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Amphetamine

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

Amphetamine
an image of the amphetamine compound
a 3d image of the amphetamine compound
Clinical data
Other namesalpha-methylphenethylamine
License data
Dependence
liability		Moderate
Routes of
administration		Medical: Oral, Nasal inhalation
Recreational: Oral, Nasal inhalation, Insufflation, Rectal, Intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityRectal 95–100%; Oral 75–100%[2]
Protein binding15–40%[3]
MetabolismHepatic: CYP2D6[4] and FMO[5]
Elimination half-lifeD-amph:9–11h;[4] L-amph:11–14h[4]
ExcretionRenal; pH-dependent range: 1–75%[4]
Identifiers
  • (RS)-1-phenylpropan-2-amine
    (RS)-1-phenyl-2-aminopropane
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
NIAID ChemDB
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard100.005.543 Edit this at Wikidata
Chemical and physical data
FormulaC9H13N
Molar mass135.2084 g·mol−1
3D model (JSmol)
Melting point11.3 °C (52.3 °F) [6]
Boiling point203 °C (397 °F) [7]
  • NC(C)Cc1ccccc1
  • InChI=1S/C9H13N/c1-8(10)7-9-5-3-2-4-6-9/h2-6,8H,7,10H2,1H3 checkY
  • Key:KWTSXDURSIMDCE-UHFFFAOYSA-N checkY
  (verify)

Amphetamine[note 1] ( /æmˈfɛtəmin/ ⓘ; contracted from alpha‑methylphenethylamine) is a potent central nervous system (CNS) stimulant of the phenethylamine class that is approved for the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy.[10] Historically, it has been used medically as a nasal decongestant and as a treatment for depression and obesity.[10][11][12] Amphetamine is also used as a performance and cognitive enhancer, and, in spite of the significant health risks associated with uncontrolled or high dose use, some individuals use it recreationally as an aphrodisiac or a euphoriant.[13][14][15][16] Although it is a prescription medication, possession and distribution of amphetamine is tightly controlled in most countries.[16][17][18] Consequently, amphetamine is illegally synthesized by clandestine chemists, trafficked, and sold.[19] Based upon drug and drug precursor seizures, amphetamine production and trafficking is much less prevalent than that of methamphetamine.[19]

Amphetamine was discovered in 1887 and exists as two enantiomers: levoamphetamine and dextroamphetamine.[note 2] It was first made available as a pharmaceutical drug under the Benzedrine brand of inhalers for a variety of medical conditions.[10][11] Presently, it is typically prescribed as amphetamine mixed salts (e.g., Adderall), dextroamphetamine (e.g., Dexedrine), or the inactive prodrug lisdexamfetamine (e.g., Vyvanse).[10][20] Amphetamine, through activation of a trace amine receptor, increases monoamine and excitatory neurotransmitter activity in the brain, with its most pronounced effects targeting the catecholamine neurotransmitters norepinephrine and dopamine.[21] At therapeutic doses, this causes psychological and cognitive effects such as euphoria, change in libido,[4] increased arousal, and improved cognitive control.[14][15][22] Similarly, it induces physical effects such as decreased reaction time, fatigue resistance, and increased muscle strength.[13]

In contrast, much larger doses of amphetamine are likely to impair cognitive function and induce rapid muscle breakdown.[14][18] Substance dependence (i.e., addiction) is a serious risk of amphetamine abuse, but only rarely arises from proper medical use.[18][23][24] Very high doses can induce a state of psychosis characterized by delusions and paranoia, and, although rare, this may also occur as a side effect during long-term use at therapeutic doses.[18][25] Moreover, recreational doses are generally much larger than prescribed therapeutic doses, and recreational use therefore carries a far greater risk of serious side effects.[26]

Amphetamine is the parent compound of its own structural class, the (substituted) amphetamines,[note 3] which includes notable substances like bupropion, cathinone, ecstasy, and methamphetamine. It is chemically related to methamphetamine; however, unlike methamphetamine, its salts lack sufficient volatility to be smoked.[27] Notably, amphetamine is also chemically related to the naturally occurring trace amine compounds phenethylamine and N-methylphenethylamine, both of which are produced within the human body.[28]


