Amphetamine

Effects

Increased alertness, Euphoria, Increased motivation, Reduced appetite, Flushing of the face, Increased body temperature, Tachycardia (Incrased heart rate) Paranoia, Insomnia. TS

Overview

Amphetamine (also known as alpha-methylphenethylamine, amfetamine, speed, or by brand names including Adderall, Dexedrine, and Tentin) is a classical stimulant substance of the phenethylamine class. It is the parent compound of the substituted amphetamines, a diverse group that includes methamphetamine, MDMA, cathinone, and bupropion. The mechanism of action involves promoting release of the neurotransmitters dopamine and norepinephrine.[1] PW

A mixture of 75% dextroamphetamine and 25% levoamphetamine. Commonly used to treat obesity, narcolepsy and ADHD. It is also used widely either as a recreational stimulant or study-aid, particularly in the USA where it is frequently prescribed.[2] TS

Amphetamine is a central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy; it is also used to treat binge eating disorder in the form of lisdexamfetamine. Historically, it has been used to treat nasal congestion and depression. Amphetamine is also used as an athletic performance enhancer and cognitive enhancer, and recreationally as an aphrodisiac and euphoriant. It is a prescription drug in many countries, and unauthorized possession and distribution of amphetamine are often tightly controlled due to the significant health risks associated with recreational use.[3] WP

Amphetamine was discovered as a chemical in 1887 by Lazăr Edeleanu, and then as a drug in the late 1920s. It exists as two enantiomers: levoamphetamine and dextroamphetamine. The first amphetamine pharmaceutical was Benzedrine. Pharmaceutical amphetamine is prescribed as racemic amphetamine, Adderall, dextroamphetamine, or lisdexamfetamine. Amphetamine increases monoamine and excitatory neurotransmission in the brain, with its most pronounced effects targeting the norepinephrine and dopamine neurotransmitter systems.[4][5] WP

At therapeutic doses, amphetamine causes emotional and cognitive effects such as euphoria, change in desire for sex, increased wakefulness, and improved cognitive control. It induces physical effects such as improved reaction time, fatigue resistance, decreased appetite, elevated heart rate, and increased muscle strength. Larger doses of amphetamine may impair cognitive function and induce rapid muscle breakdown. Addiction is a serious risk with heavy recreational amphetamine use, but is unlikely to occur from long-term medical use at therapeutic doses. Very high doses can result in psychosis, 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. WP

Amphetamine belongs to the phenethylamine class. It is also the parent compound of its own structural class, the substituted amphetamines, which includes prominent substances such as bupropion, cathinone, MDMA, and methamphetamine. As a member of the phenethylamine class, amphetamine is also chemically related to the naturally occurring trace amine neuromodulators, specifically phenethylamine and N-methylphenethylamine, both of which are produced within the human body. Phenethylamine is the parent compound of amphetamine, while N-methylphenethylamine is a positional isomer of amphetamine that differs only in the placement of the methyl group.[6] WP

History

Legal status

• Internationally, amphetamine (and its isomers dextroamphetamine and levoamphetamine) are Schedule II controlled substances under the United Nations 1971 Convention on Psychotropic Substances.[27] PW
• Australia: Amphetamine is a Schedule 8 controlled substance. Personal quantities under 1.5 grams are decriminalized in the Australian Capital Territory (ACT) as of 28 October 2023.[28][29] PW
• Austria: Amphetamine is illegal to possess, produce and sell under the SMG (Suchtmittelgesetz Österreich).[30] PW
• Brazil: Amphetamine is a Class A3 psychoactive substance.[31] PW
• Canada: Amphetamine is a Schedule I drug in Canada.[32] PW
• Finland: Amphetamine is a prohibited substance, and it's illegal to possess, buy, sell or manufacture under the Finnish Narcotics Act.[33] PW
• France: Amphetamine is scheduled as a "stupéfiant", i.e. a recognized drug of abuse. It is illegal to possess, buy, sell or manufacture, and is not prescriptible.[34] PW
• Germany: Amphetamine was added to the Opiumgesetz (Opium Act) in 1941. In accordance to the Narcotics Act reform of 1981, it is controlled under Anlage III BtMG (Narcotics Act, Schedule III). It can only be prescribed on a narcotic prescription form.[35][36] PW
• Japan: Amphetamine is prohibited even for medical use in Japan.[37] PW
• Luxembourg: Amphetamine is a prohibited substance for recreational use.[38] PW
• The Netherlands: Amphetamine is a List I controlled substance.[39] PW
• New Zealand: Amphetamine is a Class B controlled substance.[40] PW
• Poland: Amphetamine is a Group II-P controlled substance.[41] PW
• South Korea: Amphetamine is prohibited even for medical use in South Korea in compliance with the United Nations Convention on Psychotropic Substances.[42] PW
• Sweden: Amphetamine is classified as a drug by the United Nations and is included in list P II in the 1971 Psychotropic Convention, as well as in list II in Sweden.[43] PW
• Switzerland: Amphetamine is a controlled substance specifically named under Verzeichnis A. Medicinal use is permitted.[44] PW
• Thailand: Amphetamine is classified as a category 1 narcotic under the Thai Narcotic Act of 2012.[45] PW
• United Kingdom: Amphetamine is a Class B drug in the United Kingdom.[46] PW
• United States: Amphetamine is a Schedule II controlled substance in the United States.[47] PW

