sucrose, high fat food, sex, wheel running, where it promotes that consumption<sup>14,26–30</sup>. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states. }}</ref> Consequently, ΔFosB is the key transcription factor involved in amphetamine addiction and amphetamine-induced [[sex addiction]]s, which are compulsive sexual behaviors that result from amphetamine use. These sex addictions are caused by [[dopamine dysregulation syndrome]], which has been observed in some patients taking dopaminergic medications like amphetamine.<ref name="Natural and drug addictions" /><ref name="ΔFosB reward" /><ref name="Amph and sex addiction"><!--Supplemental primary source-->{{cite journal | author = Pitchers KK, Vialou V, Nestler EJ, Laviolette SR, Lehman MN, Coolen LM | title = Natural and drug rewards act on common neural plasticity mechanisms with ΔFosB as a key mediator | journal = J. Neurosci. | volume = 33 | issue = 8 | pages = 3434–3442 |date=February 2013 | pmid = 23426671 | pmc = 3865508 | doi = 10.1523/JNEUROSCI.4881-12.2013 | quote = Drugs of abuse induce neuroplasticity in the natural reward pathway, specifically the nucleus accumbens (NAc), thereby causing development and expression of addictive behavior.&nbsp;... Together, these findings demonstrate that drugs of abuse and natural reward behaviors act on common molecular and cellular mechanisms of plasticity that control vulnerability to drug addiction, and that this increased vulnerability is mediated by ΔFosB and its downstream transcriptional targets.&nbsp;... Sexual behavior is highly rewarding (Tenk et al., 2009), and sexual experience causes sensitized drug-related behaviors, including cross-sensitization to amphetamine (Amph)-induced locomotor activity (Bradley and Meisel, 2001; Pitchers et al., 2010a) and enhanced Amph reward (Pitchers et al., 2010a). Moreover, sexual experience induces neural plasticity in the NAc similar to that induced by psychostimulant exposure, including increased dendritic spine density (Meisel and Mullins, 2006; Pitchers et al., 2010a), altered glutamate receptor trafficking, and decreased synaptic strength in prefrontal cortex-responding NAc shell neurons (Pitchers et al., 2012). Finally, periods of abstinence from sexual experience were found to be critical for enhanced Amph reward, NAc spinogenesis (Pitchers et al., 2010a), and glutamate receptor trafficking (Pitchers et al., 2012). These findings suggest that natural and drug reward experiences share common mechanisms of neural plasticity}}</ref>
+[[ΔJunD]] is the transcription factor which directly opposes ΔFosB.<ref name="Nestler" /> Sufficiently overexpressing ΔJunD in the nucleus accumbens with [[viral vector]]s can completely block many of the neural and behavioral alterations seen in chronic drug abuse (i.e., the alterations mediated by ΔFosB).<ref name="Nestler" /> ΔFosB also plays an important role in regulating behavioral responses to [[natural reward]]s, such as palatable food, sex, and exercise.<ref name="Natural and drug addictions" /><ref name="Nestler" /><ref name="ΔFosB reward">{{cite journal | author = Blum K, Werner T, Carnes S, Carnes P, Bowirrat A, Giordano J, Oscar-Berman M, Gold M | title = Sex, drugs, and rock 'n' roll: hypothesizing common mesolimbic activation as a function of reward gene polymorphisms | journal = J. Psychoactive Drugs | volume = 44 | issue = 1 | pages = 38–55 | year = 2012 | pmid = 22641964 | pmc = 4040958 | doi = 10.1080/02791072.2012.662112| quote = It has been found that deltaFosB gene in the {{abbr|NAc|nucleus accumbens}} is critical for reinforcing effects of sexual reward. Pitchers and colleagues (2010) reported that sexual experience was shown to cause DeltaFosB accumulation in several limbic brain regions including the NAc, medial pre-frontal cortex, {{abbr|VTA|ventral tegmental area}}, caudate, and putamen, but not the medial preoptic nucleus.&nbsp;... these findings support a critical role for DeltaFosB expression in the NAc in the reinforcing effects of sexual behavior and sexual experience-induced facilitation of sexual performance.&nbsp;... both drug addiction and sexual addiction represent pathological forms of neuroplasticity along with the emergence of aberrant behaviors involving a cascade of neurochemical changes mainly in the brain's rewarding circuitry.}}</ref> Since both natural rewards and addictive drugs [[inducible gene|induce expression]] of ΔFosB (i.e., they cause the brain to produce more of it), chronic acquisition of these rewards can result in a similar pathological state of addiction.<ref name="Natural and drug addictions" /><ref name="Nestler">{{cite journal | author = Robison AJ, Nestler EJ | title = Transcriptional and epigenetic mechanisms of addiction | journal = Nat. Rev. Neurosci. | volume = 12 | issue = 11 | pages = 623–637 |date=November 2011 | pmid = 21989194 | pmc = 3272277 | doi = 10.1038/nrn3111 | quote = ΔFosB has been linked directly to several addiction-related behaviors&nbsp;... Importantly, genetic or viral overexpression of ΔJunD, a dominant negative mutant of JunD which antagonizes ΔFosB- and other AP-1-mediated transcriptional activity, in the {{abbr|NAc|nucleus accumbens}} or {{abbr|OFC|orbitofrontal cortex}} blocks these key effects of drug exposure<sup>14,22–24</sup>. This indicates that ΔFosB is both necessary and sufficient for many of the changes wrought in the brain by chronic drug exposure. ΔFosB is also induced in D1-type NAc {{abbr|MSNs|medium spiny neurons}} by chronic consumption of several natural rewards, including sucrose, high fat food, sex, wheel running, where it promotes that consumption<sup>14,26–30</sup>. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states. }}</ref> Consequently, ΔFosB is the most significant factor involved in both amphetamine addiction and amphetamine-induced [[sex addiction]]s, which are compulsive sexual behaviors that result from excessive amphetamine use.<ref name="Natural and drug addictions" /><ref name="Amph and sex addiction" /> These sex addictions are caused by [[dopamine dysregulation syndrome]], an addictive disorder which has been observed in some patients taking [[dopaminergic#Supplements and drugs|dopaminergic drugs]], like amphetamine, for an extended period.