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This article is about the free base and salts of amphetamine. For other uses, see Amphetamine (disambiguation).

An image of the amphetamine compound
A 3d image of the amphetamine compound
Systematic (IUPAC) name
Clinical data
AHFS/ entry
Licence data US FDA:link
Pregnancy cat. C (US)
Legal status Controlled (S8) (AU) Schedule I (CA) CD (UK) Schedule II (US) Prescription only
Dependence liability Moderate
Routes Medical: oral, nasal inhalation
Recreational: oral, nasal inhalation, insufflation, rectal, intravenous
Pharmacokinetic data
Bioavailability Rectal 95–100%; Oral 75–100%[1]
Protein binding 15–40%[2]
Metabolism CYP2D6,[3] DBH,[4] FMO3,[5] XM-ligase,[6] and ACGNAT[7]
Half-life D-amph:9–11h;[8] L-amph:11–14h[8]
Excretion Renal; pH-dependent range: 1–75%[8]
CAS number 300-62-9 7pxY
ATC code N06BA01
PubChem CID 3007
IUPHAR ligand 4804
DrugBank DB00182
ChemSpider 13852819 7pxY
KEGG D07445 7pxY
ChEBI CHEBI:2679 7pxY
NIAID ChemDB 018564
Synonyms α-methylphenethylamine
Chemical data
Formula C9H13N 
Mol. mass 135.2084 g/mol
Physical data
Density 0.9±0.1 g/cm³
Melt. point 11.3 °C (52 °F) [9]
Boiling point 203 °C (397 °F) [10]
 14pxY (what is this?)  (verify)

Amphetamine[note 1] (pronunciation: Listeni/æmˈfɛtəmn/; contracted from alphamethylphenethylamine) is a potent central nervous system (CNS) stimulant of the phenethylamine class that is used in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. Amphetamine was discovered in 1887 and exists as two enantiomers: levoamphetamine and dextroamphetamine.[note 2] Amphetamine properly refers to the racemic free base, or equal parts of the enantiomers levoamphetamine and dextroamphetamine in their pure amine forms. Nonetheless, the term is frequently used informally to refer to any combination of the enantiomers, or to either of them alone. Historically, it has been used to treat nasal congestion, depression, and obesity. Amphetamine is also used as a performance and cognitive enhancer, and recreationally as an aphrodisiac and euphoriant. It is a prescription medication in many countries, and unauthorized possession and distribution of amphetamine is often tightly controlled due to the significant health risks associated with uncontrolled or heavy use. Amphetamine is illegally synthesized by clandestine chemists, trafficked, and sold. Based upon the quantity of seized and confiscated drugs and drug precursors worldwide, illicit amphetamine production and trafficking is much less prevalent than that of methamphetamine; in parts of Europe, amphetamine is more prevalent than methamphetamine.[sources 1]

The first pharmaceutical amphetamine was Benzedrine, a brand of inhalers used to treat a variety of conditions. Presently, it is typically prescribed as Adderall,[note 3] dextroamphetamine, or the inactive prodrug lisdexamfetamine. Amphetamine, through activation of a trace amine receptor, increases biogenic amine and excitatory neurotransmitter activity in the brain, with its most pronounced effects targeting the catecholamine neurotransmitters norepinephrine and dopamine. At therapeutic doses, this causes emotional and cognitive effects such as euphoria, change in libido, increased arousal, and improved 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. Substance dependence (i.e., addiction) is a serious risk of amphetamine abuse, but only rarely arises from medical use. Very high doses can result in a 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 the parent compound of its own structural class, the substituted amphetamines,[note 4] which includes prominent substances such as bupropion, cathinone, MDMA (ecstasy), and methamphetamine. Unlike methamphetamine, amphetamine's salts lack sufficient volatility to be smoked. Amphetamine is also chemically related to the naturally occurring trace amine neurotransmitters, specifically phenethylamine and N-methylphenethylamine, both of which are produced within the human body.[sources 4]



Amphetamine is used to treat attention deficit hyperactivity disorder (ADHD) and narcolepsy, and is sometimes prescribed off-label for its past medical indications, such as depression, obesity, and nasal congestion.[22][26] Long-term amphetamine exposure in some species is known to produce abnormal dopamine system development or nerve damage,[35][36] but humans experience normal development and nerve growth.[37][38][39] Magnetic resonance imaging studies suggest that long-term treatment with amphetamine decreases abnormalities in brain structure and function found in subjects with ADHD, and improves function of the right caudate nucleus.[37][38][39]

Reviews of clinical stimulant research have established the safety and effectiveness of long-term amphetamine use for ADHD.[40][41] Controlled trials spanning two years have demonstrated continuous treatment effectiveness and safety.[41][42] One review highlighted a 9 month randomized controlled trial in children that found an average increase of 4.5 IQ points and continued improvements in attention, disruptive behaviors, and hyperactivity.[42]