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. Consequently, it is heavily regulated in most countries. Some countries, such as South Korea and Japan, have banned substituted amphetamines even for medical use. In other nations, such as Brazil (class A3), Canada (schedule I drug), the Netherlands (List I drug), the United States (schedule II drug), Australia (schedule 8), Thailand (category 1 narcotic), and United Kingdom (class B drug), amphetamine is in a restrictive national drug schedule that allows for its use as a medical treatment.[31][32][45][48–58] WP

Pharmacology

Biomolecular mechanisms

Chronic use of amphetamine at excessive doses causes alterations in gene expression in the mesocorticolimbic projection, which arise through transcriptional and epigenetic mechanisms. The most important transcription factors that produce these alterations are Delta FBJ murine osteosarcoma viral oncogene homolog B (ΔFosB), cAMP response element binding protein (CREB), and nuclear factor-kappa B (NF-κB). ΔFosB is the most significant biomolecular mechanism in addiction because ΔFosB overexpression (i.e., an abnormally high level of gene expression which produces a pronounced gene-related phenotype) in the D1-type medium spiny neurons in the nucleus accumbens is necessary and sufficient for many of the neural adaptations and regulates multiple behavioral effects (e.g., reward sensitization and escalating drug self-administration) involved in addiction. Once ΔFosB is sufficiently overexpressed, it induces an addictive state that becomes increasingly more severe with further increases in ΔFosB expression. It has been implicated in addictions to alcohol, cannabinoids, cocaine, methylphenidate, nicotine, opioids, phencyclidine, propofol, and substituted amphetamines, among others.[59–64] WP

ΔJunD, a transcription factor, and G9a, a histone methyltransferase enzyme, both oppose the function of ΔFosB and inhibit increases in its expression. Sufficiently overexpressing ΔJunD in the nucleus accumbens with viral vectors can completely block many of the neural and behavioral alterations seen in chronic drug abuse (i.e., the alterations mediated by ΔFosB). Similarly, accumbal G9a hyperexpression results in markedly increased histone 3 lysine residue 9 dimethylation (H3K9me2) and blocks the induction of ΔFosB-mediated neural and behavioral plasticity by chronic drug use, which occurs via H3K9me2-mediated repression of transcription factors for ΔFosB and H3K9me2-mediated repression of various ΔFosB transcriptional targets (e.g., CDK5). ΔFosB also plays an important role in regulating behavioral responses to natural rewards, such as palatable food, sex, and exercise. Since both natural rewards and addictive drugs induce the 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. Consequently, ΔFosB is the most significant factor involved in both amphetamine addiction and amphetamine-induced sexual addictions, which are compulsive sexual behaviors that result from excessive sexual activity and amphetamine use. These sexual addictions are associated with a dopamine dysregulation syndrome which occurs in some patients taking dopaminergic drugs.[59][65–69] WP

The effects of amphetamine on gene regulation are both dose- and route-dependent. Most of the research on gene regulation and addiction is based upon animal studies with intravenous amphetamine administration at very high doses. 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. This suggests that medical use of amphetamine does not significantly affect gene regulation.[61] WP

Pharmacodynamics

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. 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 because of its effects on monoamine transporters. The reinforcing and motivational salience-promoting effects of amphetamine are due mostly to enhanced dopaminergic activity in the mesolimbic pathway. The euphoric and locomotor-stimulating effects of amphetamine are dependent upon the magnitude and speed by which it increases synaptic dopamine and norepinephrine concentrations in the striatum.[70–74] WP⚠ Part of this sentence could not be copied from the source. Open the source to read it in full.