<ref name="Natural and drug addictions" /><ref name="ΔFosB reward" /><ref name="Amph and sex addiction"><!--Supplemental primary source-->{{cite journal | author = Pitchers KK, Vialou V, Nestler EJ, Laviolette SR, Lehman MN, Coolen LM | title = Natural and drug rewards act on common neural plasticity mechanisms with ΔFosB as a key mediator | journal = J. Neurosci. | volume = 33 | issue = 8 | pages = 3434–3442 |date=February 2013 | pmid = 23426671 | pmc = 3865508 | doi = 10.1523/JNEUROSCI.4881-12.2013 | quote = Drugs of abuse induce neuroplasticity in the natural reward pathway, specifically the nucleus accumbens (NAc), thereby causing development and expression of addictive behavior.&nbsp;... Together, these findings demonstrate that drugs of abuse and natural reward behaviors act on common molecular and cellular mechanisms of plasticity that control vulnerability to drug addiction, and that this increased vulnerability is mediated by ΔFosB and its downstream transcriptional targets.&nbsp;... Sexual behavior is highly rewarding (Tenk et al., 2009), and sexual experience causes sensitized drug-related behaviors, including cross-sensitization to amphetamine (Amph)-induced locomotor activity (Bradley and Meisel, 2001; Pitchers et al., 2010a) and enhanced Amph reward (Pitchers et al., 2010a). Moreover, sexual experience induces neural plasticity in the NAc similar to that induced by psychostimulant exposure, including increased dendritic spine density (Meisel and Mullins, 2006; Pitchers et al., 2010a), altered glutamate receptor trafficking, and decreased synaptic strength in prefrontal cortex-responding NAc shell neurons (Pitchers et al., 2012). Finally, periods of abstinence from sexual experience were found to be critical for enhanced Amph reward, NAc spinogenesis (Pitchers et al., 2010a), and glutamate receptor trafficking (Pitchers et al., 2012). These findings suggest that natural and drug reward experiences share common mechanisms of neural plasticity}}</ref>
 The effects of amphetamine on gene regulation are both dose- and route-dependent.<ref name="Addiction genetics">{{cite journal | author=Steiner H, Van Waes V | title=Addiction-related gene regulation: risks of exposure to cognitive enhancers vs. other psychostimulants | journal=Prog. Neurobiol. | volume=100 | issue= | pages=60–80 | date=January 2013 | pmid=23085425 | pmc=3525776 | doi=10.1016/j.pneurobio.2012.10.001 }}</ref> Most of the research on gene regulation and addiction is based upon animal studies with intravenous amphetamine administration at very high doses.<ref name="Addiction genetics" /> 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.<ref name="Addiction genetics" />
@@ Line 152: / Line 161: @@
 ====Pharmacological treatments====
-A [[Cochrane Collaboration]] review on amphetamine and [[methamphetamine]] addiction and abuse indicates that the current evidence on effective pharmacological treatments (i.e., drugs) is extremely limited.<ref name="Cochrane Addiction" />| group = "note" }} [[Fluoxetine]]{{#tag:ref|During short-term treatment, fluoxetine may decrease drug craving.<ref name="Cochrane Addiction" />| group = "note" }} and [[imipramine]]{{#tag:ref|During "medium-term treatment," imipramine may extend the duration of adherence to addiction treatment.<ref name="Cochrane Addiction" />| group = "note" }} have some limited benefits but neither can be considered an effective drug for amphetamine addiction or abuse.<ref name="Cochrane Addiction" /> A corroborating review indicated that amphetamine addiction is mediated through increased activation of [[dopamine receptor]]s and {{nowrap|[[wikt:colocalize|co-localized]]}} [[NMDA receptor]]s in the [[mesolimbic pathway|mesolimbic dopamine pathway]], the brain's reward center; it connects the [[ventral tegmental area]] to the [[nucleus accumbens]].<ref name="Magnesium" /> This review also noted that [[magnesium|magnesium ions]] and serotonin inhibit NMDA receptors and that the magnesium ions do so by blocking the receptor's [[calcium channel]]s.<ref name="Magnesium" /> It also suggested that, based upon animal testing, pathological (addiction-inducing) amphetamine use significantly reduces the level of intracellular magnesium throughout the brain.<ref name="Magnesium" /> Supplemental magnesium,{{#tag:ref|The review indicated that [[magnesium aspartate|magnesium L-aspartate]] and [[magnesium chloride]] produce significant changes in addictive behavior;<ref name="Magnesium" /> other forms of magnesium were not mentioned.|group="note"}} like fluoxetine treatment, has been shown to reduce amphetamine [[self-administration]] (doses given to oneself) in both humans and lab animals.<ref name="Cochrane Addiction" /><ref name="Magnesium">{{cite journal |author=Nechifor M |title=Magnesium in drug dependences |journal=Magnes. Res. |volume=21 |issue=1 |pages=5–15 |date=March 2008 |pmid=18557129 |doi= |url=}}</ref>
+A [[Cochrane Collaboration]] review on amphetamine and [[methamphetamine]] addiction indicates that the current evidence on pharmacological treatments (i.e., drugs) is extremely limited.<ref name="Cochrane Addiction">{{cite journal |author=Srisurapanont M, Jarusuraisin N, Kittirattanapaiboon P |title=Treatment for amphetamine dependence and abuse |journal=Cochrane Database Syst. Rev. |volume= |issue=4 |pages=CD003022 |year=2001 |pmid=11687171 |doi=10.1002/14651858.CD003022 |quote=Although there are a variety of amphetamines and amphetamine derivatives, the word "amphetamines" in this review stands for amphetamine, dextroamphetamine and methamphetamine only. |editor=Srisurapanont M}}</ref> [[Fluoxetine]]{{#tag:ref|During short-term treatment, fluoxetine may decrease drug craving.<ref name="Cochrane Addiction" />| group = "note" }} and [[imipramine]]{{#tag:ref|During "medium-term treatment," imipramine may extend the duration of adherence to addiction treatment.<ref name="Cochrane Addiction" />| group = "note" }} have some limited benefits but neither drug is an effective [[monotherapy]] for amphetamine addiction.