Current models of ADHD suggest that it is associated with functional impairments in some of the brain's neurotransmitter systems,[note 5] particularly those involving dopamine and norepinephrine.[43] Psychostimulants like methylphenidate and amphetamine may be effective in treating ADHD because they increase neurotransmitter activity in these systems.[43] Approximately 70% of those who use these stimulants see improvements in ADHD symptoms.[44][45] Children with ADHD who use stimulant medications generally have better relationships with peers and family members,[40][44] generally perform better in school, are less distractible and impulsive, and have longer attention spans.[40][44] The Cochrane Collaboration's review[note 6] on the treatment of adult ADHD with amphetamines stated that amphetamines improve short-term symptoms, but have higher discontinuation rates than non-stimulant medications due to their adverse effects.[47]

A Cochrane Collaboration review on the treatment of ADHD in children with tic disorders indicated that stimulants in general do not make tics worse, but high doses of dextroamphetamine in such people should be avoided.[48] Other Cochrane reviews on the use of amphetamine for improving recovery following stroke or acute brain injury indicated that it may improve recovery, but further research is needed to confirm this.[49][50][51]

Enhancing performance

Therapeutic doses of amphetamine improve cortical network efficiency, resulting in higher performance on working memory tests in all individuals.[19][52] Amphetamine and other ADHD stimulants also improve task saliency and increase arousal.[19][53] Stimulants such as amphetamine can improve performance on difficult and boring tasks,[19][53] and are used by some students as a study and test-taking aid.[54] Based upon studies of self-reported illicit stimulant use, performance-enhancing use, rather than abuse as a recreational drug, is the primary reason that students use stimulants.[55] High amphetamine doses, above the therapeutic range, can interfere with working memory and cognitive control.[19][53]

Amphetamine is used by some athletes for its psychological and performance-enhancing effects, such as increased stamina and alertness, but this is prohibited at events regulated by the World Anti-Doping Agency.[32][56][18] In healthy people at oral therapeutic doses, amphetamine has been shown to increase physical strength,[18][57] acceleration,[18][57] stamina,[18][58] endurance,[18][58] and alertness,[32] while reducing reaction time.[18] Like the psychostimulants methylphenidate and bupropion, amphetamine increases stamina and endurance in humans primarily through reuptake inhibition and effluxion of dopamine in the central nervous system.[57][58] At much higher doses, amphetamine can induce side effects that impair performance, such as rhabdomyolysis and hyperthermia.[17][28][57]


According to the International Programme on Chemical Safety (IPCS) and United States Food and Drug Administration (USFDA),[note 7] amphetamine is contraindicated in people with a history of drug abuse, heart disease, severe agitation, or severe anxiety.[59][60] It is also contraindicated in people currently experiencing arteriosclerosis, glaucoma, hyperthyroidism, or severe hypertension.[59][60] People who have experienced hypersensitivity reactions to other stimulants in the past or are taking monoamine oxidase inhibitors (MAOIs) are advised not to take amphetamine.[59][60] These agencies also state that anyone with anorexia nervosa, bipolar disorder, depression, elevated blood pressure, liver or kidney problems, mania, psychosis, Raynaud's phenomenon, seizures, thyroid problems, tics, or Tourette syndrome should monitor their symptoms while taking amphetamine.[59][60] Evidence from human studies indicates that therapeutic amphetamine use does not cause developmental abnormalities in the fetus or newborns (i.e., it is not a human teratogen), but amphetamine abuse does pose risks to the fetus.[60] Amphetamine has also been shown to pass into breast milk, so the IPCS and USFDA advise mothers to avoid breastfeeding when using it.[59][60] Due to the potential for stunted growth, the USFDA advises monitoring the height and weight of children and adolescents prescribed amphetamines.[59]

Side effects

Side effects of amphetamine are varied, and the amount of amphetamine consumed is the primary factor in determining the likelihood and severity of side effects.[17][28][32] Amphetamine products such as Adderall, Dexedrine, and their generic equivalents are currently approved by the USFDA for long-term therapeutic use.[25][28] Recreational use of amphetamine generally involves doses much larger, and therefore has a greater risk of serious side effects than dosages used for therapeutic reasons.[32]


At normal therapeutic doses, the physical side effects of amphetamine vary widely by age and among individual people.[28] Cardiovascular side effects can include irregular heartbeat (usually increased heart rate), hypertension (high blood pressure) or hypotension (low blood pressure) from a vasovagal response, and Raynaud's phenomenon.[28][32][61] Sexual side effects in males may include erectile dysfunction, frequent erections, or prolonged erections. Other potential side effects include abdominal pain, acne, blurred vision, excessive grinding of the teeth, profuse sweating, dry mouth, loss of appetite, nausea, reduced seizure threshold, tics, and weight loss.[28][32][61] Dangerous physical side effects are rare in typical pharmaceutical doses.[32]