Amphetamine potentiates monoaminergic neurotransmission primarily by entering axon terminals either through active transport by monoamine transporters (DAT, NET, and SERT) or by passive diffusion across neuronal membranes. The uptake of amphetamine through these transporters produces competitive reuptake inhibition, since amphetamine competes with endogenous monoamines for transporter-mediated clearance from the synaptic cleft. Once inside the neuronal cytosol, amphetamine can interact with its receptor protein targets to initiate signaling cascades that activate intracellular effectors which regulate monoamine transporter function and surface expression at the plasma membrane. The effect of amphetamine on monoamine transporters appears to involve phosphorylation, in which activated protein kinases attach a phosphate group to a specific amino acid residue on the transporter protein. Depending on the protein kinase involved and the residue(s) phosphorylated, phosphorylation can shift transporter function into an efflux-permissive state that causes the reverse transport of cytosolic monoamines into the synaptic cleft, or it can promote transporter internalization, whereby phosphorylated transporters are withdrawn from the plasma membrane and lower total reuptake capacity (i.e., non-competitive reuptake inhibition). As of January 2026, protein kinase A (PKA), protein kinase C (PKC), Ca²⁺/calmodulin-dependent protein kinase II (CaMKII), and Ras homolog family member A (RhoA) have all been demonstrated experimentally to regulate monoamine transporter function activity following amphetamine exposure.[75–79] WP

Amphetamine has been identified as a full agonist of trace amine-associated receptor 1 (TAAR1), a Gₛ-coupled and G₁₃-coupled G protein-coupled receptor (GPCR) discovered in 2001, which is important for regulation of brain monoamines. Several reviews have linked amphetamine's agonism at TAAR1 to modulation of monoamine transporter function and subsequent neurotransmitter efflux and reuptake inhibition at monoaminergic synapses. Upon activation by amphetamine, TAAR1 (trace amine-associated receptor 1) can couple to the Gₛ alpha subunit and increase intracellular cAMP (cyclic adenosine monophosphate) production via adenylyl cyclase activation, which triggers PKA- and PKC-mediated transporter phosphorylation. When TAAR1 couples to the G₁₃ alpha subunit, RhoA activity increases near the endoplasmic reticulum and leads to the downstream internalization of monoamine transporters; TAAR1-dependent RhoA signaling has also been shown to internalize EAAT3 (excitatory amino acid transporter 3), a neuronal glutamate transporter expressed in some monoaminergic neurons. 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. Notably, amphetamine and trace amines possess high binding affinities for TAAR1, but not for monoamine autoreceptors. Although TAAR1 is implicated in amphetamine-induced transporter phosphorylation, the magnitude of TAAR1-mediated monoamine release in humans remains unclear. Beyond its Gₛ- and G₁₃-coupled receptor-mediated effects on monoamine transporter function, TAAR1 also opens G protein-coupled inwardly rectifying potassium channels through a separate pathway, an action that reduces neuronal firing.[70][76][79–83] WP

Amphetamine is also a substrate for the vesicular monoamine transporters VMAT1 and VMAT2. Under normal conditions, VMAT2 transports cytosolic monoamines into synaptic vesicles for storage and later exocytotic release. When amphetamine accumulates in the presynaptic terminal, it collapses the vesicular pH gradient and releases vesicular monoamines into the neuronal cytosol. These displaced monoamines expand the cytosolic pool available for reverse transport, thereby increasing the capacity for monoamine efflux beyond that achieved by amphetamine-mediated transporter phosphorylation alone. Although VMAT2 is recognized as a major target in amphetamine-induced monoamine release at higher doses, some reviews have challenged its relevance at therapeutic doses.[75][84–87] WP