<ref name="Cochrane Addiction" /> A corroborating review indicated that amphetamine addiction is mediated through increased activation of [[dopamine receptor]]s and {{nowrap|[[wikt:colocalize|co-localized]]}} [[NMDA receptor]]s in the mesolimbic pathway (i.e., the nucleus accumbens).<ref name="Magnesium" /> This review also noted that [[magnesium|magnesium ions]] and serotonin inhibit NMDA receptors and that the magnesium ions do so by blocking the receptor's [[calcium channel]]s.<ref name="Magnesium" /> It also suggested that, based upon animal testing, pathological (addiction-inducing) amphetamine use significantly reduces the level of intracellular magnesium throughout the brain.<ref name="Magnesium" /> Supplemental magnesium,{{#tag:ref|The review indicated that [[magnesium aspartate|magnesium L-aspartate]] and [[magnesium chloride]] produce significant changes in addictive behavior;<ref name="Magnesium" /> other forms of magnesium were not mentioned.|group="note"}} like fluoxetine treatment, has been shown to reduce amphetamine [[self-administration]] (doses given to oneself) in both humans and lab animals.<ref name="Cochrane Addiction" /><ref name="Magnesium">{{cite journal |author=Nechifor M |title=Magnesium in drug dependences |journal=Magnes. Res. |volume=21 |issue=1 |pages=5–15 |date=March 2008 |pmid=18557129 |doi= |url=}}</ref>
 ====Behavioral treatments====
-[[Cognitive behavioral therapy]] is currently the most effective clinical treatment for psychostimulant addiction.<ref name="Nestler CBT">{{cite book | author = Malenka RC, Nestler EJ, Hyman SE | editor = Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York, USA | isbn = 9780071481274 | page = 386 | edition = 2nd | chapter = Chapter 15: Reinforcement and Addictive Disorders | quote= Currently, cognitive–behavioral therapies are the most successful treatment available for preventing the relapse of psychostimulant use.}}</ref> Additionally, research on the [[neurobiological effects of physical exercise#ΔFosB|neurobiological effects of physical exercise]] suggests that sustained aerobic exercise, especially endurance exercise (e.g., [[marathon running]]), prevents the development of drug addiction and is an effective adjunct (supplemental) treatment for amphetamine addiction.<ref name="Running vs addiction">{{cite journal | author = Lynch WJ, Peterson AB, Sanchez V, Abel J, Smith MA | title = Exercise as a novel treatment for drug addiction: a neurobiological and stage-dependent hypothesis | journal = Neurosci Biobehav Rev | volume = 37 | issue = 8 | pages = 1622–44 |date=September 2013 | pmid = 23806439 | pmc = 3788047 | doi = 10.1016/j.neubiorev.2013.06.011 | quote = these data show that exercise can affect dopaminergic signaling at many different levels, which may underlie its ability to modify vulnerability during drug use initiation. Exercise also produces neuroadaptations that may influence an individual's vulnerability to initiate drug use. Consistent with this idea, chronic moderate levels of forced treadmill running blocks not only subsequent methamphetamine-induced conditioned place preference, but also stimulant-induced increases in dopamine release in the {{abbr|NAc|nucleus accumbens}} (Chen et al., 2008) and striatum (Marques et al., 2008).&nbsp;... [These] findings indicate the efficacy of exercise at reducing drug intake in drug-dependent individuals&nbsp;... wheel running [reduces] methamphetamine self-administration under extended access conditions (Engelmann et al., 2013)&nbsp;... These findings suggest that exercise may "magnitude"-dependently prevent the development of an addicted phenotype possibly by blocking/reversing behavioral and neuro-adaptive changes that develop during and following extended access to the drug.&nbsp;... Exercise has been proposed as a treatment for drug addiction that may reduce drug craving and risk of relapse. Although few clinical studies have investigated the efficacy of exercise for preventing relapse, the few studies that have been conducted generally report a reduction in drug craving and better treatment outcomes (see Table 4).&nbsp;... Taken together, these data suggest that the potential benefits of exercise during relapse, particularly for relapse to psychostimulants, may be mediated via chromatin remodeling and possibly lead to greater treatment outcomes.}}</ref><ref name="Natural and drug addictions" /> Exercise leads to better treatment outcomes when used as an adjunct treatment, particularly for psychostimulant addictions.<ref name="Running vs addiction" /> In particular, [[aerobic exercise]] decreases psychostimulant self-administration, reduces the [[reinstatement]] (i.e., relapse) of drug-seeking, and induces increased [[dopamine receptor D2|dopamine receptor D<sub>2</sub>]] (DRD2) density in the [[striatum]]. This is the opposite of pathological stimulant use, which induces decreased striatal DRD2 density.<ref name="Natural and drug addictions">{{cite journal | author = Olsen CM | title = Natural rewards, neuroplasticity, and non-drug addictions | journal = Neuropharmacology | volume = 61 | issue = 7 | pages = 1109–1122 |date=December 2011 | pmid = 21459101 | pmc = 3139704 | doi = 10.1016/j.neuropharm.2011.03.010 | quote = Similar to environmental enrichment, studies have found that exercise reduces self-administration and relapse to drugs of abuse (Cosgrove et al., 2002; Zlebnik et al., 2010). There is also some evidence that these preclinical findings translate to human populations, as exercise reduces withdrawal symptoms and relapse in abstinent smokers (Daniel et al., 2006; Prochaska et al., 2008), and one drug recovery program has seen success in participants that train for and compete in a marathon as part of the program (Butler, 2005).&nbsp;... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some patients taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al., 2006; Aiken, 2007; Lader, 2008).}}</ref>