Amphetamine stimulates the medullary respiratory centers, producing faster and deeper breaths.[32] In a normal person at therapeutic doses, amphetamine does not noticeably stimulate breathing, but when respiration is already compromised, it may stimulate it.[32] Amphetamine also induces contraction in the urinary bladder sphincter, the muscle which controls urination, which can result in difficulty urinating; this effect can be useful in treating bed wetting and loss of bladder control.[32] The effects of amphetamine on the gastrointestinal tract are unpredictable.[32] Amphetamine may reduce gastrointestinal motility (i.e., intestinal peristalsis) if intestinal activity is high, or increase motility if the smooth muscle of the tract is relaxed.[32] Amphetamine also has a slight analgesic effect and can enhance the pain relieving effects of opiates.[32]

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]


Common psychological effects of therapeutic doses can include alertness, apprehension, concentration, decreased sense of fatigue, mood swings (elated mood followed by mildly depressed mood), increased initiative, insomnia or wakefulness, self-confidence, and sociability.[28][32] Less commonly, depending on the user's personality and current mental state, anxiety, change in libido, grandiosity, irritability, repetitive or obsessive behaviors, and restlessness can occur.[sources 6] Amphetamine psychosis can occur in heavy users.[17][28][29] Although very rare, this psychosis can also occur at therapeutic doses during long-term therapy.[17][28][30] According to the USFDA, "there is no systematic evidence that stimulants cause aggressive behavior or hostility."[28]


An amphetamine overdose can lead to many different symptoms, but is rarely fatal with appropriate care.[60][67] A moderate overdose may induce symptoms including brisk reflexes, confusion, high or low blood pressure, hyperthermia, inability to urinate, involuntary muscle twitching, irregular heartbeat, muscle pain, painful urination, rapid breathing, and severe agitation.[17][32][60] An extremely large overdose may produce symptoms such as amphetamine psychosis, bleeding in the brain, cardiogenic shock, circulatory collapse, compulsive and repetitive behavior, elevated blood potassium or low blood potassium, extreme fever, fluid accumulation in the lungs, high lung arterial blood pressure, kidney failure, metabolic acidosis, no urine production, rapid muscle breakdown, respiratory alkalosis, serotonin toxidrome, and sympathomimetic toxidrome.[sources 7] Fatal amphetamine poisoning usually involves convulsions and coma.[17][32] Tolerant individuals have been known to take as much as 5 grams, roughly 100 times the maximum therapeutic dose, at a time.[60]

Dependence, addiction, and withdrawal

Addiction is a serious risk with heavy recreational amphetamine use; it is unlikely to arise from typical medical use.[17][31][32] Tolerance develops rapidly in amphetamine abuse, so periods of extended use require increasing doses of the drug in order to achieve the same effect.[69][70]

A Cochrane Collaboration review on amphetamine and methamphetamine dependence and abuse indicates that the current evidence on effective treatments is extremely limited.[71] The review indicated that fluoxetine[note 8] and imipramine[note 9] have some limited benefits in treating abuse and addiction, but concluded, "no treatment has been demonstrated to be effective for the treatment of amphetamine dependence and abuse."[71] A corroborating review indicated that amphetamine dependence is mediated through increased activation of dopamine receptors and co-localized NMDA receptors in the mesolimbic pathway.[72] This review also noted that magnesium ions, which inhibit NMDA receptor calcium channels, and serotonin have inhibitory effects on NMDA receptors.[72] It also suggested that, based upon animal testing, pathological amphetamine use significantly reduces the level of intracellular magnesium throughout the brain.[72] Supplemental magnesium,[note 10] like fluoxetine treatment, has been shown to reduce self-administration in both humans and lab animals.[71][72]

According to another Cochrane Collaboration review on withdrawal in highly dependent amphetamine and methamphetamine abusers, "when chronic heavy users abruptly discontinue amphetamine use, many report a time-limited withdrawal syndrome that occurs within 24 hours of their last dose."[73] 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.[73] Amphetamine withdrawal symptoms can include anxiety, drug craving, depressed mood, fatigue, increased appetite, increased movement or decreased movement, lack of motivation, sleeplessness or sleepiness, and lucid dreams.[73] The review suggested that withdrawal symptoms are associated with the degree of dependence, suggesting that therapeutic use would result in far milder discontinuation symptoms.[73] Manufacturer prescribing information does not indicate the presence of withdrawal symptoms following discontinuation of amphetamine use after an extended period at therapeutic doses.[74][75][76]