In addition to membrane and vesicular monoamine transporters, amphetamine also inhibits SLC1A1, SLC22A3, and SLC22A5. SLC1A1 is excitatory amino acid transporter 3 (EAAT3), a glutamate transporter located in neurons, SLC22A3 is an extraneuronal monoamine transporter that is present in astrocytes, and SLC22A5 is a high-affinity carnitine transporter. Amphetamine is known to strongly induce cocaine- and amphetamine-regulated transcript (CART) gene expression, a neuropeptide involved in feeding behavior, stress, and reward, which induces observable increases in neuronal development and survival in vitro. The CART receptor has yet to be identified, but there is significant evidence that CART binds to a unique Gᵢ/Gₒ-coupled GPCR (G protein-coupled receptor). Amphetamine also inhibits monoamine oxidases at very high doses, resulting in less monoamine and trace amine metabolism and consequently higher concentrations of synaptic monoamines. In humans, the only post-synaptic receptor at which amphetamine is known to bind is the 5-HT1A receptor, where it acts as an agonist with low micromolar affinity.[7][87–95] WP

The full profile of amphetamine's short-term drug effects in humans is mostly derived through increased cellular communication or neurotransmission of dopamine, serotonin, norepinephrine, epinephrine, histamine, CART peptides, endogenous opioids, adrenocorticotropic hormone, corticosteroids, and glutamate, which it affects through interactions with CART (cocaine- and amphetamine-regulated transcript), 5-HT1A (serotonin receptor 1A), EAAT3 (excitatory amino acid transporter 3), TAAR1 (trace amine-associated receptor 1), VMAT1 (vesicular monoamine transporter 1), VMAT2 (vesicular monoamine transporter 2), and possibly other biological targets. Amphetamine also activates seven human carbonic anhydrase enzymes, several of which are expressed in the human brain.[7][70][72][88][96–101] WP

Dextroamphetamine displays higher binding affinity for DAT than levoamphetamine, whereas both enantiomers share comparable affinity at NET; Consequently, dextroamphetamine produces greater CNS (central nervous system) stimulation than levoamphetamine, roughly three to four times more, but levoamphetamine has slightly stronger cardiovascular and peripheral effects. Dextroamphetamine is also a more potent agonist of TAAR1 (trace amine-associated receptor 1) than levoamphetamine.[75][102][103][104] WP

Dopamine

In certain brain regions, amphetamine increases the concentration of dopamine in the synaptic cleft by modulating DAT (dopamine transporter) through several overlapping processes. Amphetamine can enter the presynaptic neuron either through DAT (dopamine transporter) or, to a lesser extent, by diffusing across the neuronal membrane directly. As a consequence of DAT uptake, amphetamine produces competitive reuptake inhibition at the transporter. Upon entering the presynaptic neuron, amphetamine provokes the release of Ca²⁺ from endoplasmic reticulum stores, an effect that raises intracellular calcium to levels sufficient for downstream kinase-dependent signalling. In parallel, amphetamine also increases intracellular cAMP (cyclic adenosine monophosphate), which activates protein kinase A (PKA) and protein kinase C (PKC), whilst elevated intracellular Ca²⁺ activates PKC alone. Phosphorylation of DAT by either kinase induces transporter internalization (non-competitive reuptake inhibition), but PKC-mediated phosphorylation alone induces the reversal of dopamine transport through DAT (i.e., dopamine efflux).[70][75][76][78][79][86] WP

TAAR1 (trace amine associated receptor 1) has been identified as a biomolecular target of amphetamine that initiates some of amphetamine's kinase-dependent signaling cascades. When TAAR1 (trace amine associated receptor 1) signals via Gs-coupled receptors, intracellular cAMP (cyclic adenosine monophosphate) increases through adenylyl cyclase activation and activates PKA and PKC, in turn phosphorylating DAT (dopamine transporter). TAAR1 (trace amine associated receptor 1) also couples G-protein alpha subunit G₁₃; when triggered by amphetamine, this pathway activates Ras homolog A (RhoA) and its downstream protein kinase, Rho-associated coiled-coil kinase (ROCK), an effect that internalizes both DAT (dopamine transporter) and the neuronal glutamate transporter EAAT3. Transporter internalization via TAAR1 (trace amine associated receptor 1)'s G₁₃-coupled pathway is transient because Gₛ-cAMP-PKA signaling functionally inhibits RhoA's downstream activity; once intracellular cAMP (cyclic adenosine monophosphate) sufficiently accumulates, PKA is activated and phosphorylates RhoA, thereby terminating ROCK-mediated transporter internalization. In addition to presynaptic actions that regulate DAT, TAAR1 (trace amine associated receptor 1) activation exerts a somatodendritic inhibitory influence on midbrain dopamine neurons by reducing their firing rate via G protein-coupled inwardly-rectifying potassium channels, an effect that is expected to reduce action potential-dependent (vesicular) dopamine release into the synaptic cleft.[76][80][83][105–109] WP