+[[Cognitive behavioral therapy]] is currently the most effective clinical treatment for psychostimulant addiction.<ref name="Nestler CBT">{{cite book | author = Malenka RC, Nestler EJ, Hyman SE | editor = Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York, USA | isbn = 9780071481274 | page = 386 | edition = 2nd | chapter = Chapter 15: Reinforcement and Addictive Disorders | quote= Currently, cognitive–behavioral therapies are the most successful treatment available for preventing the relapse of psychostimulant use.}}</ref> Additionally, research on the [[neurobiological effects of physical exercise#ΔFosB|neurobiological effects of physical exercise]] suggests that daily aerobic exercise, especially endurance exercise (e.g., [[marathon running]]), prevents the development of drug addiction and is an effective adjunct (supplemental) treatment for amphetamine addiction.<ref name="Running vs addiction">{{cite journal | author = Lynch WJ, Peterson AB, Sanchez V, Abel J, Smith MA | title = Exercise as a novel treatment for drug addiction: a neurobiological and stage-dependent hypothesis | journal = Neurosci Biobehav Rev | volume = 37 | issue = 8 | pages = 1622–44 |date=September 2013 | pmid = 23806439 | pmc = 3788047 | doi = 10.1016/j.neubiorev.2013.06.011 | quote = these data show that exercise can affect dopaminergic signaling at many different levels, which may underlie its ability to modify vulnerability during drug use initiation. Exercise also produces neuroadaptations that may influence an individual's vulnerability to initiate drug use. Consistent with this idea, chronic moderate levels of forced treadmill running blocks not only subsequent methamphetamine-induced conditioned place preference, but also stimulant-induced increases in dopamine release in the {{abbr|NAc|nucleus accumbens}} (Chen et al., 2008) and striatum (Marques et al., 2008).&nbsp;... [These] findings indicate the efficacy of exercise at reducing drug intake in drug-dependent individuals&nbsp;... wheel running [reduces] methamphetamine self-administration under extended access conditions (Engelmann et al., 2013)&nbsp;... These findings suggest that exercise may "magnitude"-dependently prevent the development of an addicted phenotype possibly by blocking/reversing behavioral and neuro-adaptive changes that develop during and following extended access to the drug.&nbsp;... Exercise has been proposed as a treatment for drug addiction that may reduce drug craving and risk of relapse. Although few clinical studies have investigated the efficacy of exercise for preventing relapse, the few studies that have been conducted generally report a reduction in drug craving and better treatment outcomes (see Table 4).&nbsp;... Taken together, these data suggest that the potential benefits of exercise during relapse, particularly for relapse to psychostimulants, may be mediated via chromatin remodeling and possibly lead to greater treatment outcomes.}}</ref><ref name="Natural and drug addictions" /> Exercise leads to better treatment outcomes when used as an adjunct treatment, particularly for psychostimulant addictions.<ref name="Running vs addiction" /> In particular, [[aerobic exercise]] decreases psychostimulant self-administration, reduces the [[reinstatement]] (i.e., relapse) of drug-seeking, and induces increased [[dopamine receptor D2|dopamine receptor D<sub>2</sub>]] (DRD2) density in the [[striatum]]. This is the opposite of pathological stimulant use, which induces decreased striatal DRD2 density.<ref name="Natural and drug addictions">{{cite journal | author = Olsen CM | title = Natural rewards, neuroplasticity, and non-drug addictions | journal = Neuropharmacology | volume = 61 | issue = 7 | pages = 1109–1122 |date=December 2011 | pmid = 21459101 | pmc = 3139704 | doi = 10.1016/j.neuropharm.2011.03.010 | quote = Similar to environmental enrichment, studies have found that exercise reduces self-administration and relapse to drugs of abuse (Cosgrove et al., 2002; Zlebnik et al., 2010). There is also some evidence that these preclinical findings translate to human populations, as exercise reduces withdrawal symptoms and relapse in abstinent smokers (Daniel et al., 2006; Prochaska et al., 2008), and one drug recovery program has seen success in participants that train for and compete in a marathon as part of the program (Butler, 2005).&nbsp;... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some patients taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al., 2006; Aiken, 2007; Lader, 2008).}}</ref>
 ====Withdrawal====
-According to another Cochrane Collaboration review on withdrawal in highly addicted amphetamine and methamphetamine abusers, "when chronic heavy users abruptly discontinue amphetamine use, many report a time-limited withdrawal syndrome that occurs within 24&nbsp;hours of their last dose."<ref name="Cochrane Withdrawal">{{cite journal | author = Shoptaw SJ, Kao U, Heinzerling K, Ling W | title = Treatment for amphetamine withdrawal | journal = Cochrane Database Syst. Rev. | volume = | issue = 2 | pages = CD003021 | year = 2009 | pmid = 19370579 | doi = 10.1002/14651858.CD003021.pub2 | editor = Shoptaw SJ |quote = The prevalence of this withdrawal syndrome is extremely common (Cantwell 1998; Gossop 1982) with 87.6% of 647 individuals with amphetamine dependence reporting six or more signs of amphetamine withdrawal listed in the DSM when the drug is not available (Schuckit 1999)&nbsp;... The severity of withdrawal symptoms is greater in amphetamine dependent individuals who are older and who have more extensive amphetamine use disorders (McGregor 2005). Withdrawal symptoms typically present within 24 hours of the last use of amphetamine, with a withdrawal syndrome involving two general phases that can last 3 weeks or more. The first phase of this syndrome is the initial "crash" that resolves within about a week (Gossop 1982;McGregor 2005)&nbsp;...}}</ref> 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 first week.<ref name="Cochrane Withdrawal" /> Amphetamine withdrawal symptoms can include anxiety, [[Craving (withdrawal)|drug craving]], [[Dysphoria|depressed mood]], [[Fatigue (medical)|fatigue]], [[hyperphagia|increased appetite]], increased movement or [[psychomotor retardation|decreased movement]], lack of motivation, sleeplessness or sleepiness, and [[lucid dream]]s.