Current models of addiction from chronic drug use involve alterations in gene expression in certain parts of the brain.[77][78][79] The most important transcription factors that produce these alterations are ΔFosB, cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), and nuclear factor kappa B (NFκB).[78] ΔFosB is the most significant, since its overexpression in the nucleus accumbens is necessary and sufficient for many of the neural adaptations seen in drug addiction;[78] it has been implicated in addictions to alcohol, cannabinoids, cocaine, nicotine, phenylcyclidine, and substituted amphetamines.[77][78][80] ΔJunD is the transcription factor which directly opposes ΔFosB.[78] Increases in nucleus accumbens ΔJunD expression can reduce or, with a large increase, even block most of the neural alterations seen in chronic drug abuse (i.e., the alterations mediated by ΔFosB).[78] ΔFosB also plays an important role in regulating behavioral responses to natural rewards, such as palatable food, sex, and exercise.[78][81] Since natural rewards, like drugs of abuse, induce ΔFosB, chronic acquisition of these rewards can result in a similar pathological addictive state.[78][81] Consequently, ΔFosB is the key transcription factor involved in amphetamine addiction, especially amphetamine-induced sex addictions.[78][81][82] ΔFosB inhibitors (drugs that oppose its action) may be an effective treatment for addiction and addictive disorders.[83]

The effects of amphetamine on gene regulation are both dose- and route-dependent.[79] Most of the research on gene regulation and addiction is based upon animal studies with intravenous amphetamine administration at very high doses.[79] 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.[79]


The main section for this topic is on the page Stimulant psychosis, in the section Substituted amphetamines.

Abuse of amphetamine can result in a stimulant psychosis that may present with a variety of symptoms (e.g., paranoia, hallucinations, delusions).[29] A Cochrane Collaboration review on treatment for amphetamine, dextroamphetamine, and methamphetamine abuse-induced psychosis states that about 5–15% of users fail to recover completely.[29][84] The same review asserts that, based upon at least one trial, antipsychotic medications effectively resolve the symptoms of acute amphetamine psychosis.[29] Psychosis very rarely arises from therapeutic use.[30][59]


In rodents and primates, sufficiently high doses of amphetamine cause dopaminergic neurotoxicity, or damage to dopamine neurons, which is characterized as reduced transporter and receptor function.[85] There is no evidence that amphetamine is directly neurotoxic in humans.[86][87] High-dose amphetamine can cause indirect neurotoxicity as a result of increased oxidative stress from reactive oxygen species and autoxidation of dopamine.[35][88][89]


Many types of substances are known to interact with amphetamine, resulting in altered drug action or metabolism of amphetamine, the interacting substance, or both.[8][90] Inhibitors of the enzymes that metabolize amphetamine (i.e., CYP2D6 and flavin containing monooxygenase) will prolong its elimination half-life.[5][90] Amphetamine also interacts with MAOIs, particularly monoamine oxidase A inhibitors, since both MAOIs and amphetamine increase plasma catecholamines; therefore, concurrent use of both is dangerous.[90] Amphetamine will modulate the activity of most psychoactive drugs. In particular, amphetamine may decrease the effects of sedatives and depressants and increase the effects of stimulants and antidepressants.[90] Amphetamine may also decrease the effects of antihypertensives and antipsychotics due to its effects on blood pressure and dopamine respectively.[90] There is no significant effect on consuming amphetamine with food in general, but the pH of gastrointestinal content and urine affects the absorption and excretion of amphetamine, respectively.[90] Acidic substances reduce the absorption of amphetamine and increase urinary excretion, and alkaline substances do the opposite.[90] Due to the effect pH has on absorption, amphetamine also interacts with gastric acid reducers such as proton pump inhibitors and H2 antihistamines, which increase gastrointestinal pH.[90]



For a simpler and less technical explanation of amphetamine's mechanism of action, see the mechanism of action section in the Adderall article.

Pharmacodynamics of amphetamine enantiomers in a dopamine neuron

A pharmacodynamic model of amphetamine and TAAR1
via AADC
Amphetamine enters the presynaptic neuron across the neuronal membrane or through DAT. Once inside, it binds to TAAR1 or enters synaptic vesicles through VMAT2. When amphetamine enters the synaptic vesicles through VMAT2, dopamine is released into the cytosol (yellow-orange area). When amphetamine binds to TAAR1, it reduces dopamine receptor firing rate via potassium channels and triggers protein kinase A (PKA) and protein kinase C (PKC) signaling, resulting in DAT phosphorylation. PKA-phosphorylation causes DAT to withdraw into the presynaptic neuron (internalize) and cease transport. PKC-phosphorylated DAT may either operate in reverse or, like PKA-phosphorylated DAT, internalize and cease transport.