Amphetamine's effect on intracellular calcium is associated with DAT phosphorylation through Ca²⁺/calmodulin-dependent protein kinase II alpha (CAMKIIα), in turn producing dopamine efflux. Because conventional PKC isoforms can be activated by Ca²⁺ and diacylglycerol, elevated intracellular calcium can promote PKC-dependent DAT phosphorylation independent of TAAR1.[76][78][86][110] WP⚠ A table follows this text in the source and is not copied here. Open the source to see it.

Amphetamine is also a substrate for the presynaptic vesicular monoamine transporter, VMAT2 (vesicular monoamine transporter 2). Following amphetamine uptake at VMAT2, amphetamine induces the collapse of the vesicular pH gradient, which results in a dose-dependent release of dopamine molecules from synaptic vesicles into the cytosol via dopamine efflux through VMAT2. Subsequently, the cytosolic dopamine molecules are released from the presynaptic neuron into the synaptic cleft via reverse transport at DAT (dopamine transporter).[84][85] WP

Norepinephrine

Similar to dopamine, amphetamine dose-dependently increases the level of synaptic norepinephrine, the direct precursor of epinephrine. Amphetamine is believed to affect norepinephrine analogously to dopamine. In other words, amphetamine induces competitive NET (norepinephrine transporter) reuptake inhibition, TAAR1 (trace amine associated receptor 1)-mediated non-competitive reuptake inhibition and reverse transport at phosphorylated NET, CAMKIIα-mediated NET efflux independent of TAAR1, and norepinephrine release from VMAT2 (vesicular monoamine transporter 2). In locus coeruleus norepinephrine neurons, TAAR1-dependent RhoA signaling promotes EAAT3 internalization and subsequent glutamate reuptake inhibition.[75][76][79] WP

Serotonin

Amphetamine exerts analogous, yet less pronounced, effects on serotonin as on dopamine and norepinephrine. Amphetamine affects serotonin via VMAT2 (vesicular monoamine transporter 2) inhibition and SERT (serotonin transporter) phosphorylation. Like dopamine, amphetamine has low, micromolar affinity at the human 5-HT1A receptor.[70][94][95] WP

Other neurotransmitters, peptides, hormones, and enzymes

Acute amphetamine administration in humans increases endogenous opioid release in several brain structures in the reward system. Extracellular levels of glutamate, the primary excitatory neurotransmitter in the brain, have been shown to increase in the striatum following exposure to amphetamine. This increase in extracellular glutamate presumably occurs via the amphetamine-induced internalization of EAAT3, a glutamate reuptake transporter in some dopamine and norepinephrine neurons. This internalization is mediated by RhoA activation and its downstream effector ROCK, a process that is TAAR1 (trace amine associated receptor 1)-dependent. Amphetamine also induces the selective release of histamine from mast cells and efflux from histaminergic neurons through VMAT2 (vesicular monoamine transporter 2). Acute amphetamine administration can also increase adrenocorticotropic hormone and corticosteroid levels in blood plasma by stimulating the hypothalamic–pituitary–adrenal axis.[72][76][79][96–100][111] WP

In December 2017, the first study assessing the interaction between amphetamine and human carbonic anhydrase enzymes was published; of the eleven carbonic anhydrase enzymes it examined, it found that amphetamine potently activates seven, four of which are highly expressed in the human brain, with low nanomolar through low micromolar activating effects. Based upon preclinical research, cerebral carbonic anhydrase activation has cognition-enhancing effects; but, based upon the clinical use of carbonic anhydrase inhibitors, carbonic anhydrase activation in other tissues may be associated with adverse effects, such as ocular activation exacerbating glaucoma.[101][112] WP