<ref name="Cochrane Withdrawal" /> The review indicated that withdrawal symptoms are associated with the degree of dependence, suggesting that therapeutic use would result in far milder discontinuation symptoms.<ref name="Cochrane Withdrawal" /> Manufacturer prescribing information does not indicate the presence of withdrawal symptoms following discontinuation of amphetamine use after an extended period at therapeutic doses.<ref>{{cite web | title=Adderall IR Prescribing Information | url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/011522s040lbl.pdf | publisher = Barr Laboratories, Inc. | work = United States Food and Drug Administration |date=March 2007 | accessdate = 4 November 2013 }}</ref><ref>{{cite web | title = Dexedrine Medication Guide | url = http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/017078s046lbl.pdf | publisher = Amedra Pharmaceuticals LLC | work = United States Food and Drug Administration | date = May 2013 | accessdate = 4 November 2013 }}</ref><ref>{{cite web | title = Adderall XR Prescribing Information | url = http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021303s026lbl.pdf | publisher = Shire US Inc | work = United States Food and Drug Administration |date=December 2013 | accessdate = 30 December 2013 }}</ref>
+According to another Cochrane Collaboration review on [[drug withdrawal|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&nbsp;hours of their last dose."<ref name="Cochrane Withdrawal">{{cite journal | author = Shoptaw SJ, Kao U, Heinzerling K, Ling W | title = Treatment for amphetamine withdrawal | journal = Cochrane Database Syst. Rev. | volume = | issue = 2 | pages = CD003021 | year = 2009 | pmid = 19370579 | doi = 10.1002/14651858.CD003021.pub2 | editor = Shoptaw SJ |quote = The prevalence of this withdrawal syndrome is extremely common (Cantwell 1998; Gossop 1982) with 87.6% of 647 individuals with amphetamine dependence reporting six or more signs of amphetamine withdrawal listed in the DSM when the drug is not available (Schuckit 1999)&nbsp;... The severity of withdrawal symptoms is greater in amphetamine dependent individuals who are older and who have more extensive amphetamine use disorders (McGregor 2005). Withdrawal symptoms typically present within 24 hours of the last use of amphetamine, with a withdrawal syndrome involving two general phases that can last 3 weeks or more. The first phase of this syndrome is the initial "crash" that resolves within about a week (Gossop 1982;McGregor 2005)&nbsp;...}}</ref> 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 first week.<ref name="Cochrane Withdrawal" /> Amphetamine withdrawal symptoms can include anxiety, [[Craving (withdrawal)|drug craving]], [[Dysphoria|depressed mood]], [[Fatigue (medical)|fatigue]], [[hyperphagia|increased appetite]], increased movement or [[psychomotor retardation|decreased movement]], lack of motivation, sleeplessness or sleepiness, and [[lucid dream]]s.<ref name="Cochrane Withdrawal" /> The review indicated that withdrawal symptoms are associated with the degree of dependence, suggesting that therapeutic use would result in far milder discontinuation symptoms.<ref name="Cochrane Withdrawal" /> Manufacturer prescribing information does not indicate the presence of withdrawal symptoms following discontinuation of amphetamine use after an extended period at therapeutic doses.<ref>{{cite web | title=Adderall IR Prescribing Information | url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/011522s040lbl.pdf | publisher = Barr Laboratories, Inc. | work = United States Food and Drug Administration |date=March 2007 | accessdate = 4 November 2013 }}</ref><ref>{{cite web | title = Dexedrine Medication Guide | url = http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/017078s046lbl.pdf | publisher = Amedra Pharmaceuticals LLC | work = United States Food and Drug Administration | date = May 2013 | accessdate = 4 November 2013 }}</ref><ref>{{cite web | title = Adderall XR Prescribing Information | url = http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021303s026lbl.pdf | publisher = Shire US Inc | work = United States Food and Drug Administration |date=December 2013 | accessdate = 30 December 2013 }}</ref>
-===Psychosis and toxicity===
+===Toxicity and psychosis===
-:''For more information on amphetamine psychosis, see [[Stimulant psychosis#Substituted amphetamines]].''
+{{see also|Stimulant psychosis}}
+In rodents and primates, sufficiently high doses of amphetamine cause dopaminergic [[neurotoxicity]], or damage to dopamine neurons, which is characterized by reduced transporter and receptor function.<ref name="Humans&Animals">{{cite journal| author=Advokat C| title=Update on amphetamine neurotoxicity and its relevance to the treatment of ADHD | journal=J. Atten. Disord. | year = 2007 | volume= 11 | issue= 1 | pages= 8–16 | pmid=17606768 | doi=10.1177/1087054706295605}}</ref> There is no evidence that amphetamine is directly neurotoxic in humans.<ref>{{cite web | title=Amphetamine | url=http://toxnet.nlm.nih.gov/cgi-bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+300-62-9 | work=Hazardous Substances Data Bank | publisher=National Library of Medicine | accessdate=26 February 2014 | quote = Direct toxic damage to vessels seems unlikely because of the dilution that occurs before the drug reaches the cerebral circulation.}}</ref><ref name = "Malenka_2009_02">{{cite book | author = Malenka RC, Nestler EJ, Hyman SE | editor = Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York, USA | isbn = 9780071481274 | page = 370 | edition = 2nd | chapter = Chapter 15: Reinforcement and addictive disorders | quote = Unlike cocaine and amphetamine, methamphetamine is directly toxic to midbrain dopamine neurons.}}</ref> However, large doses of amphetamine may cause indirect neurotoxicity as a result of increased oxidative stress from [[reactive oxygen species]] and [[autoxidation]] of dopamine.<ref name="pmid22392347">{{cite journal |author=Carvalho M, Carmo H, Costa VM, Capela JP, Pontes H, Remião F, Carvalho F, Bastos Mde L |title=Toxicity of amphetamines: an update |journal=Arch. Toxicol. |volume=86 |issue=8 |pages=1167–1231 |date=August 2012 |pmid=22392347 |doi=10.1007/s00204-012-0815-5 |url=}}</ref><ref name="Autoxidation1">{{cite journal | author = Sulzer D, Zecca L | title = Intraneuronal dopamine-quinone synthesis: a review | journal = Neurotox. Res. | volume = 1 | issue = 3 | pages = 181–195 |date=February 2000 | pmid = 12835101 | doi = 10.1007/BF03033289 }}</ref><ref name="Autoxidation2">{{cite journal | author = Miyazaki I, Asanuma M | title = Dopaminergic neuron-specific oxidative stress caused by dopamine itself | journal = Acta Med. Okayama | volume = 62 | issue = 3 | pages = 141–150 |date=June 2008 | pmid = 18596830 | doi = }}</ref>