Amphetamine exerts its behavioral effects by altering the use of monoamines as neuronal signals in the brain, primarily in catecholamine neurons in the reward and executive function pathways of the brain, collectively known as the mesocorticolimbic projection.[27][91][92] 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.[27][91][93] The reinforcing and task saliency effects of amphetamine are mostly due to enhanced dopaminergic activity in the mesolimbic pathway.[19]

Amphetamine has been identified as a potent full agonist of trace amine-associated receptor 1 (TAAR1), a Gs-coupled and Gq-coupled G protein-coupled receptor (GPCR) discovered in 2001, which is important for regulation of brain monoamines.[27][92][94] Activation of TAAR1 increases cAMP production via adenylyl cyclase activation and inhibits monoamine transporter function.[27][95] Monoamine autoreceptors (e.g., D2 short, presynaptic α2, and presynaptic 5-HT1A) have the opposite effect of TAAR1, and together these receptors provide a regulatory system for monoamines.[27] Notably, amphetamine and trace amines bind to TAAR1, but not monoamine autoreceptors.[27] 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.[27] 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.[27]

In addition to the neuronal monoamine transporters, amphetamine also inhibits vesicular monoamine transporter 2 (VMAT2), SLC22A3, and SLC22A5.[96][97] SLC22A3 is an extraneuronal monoamine transporter that is present in astrocytes and SLC22A5 is a high-affinity carnitine transporter.[96][98] Amphetamine also mildly inhibits both the CYP2A6 and CYP2D6 liver enzymes.[3] Amphetamine is known to strongly induce cocaine and amphetamine regulated transcript (CART) gene expression,[92][96] a neuropeptide involved in feeding behavior, stress, and reward, which induces observable increases in neuronal development and survival in vitro.[96][99] The CART receptor has yet to be identified, but there is significant evidence that CART binds to a unique Gi/Go-coupled GPCR.[99][100] Amphetamine also inhibits monoamine oxidase at very high doses, resulting in less dopamine and phenethylamine metabolism and consequently higher concentrations of synaptic monoamines.[11][101][102]

The full profile of amphetamine's short-term drug effects is derived through increased cellular communication or neurotransmission of dopamine,[27] serotonin,[27] norepinephrine,[27] epinephrine,[93] histamine,[93] CART peptides,[92] acetylcholine,[103][104] and glutamate,[105][106] which it effects through interactions with CART, TAAR1, and VMAT2.[27][92][93]

Dextroamphetamine is a more potent agonist of TAAR1 than levoamphetamine.[107] Consequently, dextroamphetamine produces greater CNS stimulation than levoamphetamine, roughly three to four times more, but levoamphetamine has slightly stronger cardiovascular and peripheral effects.[32][107]


In certain brain regions, amphetamine increases the concentration of dopamine in the synaptic cleft.[27] Amphetamine can enter the presynaptic neuron either through DAT or by diffusing across the neuronal membrane directly.[27] As a consequence of DAT uptake, amphetamine produces competitive reuptake inhibition at the transporter.[27] Upon entering the presynaptic neuron, amphetamine activates TAAR1 which, through protein kinase A (PKA) and protein kinase C (PKC) signaling, causes DAT phosphorylation.[27] Phosphorylation by either protein kinase can result in DAT internalization (non-competitive reuptake inhibition), but PKC-mediated phosphorylation alone induces reverse transporter function (dopamine efflux).[27][108] Through direct activation of G protein-coupled inwardly-rectifying potassium channels and indirect activation of D2 autoreceptors (via increased dopamine release), TAAR1 reduces the firing rate of post-synaptic dopamine receptors, preventing a hyper-dopaminergic state.[109][110][111]

Amphetamine is also a substrate for the presynaptic vesicular monoamine transporter, VMAT2.[93] Following amphetamine uptake at VMAT2, the synaptic vesicle releases dopamine molecules into the cytosol in exchange.[93] Subsequently, the cytosolic dopamine molecules exit the presynaptic neuron via reverse transport at DAT.[27][93]


Similar to dopamine, amphetamine dose-dependently increases the level of synaptic norepinephrine, the direct precursor of epinephrine.[34][91] Based upon neuronal TAAR1 mRNA expression, amphetamine is thought to affect norepinephrine analogously to dopamine.[27][93][108] 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.[27][93]


Amphetamine exerts analogous, yet less pronounced, effects on serotonin as on dopamine and norepinephrine.[27][91] Amphetamine affects serotonin via VMAT2 and, like norepinephrine, is thought to phosphorylate SERT via TAAR1.[27][93]


Amphetamine has no direct effect on acetylcholine, but several studies have noted that acetylcholine release increases after its use.[103][104] In lab animals, high doses of amphetamine greatly increase acetylcholine levels in certain brain regions, including the hippocampus and caudate nucleus.[103] In humans, a similar phenomenon occurs via the cholinergic–dopaminergic link, mediated by the neuropeptide ghrelin, in the ventral tegmentum.[104] This heightened cholinergic activity leads to increased nicotinic receptor activation in the CNS; a factor which likely contributes to the nootropic effects of amphetamine.[112]

Other relevant activity

Extracellular levels of glutamate, the primary excitatory neurotransmitter in the brain, have been shown to increase upon exposure to amphetamine.[105][106] This cotransmission effect was found in the mesolimbic pathway, an area of the brain implicated in reward, where amphetamine is known to affect dopamine neurotransmission.[105][106] Amphetamine also induces effluxion of histamine from synaptic vesicles in CNS mast cells and histaminergic neurons through VMAT2.[93]