Sex-dependent differences

Clinical research indicates that the pharmacological effects of amphetamine may vary depending on sex and menstrual cycle phase, possibly due to fluctuations in estrogen and progesterone. In menstruating individuals, subjective and behavioral responses to amphetamine are heightened during the follicular phase (i.e., when estrogen levels are higher), and reduced during the luteal phase (i.e., when progesterone is elevated). Reviews of human studies have also noted that men typically report stronger positive subjective responses to amphetamine compared to women tested during the luteal phase, whereas these sex differences are absent when women are tested during the follicular phase; subjective responses to amphetamine appear to correlate positively with plasma or salivary estrogen concentrations. Moreover, neuroimaging studies have reported significant sex differences in the neural response to amphetamine in humans, including differences in dopamine release within the striatum and other brain regions.[113] WP

Preclinical studies have also produced findings of sex-dependent differences in drug response to amphetamine. In contrast to human studies, adult female rats exhibit markedly greater dopamine release in the nucleus accumbens and more pronounced behavioral effects from amphetamine administration relative to males, effects that may be modulated by fluctuating estradiol levels across the estrous cycle or more broadly by adult gonadal hormones.[113][114] WP

Some evidence suggests that amphetamine may be more strongly modulated by ovarian sex hormones than other psychostimulants such as methylphenidate, which may result in relatively greater variability in drug response across the menstrual cycle. Although preliminary observational evidence suggests potential benefit from adjusting amphetamine doses according to menstrual cycle phases, randomized controlled trials have not evaluated this practice.[115] WP

Pharmacokinetics

The oral bioavailability of amphetamine varies with gastrointestinal pH; it is well absorbed from the gut, and bioavailability is typically 90%. Amphetamine is a weak base with a pKₐ of 9.9; 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. Conversely, an acidic pH means the drug is predominantly in a water-soluble cationic (salt) form, and less is absorbed. Between 16-20% of amphetamine circulating in the bloodstream is bound to plasma proteins. Following absorption, amphetamine readily distributes into most tissues in the body, with high concentrations occurring in cerebrospinal fluid and brain tissue.[7][11][116][117] WP

The half-lives of amphetamine enantiomers differ and vary with urine pH. At normal urine pH, the half-lives of dextroamphetamine and levoamphetamine are 9–11 hours and 11–14 hours, respectively. Highly acidic urine will reduce the enantiomer half-lives to 7 hours; highly alkaline urine will increase the half-lives up to 34 hours. 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. Amphetamine is eliminated via the kidneys, with 30–40% of the drug being excreted unchanged at normal urinary pH. When the urinary pH is basic, amphetamine is in its free base form, so less is excreted. 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. Following oral administration, amphetamine appears in urine within 3 hours. Roughly 90% of ingested amphetamine is eliminated 3 days after the last oral dose.[11] WP

CYP2D6, dopamine β-hydroxylase (DBH), flavin-containing monooxygenase 3 (FMO3), butyrate-CoA ligase (XM-ligase), and glycine N-acyltransferase (GLYAT) are the enzymes known to metabolize amphetamine or its metabolites in humans. Amphetamine has a variety of excreted metabolic products, including 4-hydroxyamphetamine, 4-hydroxynorephedrine, 4-hydroxyphenylacetone, N-hydroxyamphetamine, benzoic acid, hippuric acid, norephedrine, and phenylacetone. Among these metabolites, the active sympathomimetics are 4-hydroxyamphetamine, 4-hydroxynorephedrine, norephedrine, and N-hydroxyamphetamine. The main metabolic pathways involve aromatic para-hydroxylation, aliphatic alpha- and beta-hydroxylation, N-oxidation, N-dealkylation, and deamination. The known metabolic pathways, detectable metabolites, and metabolizing enzymes in humans include the following:[118–124] WP⚠ A diagram follows this text in the source and is not copied here. Open the source to see it.