-Amphetamine abuse can result in stimulant psychosis that may involve a variety of symptoms, such as [[paranoia]] and [[delusion]]s.<ref name="Cochrane" /> A Cochrane Collaboration review on treatment for amphetamine, dextroamphetamine, and methamphetamine abuse-induced psychosis states that about&nbsp;5–15% of users fail to recover completely.<ref name="Cochrane">{{cite journal | editor =<!--Shoptaw SJ--> Shoptaw SJ, Ali R | author = Shoptaw SJ, Kao U, Ling W | title = Treatment for amphetamine psychosis | journal = Cochrane Database Syst. Rev. | volume = | issue = 1 | pages = CD003026 | year = 2009 | pmid = 19160215 | doi = 10.1002/14651858.CD003026.pub3 | quote=A minority of individuals who use amphetamines develop full-blown psychosis requiring care at emergency departments or psychiatric hospitals. In such cases, symptoms of amphetamine psychosis commonly include paranoid and persecutory delusions as well as auditory and visual hallucinations in the presence of extreme agitation. More common (about 18%) is for frequent amphetamine users to report psychotic symptoms that are sub-clinical and that do not require high-intensity intervention&nbsp;...<br />About 5–15% of the users who develop an amphetamine psychosis fail to recover completely (Hofmann 1983)&nbsp;...<br />Findings from one trial indicate use of antipsychotic medications effectively resolves symptoms of acute amphetamine psychosis.}}</ref><ref name="Hofmann">{{cite book | author = Hofmann FG | title = A Handbook on Drug and Alcohol Abuse: The Biomedical Aspects | publisher = Oxford University Press | isbn = 9780195030570 | location = New York, USA | year = 1983 | page = 329 | edition = 2nd }}</ref> According to the same review, there is at least one trial that shows [[antipsychotic]] medications effectively resolve the symptoms of acute amphetamine psychosis.<ref name="Cochrane"/> Psychosis very rarely arises from therapeutic use.<ref name="Stimulant Misuse" /><ref name="FDA Contra Warnings">{{cite web | title = Adderall XR Prescribing Information | url = http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021303s026lbl.pdf | pages = 4–6 | publisher = Shire US Inc | work = United States Food and Drug Administration | date = December 2013 | accessdate = 30 December 2013 }}</ref>
+A severe amphetamine overdose can result in a stimulant psychosis that may involve a variety of symptoms, such as [[paranoia]] and [[delusion]]s.<ref name="Cochrane" /> A Cochrane Collaboration review on treatment for amphetamine, dextroamphetamine, and methamphetamine psychosis states that about&nbsp;5–15% of users fail to recover completely.<ref name="Cochrane">{{cite journal | editor =<!--Shoptaw SJ--> Shoptaw SJ, Ali R | author = Shoptaw SJ, Kao U, Ling W | title = Treatment for amphetamine psychosis | journal = Cochrane Database Syst. Rev. | volume = | issue = 1 | pages = CD003026 | year = 2009 | pmid = 19160215 | doi = 10.1002/14651858.CD003026.pub3 | quote=A minority of individuals who use amphetamines develop full-blown psychosis requiring care at emergency departments or psychiatric hospitals. In such cases, symptoms of amphetamine psychosis commonly include paranoid and persecutory delusions as well as auditory and visual hallucinations in the presence of extreme agitation. More common (about 18%) is for frequent amphetamine users to report psychotic symptoms that are sub-clinical and that do not require high-intensity intervention&nbsp;...<br />About 5–15% of the users who develop an amphetamine psychosis fail to recover completely (Hofmann 1983)&nbsp;...<br />Findings from one trial indicate use of antipsychotic medications effectively resolves symptoms of acute amphetamine psychosis.}}</ref><ref name="Hofmann">{{cite book | author = Hofmann FG | title = A Handbook on Drug and Alcohol Abuse: The Biomedical Aspects | publisher = Oxford University Press | isbn = 9780195030570 | location = New York, USA | year = 1983 | page = 329 | edition = 2nd }}</ref> According to the same review, there is at least one trial that shows [[antipsychotic]] medications effectively resolve the symptoms of acute amphetamine psychosis.<ref name="Cochrane"/> Psychosis very rarely arises from therapeutic use.<ref name="Stimulant Misuse" /><ref name="FDA Contra Warnings">{{cite web | title = Adderall XR Prescribing Information | url = http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021303s026lbl.pdf | pages = 4–6 | publisher = Shire US Inc | work = United States Food and Drug Administration | date = December 2013 | accessdate = 30 December 2013 }}</ref>