The oral bioavailability of amphetamine varies with gastrointestinal pH;[90] it is well absorbed from the gut, and bioavailability is typically over 75% for dextroamphetamine.[1] Amphetamine is a weak base with a pKa of 9–10;[8] consequently, when the pH is basic, more of the drug is in its lipid soluble free base form, and more is absorbed through the lipid-rich cell membranes of the gut epithelium.[8][90] Conversely, an acidic pH means the drug is predominantly in a water soluble cationic (salt) form, and less is absorbed.[8] Approximately 15–40% of amphetamine circulating in the bloodstream is bound to plasma proteins.[2]

The half-life of amphetamine enantiomers differ and vary with urine pH.[8] At normal urine pH, the half-lives of dextroamphetamine and levoamphetamine are 9–11 hours and 11–14 hours, respectively.[8] An acidic diet will reduce the enantiomer half-lives to 8–11 hours; an alkaline diet will increase the range to 16–31 hours.[113][114] 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.[8] Amphetamine is eliminated via the kidneys, with 30–40% of the drug being excreted unchanged at normal urinary pH.[8] When the urinary pH is basic, amphetamine is in its free base form, so less is excreted.[8] 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.[8] Amphetamine is usually eliminated within two days of the last oral dose.[113] Apparent half-life and duration of effect increase with repeated use and accumulation of the drug.[115]

The prodrug lisdexamfetamine is not as sensitive to pH as amphetamine when being absorbed in the gastrointestinal tract;[116] following absorption into the blood stream, it is converted by red blood cell-associated enzymes to dextroamphetamine via hydrolysis.[116] The elimination half-life of lisdexamfetamine is generally less than one hour.[116]

CYP2D6, dopamine β-hydroxylase, flavin-containing monooxygenase, butyrate-CoA ligase, and glycine N-acyltransferase are the enzymes known to metabolize amphetamine or its metabolites in humans.[sources 8] Amphetamine has a variety of excreted metabolic products, including 4-hydroxyamfetamine, 4-hydroxynorephedrine, 4-hydroxyphenylacetone, benzoic acid, hippuric acid, norephedrine, and phenylacetone.[8][113][117] Among these metabolites, the active sympathomimetics are 4‑hydroxyamphetamine,[118] 4‑hydroxynorephedrine,[119] and norephedrine.[120] The main metabolic pathways involve aromatic para-hydroxylation, aliphatic alpha- and beta-hydroxylation, N-oxidation, N-dealkylation, and deamination.[8][113] The known pathways and detectable metabolites in humans include the following:[5][8][117]

Metabolic pathways of amphetamine

Graphic of several routes of amphetamine metabolism
The primary active metabolites of amphetamine are 4-hydroxyamphetamine and norephedrine;[117] at normal urine pH, about 30–40% of amphetamine is excreted unchanged and roughly 50% is excreted as the inactive metabolites (bottom row).[8] The remaining 10–20% is excreted as the active metabolites.[8] Benzoic acid is metabolized by butyrate-CoA ligase into an intermediate product, benzoyl-CoA,[6] which is then metabolized by glycine N-acyltransferase into hippuric acid.[7]

Related endogenous compounds

For more details on related compounds, see Trace amines.

Amphetamine has a very similar structure and function to the endogenous trace amines, which are naturally occurring neurotransmitter molecules produced in the human body and brain.[27][34] Among this group, the most closely related compounds are phenethylamine, the parent compound of amphetamine, and N-methylphenethylamine, an isomer of amphetamine (i.e., it has an identical molecular formula).[27][34][121] In humans, phenethylamine is produced directly from L-phenylalanine by the aromatic amino acid decarboxylase (AADC) enzyme, which converts L-DOPA into dopamine as well.[34][121] In turn, N‑methylphenethylamine is metabolized from phenethylamine by phenylethanolamine N-methyltransferase, the same enzyme that metabolizes norepinephrine into epinephrine.[34][121] Like amphetamine, both phenethylamine and N‑methylphenethylamine regulate monoamine neurotransmission via TAAR1;[27][121] unlike amphetamine, both of these substances are broken down by monoamine oxidase B, and therefore have a shorter half-life than amphetamine.[34][121]

Physical and chemical properties

An image of amphetamine free base
A vial of the colorless amphetamine free base
Graphical representation of Amphetamine stereoisomers
The skeletal structures of L-amph and D-amph
An image of phenyl-2-nitropropene and amphetamine hydrochloride
Amphetamine hydrochloride (left bowl)
Phenyl-2-nitropropene (right cups)