Pharmacomicrobiomics

The human metagenome (i.e., the genetic composition of an individual and all microorganisms that reside on or within the individual's body) varies considerably between individuals. Since the total number of microbial and viral cells in the human body (over 100 trillion) greatly outnumbers human cells (tens of trillions), there is considerable potential for interactions between drugs and an individual's microbiome, including: drugs altering the composition of the human microbiome, drug metabolism by microbial enzymes modifying the drug's pharmacokinetic profile, and microbial drug metabolism affecting a drug's clinical efficacy and toxicity profile. The field that studies these interactions is known as pharmacomicrobiomics.[125–129] WP

Similar to most biomolecules and other orally administered xenobiotics (i.e., drugs), amphetamine is predicted to undergo promiscuous metabolism by human gastrointestinal microbiota (primarily bacteria) prior to absorption into the blood stream. The first amphetamine-metabolizing microbial enzyme, tyramine oxidase from a strain of E. coli commonly found in the human gut, was identified in 2019. This enzyme was found to metabolize amphetamine, tyramine, and phenethylamine with roughly the same binding affinity for all three compounds.[129] WP

Related endogenous compounds

Amphetamine has a very similar structure and function to the endogenous trace amines, which are naturally occurring neuromodulator molecules produced in the human body and brain. Among this group, the most closely related compounds are phenethylamine, the parent compound of amphetamine, and N-methylphenethylamine, a structural isomer of amphetamine (i.e., it has an identical molecular formula). 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. In turn, N-methylphenethylamine is metabolized from phenethylamine by phenylethanolamine N-methyltransferase, the same enzyme that metabolizes norepinephrine into epinephrine. Like amphetamine, both phenethylamine and N-methylphenethylamine regulate monoamine neurotransmission via TAAR1 (trace amine-associated receptor 1); unlike amphetamine, both of these substances are broken down by monoamine oxidase B, and therefore have a shorter half-life than amphetamine.[70][130][131][132] WP

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. Techniques such as immunoassay, which is the most common form of amphetamine test, may cross-react with a number of sympathomimetic drugs. Chromatographic methods specific for amphetamine are employed to prevent false positive results. 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 that contain levomethamphetamine, or illicitly obtained substituted amphetamines. Several prescription drugs produce amphetamine as a metabolite, including benzphetamine, clobenzorex, famprofazone, fenproporex, lisdexamfetamine, mesocarb, methamphetamine, prenylamine, and selegiline, among others. These compounds may produce positive results for amphetamine on drug tests. Amphetamine is generally only detectable by a standard drug test for approximately 24 hours, although a high dose may be detectable for 2–4 days.[74][133–139] WP

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. 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. 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. 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.[134][136] WP

Chemistry

Formula

C9H13N PC

CAS number

300-62-9 PC

Molar mass (g/mol)

135.21 PC

IUPAC name (computed by PubChem)

1-phenylpropan-2-amine PC

SMILES

CC(CC1=CC=CC=C1)N PC

InChIKey

KWTSXDURSIMDCE-UHFFFAOYSA-N PC

PubChem CID

3007

Pop culture

No references added yet.

References

1. Journal / agency Kish, S. J. Pharmacologic mechanisms of crystal meth. Canadian Medical Association Journal. 17 June 2008. doi:10.1503/cmaj.071675
2. Other Use of naltrexone has been found to successfully aid in recovery from amphetamine addiction
3. Other Amphetamine is contracted from alpha-methylphenethylamine. Synonyms and alternate spellings include: 1-phenylpropan-2-amine (IUPAC name), α-methylphenethylamine, amfetamine (International Nonproprietary Name [INN]), β-phenylisopropylamine, thyramine, and speed
4. Other Enantiomers are molecules that are mirror images of one another; they are structurally identical, but of the opposite orientation. Levoamphetamine and dextroamphetamine are also known as L-amph or levamfetamine (INN) and D-amph or dexamfetamine (INN) respectively
5. Other The brand name Adderall is used throughout this article to refer to the amphetamine four-salt mixture it contains (dextroamphetamine sulfate 25%, dextroamphetamine saccharate 25%, amphetamine sulfate 25%, and amphetamine aspartate 25%). The nonproprietary name, which lists all four active constituent chemicals, is excessively lengthy
6. Other The term "amphetamines" also refers to a chemical class, but, unlike the class of substituted amphetamines, the "amphetamines" class does not have a standardized definition in academic literature. One of the more restrictive definitions of this class includes only the racemate and enantiomers of amphetamine and methamphetamine. The most general definition of the class encompasses a broad range of pharmacologically and structurally related compounds. 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 its structural class
7. Harm reduction site Drugbank - Amphetamine
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