-In rodents and primates, sufficiently high doses of amphetamine cause dopaminergic [[neurotoxicity]], or damage to dopamine neurons, which is characterized by reduced transporter and receptor function.<ref name="Humans&Animals">{{cite journal| author=Advokat C| title=Update on amphetamine neurotoxicity and its relevance to the treatment of ADHD | journal=J. Atten. Disord. | year = 2007 | volume= 11 | issue= 1 | pages= 8–16 | pmid=17606768 | doi=10.1177/1087054706295605}}</ref> There is no evidence that amphetamine is directly neurotoxic in humans.<ref>{{cite web | title=Amphetamine | url=http://toxnet.nlm.nih.gov/cgi-bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+300-62-9 | work=Hazardous Substances Data Bank | publisher=National Library of Medicine | accessdate=26 February 2014 | quote = Direct toxic damage to vessels seems unlikely because of the dilution that occurs before the drug reaches the cerebral circulation.}}</ref><ref name = "Malenka_2009_02">{{cite book | author = Malenka RC, Nestler EJ, Hyman SE | editor = Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York, USA | isbn = 9780071481274 | page = 370 | edition = 2nd | chapter = Chapter 15: Reinforcement and addictive disorders | quote = Unlike cocaine and amphetamine, methamphetamine is directly toxic to midbrain dopamine neurons.}}</ref> However, large doses of amphetamine may indirectly cause neurotoxicity as a result of increased oxidative stress from [[reactive oxygen species]] and [[autoxidation]] of dopamine.<ref name="pmid22392347">{{cite journal |author=Carvalho M, Carmo H, Costa VM, Capela JP, Pontes H, Remião F, Carvalho F, Bastos Mde L |title=Toxicity of amphetamines: an update |journal=Arch. Toxicol. |volume=86 |issue=8 |pages=1167–1231 |date=August 2012 |pmid=22392347 |doi=10.1007/s00204-012-0815-5 |url=}}</ref><ref name="Autoxidation1">{{cite journal | author = Sulzer D, Zecca L | title = Intraneuronal dopamine-quinone synthesis: a review | journal = Neurotox. Res. | volume = 1 | issue = 3 | pages = 181–195 |date=February 2000 | pmid = 12835101 | doi = 10.1007/BF03033289 }}</ref><ref name="Autoxidation2">{{cite journal | author = Miyazaki I, Asanuma M | title = Dopaminergic neuron-specific oxidative stress caused by dopamine itself | journal = Acta Med. Okayama | volume = 62 | issue = 3 | pages = 141–150 |date=June 2008 | pmid = 18596830 | doi = }}</ref></onlyinclude>
+}}</onlyinclude>
 ==Interactions==
@@ Line 263: / Line 273: @@
 Amphetamine derivatives, often referred to as "amphetamines" or "substituted amphetamines", are a broad range of chemicals that contain amphetamine as a "backbone".<ref name="DrugBank Header">{{cite encyclopedia | title=Amphetamine | section-url=http://www.drugbank.ca/drugs/DB00182 | work=DrugBank | publisher= University of Alberta | accessdate=30 September 2013 | date=8 February 2013 | section=Compound Summary }}</ref><ref name="Schep">{{cite journal | author=Schep LJ, Slaughter RJ, Beasley DM | title=The clinical toxicology of metamfetamine | journal=Clin. Toxicol. (Phila.) | volume=48 | issue=7 | pages=675–694 |date=August 2010 | pmid=20849327 | doi=10.3109/15563650.2010.516752 | issn=1556-3650}}</ref> The class includes stimulants like methamphetamine, serotonergic [[empathogens]] like [[MDMA]] (ecstasy), and [[decongestant]]s like [[ephedrine]], among other subgroups.<ref name="DrugBank Header" /><ref name="Schep" /> This class of chemicals is sometimes referred to collectively as the "amphetamine family."<ref>{{cite web | title = Amphetamine, Methamphetamine, & Cystal Meth | url = http://www.cqld.ca/livre/en/en/07-amphetamine.htm | work = Addiction Prevention Centre | accessdate = 10 October 2013 }}</ref>
+===Synthesis===
+{{Details3|[[History and culture of substituted amphetamines#Illegal synthesis|Illegal synthesis of substituted amphetamines]]|illicit amphetamine synthesis}}
+Since the first preparation was reported in 1887,<ref name="Vermont"/> numerous synthetic routes to amphetamine have been developed.<ref name = "Allen_Cantrell_1989">{{cite journal | author = Allen A, Cantrell TS | title = Synthetic reductions in clandestine amphetamine and methamphetamine laboratories: A review | journal = Forensic Science International | date = August 1989 | volume = 42 | issue = 3 | pages = 183–199 | doi = 10.1016/0379-0738(89)90086-8 }}</ref><ref name = "Allen_Ely_2009">{{cite journal | url = http://www.nwafs.org/newsletters/2011_Spring.pdf | title = Review: Synthetic Methods for Amphetamine | author = Allen A, Ely R | format = PDF | work = | publisher = Northwest Association of Forensic Scientists | volume = 37 | issue = 2 | year = 2009 | pages = 15–25 | journal = Crime Scene | accessdate = 6 December 2014}}</ref> Many of these syntheses are based on classic organic reactions. One such example is the [[Friedel–Crafts reaction#Friedel–Crafts alkylation|Friedel–Crafts]] alkylation of [[chlorobenzene]] by [[allyl chloride]] to yield beta chloropropylbenzene which is then reacted with ammonia to produce racemic amphetamine (method 1).<ref name="pmid20985610">{{cite journal | author = Patrick TM, McBee ET, Hass HB | title = Synthesis of arylpropylamines; from allyl chloride | journal = J. Am. Chem. Soc. | volume = 68 | issue = | pages = 1009–1011 | date = June 1946 | pmid = 20985610 | doi = 10.1021/ja01210a032 }}</ref> Another example employs the [[Ritter reaction]] (method 2). In this route, [[allylbenzene]] is reacted [[acetonitrile]] in sulfuric acid to yield an [[organosulfate]] which in turn is treated with sodium hydroxide to give amphetamine via an [[acetamide]] intermediate.<ref name="pmid18105933">{{cite journal | author = Ritter JJ, Kalish J | title = A new reaction of nitriles; synthesis of t-carbinamines | journal = J. Am. Chem. Soc. | volume = 70 | issue = 12 | pages = 4048–4050 | date = December 1948 | pmid = 18105933 | doi = 10.1021/ja01192a023 }}</ref><ref name=Krimen_Cota_1969>{{cite journal | author = Krimen LI, Cota DJ | journal = Organic Reactions | year = 1969 | volume = 17 | page = 216 | doi = 10.1002/0471264180.or017.03}}</ref> A third route starts with {{nowrap|[[ethyl acetoacetate|ethyl 3-oxobutanoate]]}} which through a double alkylation with [[methyl iodide]] followed by [[benzyl chloride]] can be converted into {{nowrap|2-methyl-3-phenyl-propanoic}} acid. This synthetic intermediate can be transformed into amphetamine using either a [[Hofmann rearrangement|Hofmann]] or [[Curtius rearrangement]] (method 3).<ref name = "US2413493">{{ cite patent | country = US | number = 2413493 | status = patent | title = Synthesis of isomer-free benzyl methyl acetoacetic methyl ester | pubdate = 31 December 1946 | fdate = 3 June 1943 | pridate = 3 June 1943 | inventor = Bitler WP, Flisik AC, Leonard N | assign1 = Kay Fries Chemicals Inc }}</ref>