Amphetamine is a methyl homolog of the mammalian neurotransmitter phenethylamine with the chemical formula C9H13N. The carbon atom adjacent to the primary amine is a stereogenic center, and amphetamine is composed of a racemic 1:1 mixture of two enantiomeric mirror images.[12] This racemic mixture can be separated into its optical isomers:[note 11] levoamphetamine and dextroamphetamine.[12] Physically, at room temperature, the pure free base of amphetamine is a mobile, colorless, and volatile liquid with a characteristically strong amine odor, and acrid, burning taste.[122] Frequently prepared solid salts of amphetamine include amphetamine aspartate,[17] hydrochloride,[123] phosphate,[124] saccharate,[17] and sulfate,[17] the last of which is the most common amphetamine salt.[33] Amphetamine is also the parent compound of its own structural class, which includes a number of psychoactive derivatives.[12] In organic chemistry, amphetamine is an excellent chiral ligand for the stereoselective synthesis of 1,1'-bi-2-naphthol.[125]


For a more comprehensive list, see Substituted amphetamine.

Amphetamine derivatives, often referred to as "amphetamines" or "substituted amphetamines", are a broad range of chemicals that contain amphetamine as a "backbone".[126][127] The class includes stimulants like methamphetamine, serotonergic empathogens like MDMA (ecstasy), and decongestants like ephedrine, among other subgroups.[126][127] This class of chemicals is sometimes referred to collectively as the "amphetamine family."[128]


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

Since the first preparation was reported in 1887,[129] many synthetic routes to amphetamine have been developed.[130][131] Many are based on classic organic reactions. One such example is the Friedel–Crafts alkylation of chlorobenzene by allyl chloride to yield beta chloropropylbenzene which is then reacted with ammonia to produce racemic amphetamine (method 1).[132] 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.[133][134] A third route starts with ethyl 3-oxobutanoate which through a double alkylation with 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).[135]

A significant number of amphetamine syntheses feature a reduction of a nitro, imine, oxime or other nitrogen-containing functional group.[130] 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).[136][137] 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).[137]

The most common route of both legal and illicit amphetamine synthesis employs a non-metal reduction known as the Leuckart reaction (method 6).[33][137] In the first step, a reaction between phenylacetone and formamide, either using additional formic acid or formamide itself as a reducing agent, yields 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.[137][138] Other methods include reductive amination.

A number of chiral resolutions have been developed to separate the two enantiomers of amphetamine.[131] For example, racemic amphetamine can be treated with d-tartaric acid to form a diastereoisomeric salt which is fractionally crystallized to yield dextroamphetamine.[139] Chiral resolution remains the most economical method for obtaining optically pure amphetamine on a large scale.[140] In addition, several enantioselective syntheses of amphetamine have been developed. In one example, optically pure (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.[140]

Amphetamine synthetic routes
Diagram of amphetamine synthesis by Friedel–Crafts alkylation
Method 1: Synthesis by Friedel–Crafts alkylation
Diagram of amphetamine via Ritter synthesis
Method 2: Ritter synthesis
Diagram of amphetamine synthesis via Hofmann and Curtius rearrangements
Method 3: Synthesis via Hofmann and Curtius rearrangements
Diagram of amphetamine synthesis by Knoevenagel condensation
Method 4: Synthesis by Knoevenagel condensation
Diagram of amphetamine synthesis from phenylacetone and ammonia
Method 5: Synthesis using phenylacetone and ammonia
Diagram of amphetamine synthesis by the Leuckart reaction
Method 6: Synthesis by the Leuckart reaction
Diagram of a chiral resolution of racemic amphetamine and a stereoselective synthesis
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 drug test for sports, employment, poisoning diagnostics, and forensics.[sources 9] Techniques such as immunoassay, which is the most common form of amphetamine test, may cross-react with a number of sympathomimetic drugs.[144] Chromatographic methods specific for amphetamine are employed to prevent false positive results.[145] Chiral separation techniques may be employed to help distinguish the source of the drug, whether prescription amphetamine, prescription amphetamine prodrugs, (e.g., selegiline), over-the-counter drug products (e.g., Vicks Vapoinhaler) or illicitly obtained substituted amphetamines.[145][146][147] Several prescription drugs produce amphetamine as a metabolite, including benzphetamine, clobenzorex, famprofazone, fenproporex, lisdexamfetamine, mesocarb, methamphetamine, prenylamine, and selegiline, among others.[22][148][149] These compounds may produce positive results for amphetamine on drug tests.[148][149] 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.[144]

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.[146] 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.[145] 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.[145] 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.[145]

History, society, and culture

Amphetamine was first synthesized in 1887 in Germany by Romanian chemist Lazăr Edeleanu who named it phenylisopropylamine;[129][150][151] its stimulant effects remained unknown until 1927, when it was independently resynthesized by Gordon Alles and reported to have sympathomimetic properties.[151] Amphetamine had no pharmacological use until 1934, when Smith, Kline and French began selling it as an inhaler under the trade name Benzedrine as a decongestant.[23] During World War II, amphetamines and methamphetamine were used extensively by both the Allied and Axis forces for their stimulant and performance-enhancing effects.[129][152][153] As the addictive properties of the drug became known, governments began to place strict controls on the sale of amphetamine.[129] For example, during the early 1970s in the United States, amphetamine became a schedule II controlled substance under the Controlled Substances Act.[154] In spite of strict government controls, amphetamine has been used legally or illicitly by people from a variety of backgrounds, including authors,[155] musicians,[156] mathematicians,[157] and athletes.[18] Amphetamine is still illegally synthesized today in clandestine labs and sold on the black market, primarily in European countries.[24] Outside Europe, the illicit market for amphetamine is much smaller than the market for methamphetamine.[24]

Legal status

As a result of the United Nations Convention on Psychotropic Substances, amphetamine became a schedule II controlled substance, as defined in the treaty, in all (183) state parties.[16] Consequently, it is heavily regulated in most countries.[158][159] Some countries, such as South Korea and Japan, have banned substituted amphetamines even for medical use.[160][161] In other nations, such as Canada (schedule I drug),[162] the United States (schedule II drug),[17] Thailand (category 1 narcotic),[163] and United Kingdom (class B drug),[164] amphetamine is in a restrictive national drug schedule that allows for its use as a medical treatment.[21][24]

Pharmaceutical products

The only currently prescribed amphetamine formulation that contains both enantiomers is Adderall.[note 3][12][22] Amphetamine is also prescribed in enantiopure and prodrug form as dextroamphetamine and lisdexamfetamine respectively.[25][165] Lisdexamfetamine is structurally different from amphetamine, and is inactive until it metabolizes into dextroamphetamine.[165] The free base of racemic amphetamine was previously available as Benzedrine, Psychedrine, and Sympatedrine.[12][22] Levoamphetamine was previously available as Cydril.[22] All current amphetamine pharmaceuticals are salts due to the comparatively high volatility of the free base.[22][25][33] Some of the current brands and their generic equivalents are listed below.

Amphetamine pharmaceuticals
United States
Adopted Name
(D:L) ratio
of salts
Adderall 3:1 tablet [22][25]
Adderall XR 3:1 capsule [22][25]
Dexedrine dextroamphetamine sulfate 1:0 capsule [22][25]
ProCentra dextroamphetamine sulfate 1:0 tablet [25]
Vyvanse lisdexamfetamine dimesylate 1:0 capsule [22][165]
Zenzedi dextroamphetamine sulfate 1:0 liquid [25]
An image of the lisdexamphetamine compound
The skeletal structure of lisdexamfetamine


  1. Synonyms and alternate spellings include: 1-phenylpropan-2-amine (IUPAC name), α-methylbenzeneethanamine, α-methylphenethylamine, amfetamine (International Nonproprietary Name [INN]), β-phenylisopropylamine, desoxynorephedrine, and speed.[11][12][13]
  2. Enantiomers are molecules that are mirror images of one another; they are structurally identical, but of the opposite orientation.[14]
    Levoamphetamine and dextroamphetamine are also known as L-amph or levamfetamine (INN) and D-amph or dexamfetamine (INN) respectively.[11]
  3. 3.0 3.1 "Adderall" is a brand name as opposed to a nonproprietary name; because the latter ("dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine sulfate, and amphetamine aspartate"[25]) is excessively long, this article exclusively refers to this amphetamine mixture by the brand name.
  4. Due to confusion that may arise from use of the plural form, this article will only use the terms "amphetamine" and "amphetamines" to refer to racemic amphetamine, levoamphetamine, and dextroamphetamine and reserve the term "substituted amphetamines" for the class.
  5. This involves impaired dopamine neurotransmission in the mesocortical and mesolimbic pathways and norepinephrine neurotransmission in the prefrontal cortex and locus coeruleus.[43]
  6. Cochrane Collaboration reviews are high quality meta-analytic systematic reviews of randomized controlled trials.[46]
  7. The statements supported by the USFDA come from prescribing information, which is the copyrighted intellectual property of the manufacturer and approved by the USFDA.
  8. During short-term treatment, fluoxetine may decrease drug craving.[71]
  9. During "medium-term treatment," imipramine may extend the duration of adherence to addiction treatment.[71]
  10. The review indicated that magnesium L-aspartate and magnesium chloride produce significant changes in addictive behavior;[72] other forms of magnesium were not mentioned.
  11. Enantiomers are molecules that are mirror images of one another; they are structurally identical, but of the opposite orientation.[14]

Reference notes

  1. [15][16][17][18][19][20][21][22][23][24]
  2. [18][19][20][22][23][26][27][28]
  3. [17][19][29][30][31][32]
  4. [33][34]
  5. [62][63][64][65]
  6. [20][28][32][66]
  7. [13][17][32][67][68]
  8. [3][4][5][6][7]
  9. [18][141][142][143]


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    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 ..."
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