+A significant number of amphetamine syntheses feature a [[Organic redox reaction#Organic reductions|reduction]] of a [[nitro group|nitro]], [[imine]], [[oxime]] or other nitrogen-containing [[functional group]].<ref name = "Allen_Cantrell_1989"/> In one such example, a [[Knoevenagel condensation]] of [[benzaldehyde]] with [[nitroethane]] yields {{nowrap|[[phenyl-2-nitropropene]]}}. The double bond and nitro group of this intermediate is [[organic redox reaction|reduced]] using either catalytic [[hydrogenation]] or by treatment with [[lithium aluminium hydride]] (method 4).<ref name="Delta Isotope">{{cite journal | author = Collins M, Salouros H, Cawley AT, Robertson J, Heagney AC, Arenas-Queralt A | title = δ<sup>13</sup>C and δ<sup>2</sup>H isotope ratios in amphetamine synthesized from benzaldehyde and nitroethane | journal = Rapid Commun. Mass Spectrom. | volume = 24 | issue = 11 | pages = 1653–1658 |date=June 2010 | pmid = 20486262 | doi = 10.1002/rcm.4563 }}</ref><ref name="Amph Synth">{{cite web | url = http://www.unodc.org/pdf/scientific/stnar34.pdf | title = Recommended methods of the identification and analysis of amphetamine, methamphetamine, and their ring-substituted analogues in seized materials | pages = 9–12 | accessdate = 14 October 2013 | year = 2006 | work = United Nations Office on Drugs and Crime | publisher = United Nations}}</ref> 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).<ref name="Amph Synth" />
+The most common route of both legal and illicit amphetamine synthesis employs a non-metal reduction known as the [[Leuckart reaction]] (method 6).<ref name="EMC"/><ref name="Amph Synth" /> In the first step, a reaction between phenylacetone and [[formamide]], either using additional [[formic acid]] or formamide itself as a reducing agent, yields {{nowrap|[[N-formylamphetamine|''N''-formylamphetamine]]}}. This intermediate is then hydrolyzed using hydrochloric acid, and subsequently basified, 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.<ref name="Amph Synth" /><ref>{{cite journal | doi = 10.1021/jo01145a001 | title = The Mechanism of the Leuckart Reaction |date=May 1951 | author = Pollard CB, Young DC | journal = J. Org. Chem. | volume = 16 | issue = 5 | pages = 661–672}}</ref>
+A number of [[chiral resolution]]s have been developed to separate the two enantiomers of amphetamine.<ref name = "Allen_Ely_2009"/> For example, racemic amphetamine can be treated with {{nowrap|d-[[tartaric acid]]}} to form a [[diastereoisomer]]ic salt which is [[fractional crystallization (chemistry)|fractionally]] crystallized to yield dextroamphetamine.<ref name = "US2276508">{{ cite patent | country = US | number = 2276508 | status = patent | title = Method for the separation of optically active alpha-methylphenethylamine | pubdate = 17 March 1942 | fdate = 3 November 1939 | pridate = 3 November 1939 | inventor = Nabenhauer FP | assign1 = Smith Kline French }}</ref> Chiral resolution remains the most economical method for obtaining optically pure amphetamine on a large scale.<ref name = "Gray_2007"/> In addition, several [[enantioselective synthesis|enantioselective]] syntheses of amphetamine have been developed. In one example, [[optically pure]] {{nowrap|(''R'')-1-phenyl-ethanamine}} is condensed with phenylacetone to yield a chiral [[schiff base]]. In the key step, this intermediate is reduced by [[catalytic hydrogenation]] with a transfer of chirality to the carbon atom alpha to the amino group. Cleavage of the [[benzylic]] amine bond by hydrogenation yields optically pure dextroamphetamine.<ref name = "Gray_2007">{{Cite book | editor = Johnson DS, Li JJ | author = Gray DL | title = The Art of Drug Synthesis | chapter = Approved Treatments for Attention Deficit Hyperactivity Disorder: Amphetamine (Adderall), Methylphenidate (Ritalin), and Atomoxetine (Straterra) | chapterurl = http://books.google.com/books?id=zvruBDAulWEC&lpg=PP1&dq=The%20Art%20of%20Drug%20Synthesis%20(Wiley%20Series%20on%20Drug%20Synthesis)&pg=SA17-PA4#v=onepage&q=amphetamine&f=false | year = 2007 | publisher = Wiley-Interscience | location = New York, USA | isbn = 9780471752158 | page = 247 }}</ref>
+{| style="margin: 1em auto;"
+|- style="vertical-align: top;"
+|+'''Amphetamine synthetic routes'''
+|<!--Left cell: nested table-->
+{|
+|{{multiple image
+<!-- Essential parameters -->
+| align = center
+| direction = vertical
+| width = 370
+<!-- Extra parameters -->
+| header =
+| header_align = center
+| header_background =
+| footer =
+| footer_align =
+| footer_background =
+| background color =
+|image1=Amphetamine Friedel-Crafts alkylation.svg
+|caption1=Method 1: Synthesis by Friedel–Crafts alkylation
+|alt1=Diagram of amphetamine synthesis by Friedel–Crafts alkylation
+|image2=Amphetamine Ritter Synthesis.svg
+|caption2=Method 2: Ritter synthesis
+|alt2=Diagram of amphetamine via Ritter synthesis
+|image3=Amphetamine Hofmann Curtius Synthesis.svg
+|caption3=Method 3: Synthesis via Hofmann and Curtius rearrangements
+|alt3=Diagram of amphetamine synthesis via Hofmann and Curtius rearrangements
+|image4=Amphetamine Knoevenagel synthesis.svg
+|caption4=Method 4: Synthesis by Knoevenagel condensation
+|alt4=Diagram of amphetamine synthesis by Knoevenagel condensation
+}}
+|}
+|<!--Right cell: nested table-->
+{|
+|{{multiple image
+<!-- Essential parameters -->
+| align = center
+| direction = vertical
+| width = 370
+<!-- Extra parameters -->
+| header =
+| header_align = center
+| header_background =
+| footer =
+| footer_align =
+| footer_background =
+| background color =
+|image1=Amphetamine p2p ammonia synthesis.svg
+|caption1=Method 5: Synthesis using phenylacetone and ammonia<br />&nbsp;
+|alt1=Diagram of amphetamine synthesis from phenylacetone and ammonia
+|image2=Amphetamine Leukart synthesis.svg
+|caption2=Method 6: Synthesis by the Leuckart reaction<br />&nbsp;
+|alt2=Diagram of amphetamine synthesis by the Leuckart reaction
+|image3=Amphetamine resolution and chiral synthesis.svg
+|caption3=Top: Chiral resolution of amphetamine <br />Bottom: Stereoselective synthesis of amphetamine
+|alt3=Diagram of a chiral resolution of racemic amphetamine and a stereoselective synthesis
+}}
+|}
+|}
+{{clear}}
 ===Detection in body fluids===