Uses

See also: Amphetamine mixed salts (medication), Dextroamphetamine, and Lisdexamfetamine

Medical

See also: Attention deficit hyperactivity disorder and Narcolepsy

Amphetamine, in the form of amphetamine mixed salts (e.g., Adderall), dextroamphetamine (e.g., Dexedrine), or lisdexamfetamine (e.g., Vyvanse), is generally used to treat ADHD and narcolepsy.[10][20][29] Historically, amphetamine has also been used as a treatment for depression, obesity, and nasal congestion.[10][11][12]

Long-term exposure to amphetamine throughout adolescence in non-human primates has been observed in two studies.[30][31] One of these studies found no discernible adverse effect on their physiology, behavior, or dopamine system development, while the other observed large lasting reductions to striatal dopamine and dopamine-associated proteins and metabolites.[30][31][32] In contrast for humans, according to Millichap on the use of ADHD stimulants, "[research] has confirmed the effectiveness and safety of the long-term use of [stimulant] medication."[33] Moreover, he emphasized one notable study, stating "a multicenter, placebo-controlled trial of amphetamine treatment for ADHD in Sweden found significant improvements in attention, hyperactivity, and disruptive behaviors and a mean change in IQ of +4.5 after more than 9 months of amphetamine [use];"[34] however, he also noted that the population in the study had a remarkably high incidence of comorbid disorders associated with ADHD.[34] Consequently, the author asserted that other long-term trials of stimulants in ADHD with less comorbidity would be expected to show greater functional improvements and fewer side effects.[34]

The exact etiologies of ADHD are not completely understood;[35] however, the current models of ADHD involve impaired dopamine neurotransmission in the mesocortical and mesolimbic pathways and norepinephrine neurotransmission in the prefrontal cortex and locus coeruleus.[36] Consequently, psychostimulants like methylphenidate and amphetamine that act on these systems are used to treat ADHD.[36] Approximately 70% of individuals who use these stimulants see improvements in ADHD symptoms.[37] In particular, children with ADHD who use stimulant medications generally have better relationships with peers and family members.[33][37] Children also generally perform better in school, are less distractible and impulsive, and have longer attention spans.[33][37]

A Cochrane Collaboration review on the treatment of ADHD in children with comorbid tic disorders indicated that stimulants in general do not exacerbate tics, but high dose dextroamphetamine use in such individuals should be avoided.[38] Other Cochrane reviews on the use of amphetamine for improving recovery following a stroke or acute traumatic brain injury indicated that it may improve recovery, but further research is needed to confirm this.[39][40]

Performance-enhancing

Therapeutic doses of psychostimulants, including amphetamine, improve performance on working memory tests both in normal functioning individuals and those with ADHD.[14] Moreover, these stimulants also increase arousal and, within the nucleus accumbens, improve task saliency.[14] Thus, stimulants improve performance on effortful and tedious tasks as well.[14] Consequently, amphetamine is used by some college and high-school students as a study and test-taking aid.[41] Based upon studies of self-reported illicit stimulant use among college students, performance-enhancing use, as opposed to abuse as a recreational drug, is the primary reason that students use stimulants.[42] In contrast, at doses much higher than those medically prescribed, stimulants can interfere with working memory and cognitive control.[14]

In addition, amphetamine is also used by some professional, collegiate and high school athletes for its strong stimulant effects.[13][43] However, in competitive sports, this form of use is generally prohibited by anti-doping regulations.[13] At moderate therapeutic doses, amphetamine has been shown to increase physical strength,[13] acceleration,[13] stamina,[13][44] and endurance,[13][44] while reducing reaction time.[13] Like methylphenidate and bupropion, amphetamine increases stamina and endurance in humans primarily through reuptake inhibition and effluxion of dopamine in the central nervous system.[44] Similar to cognition enhancement, very high amphetamine doses can induce side effects that impair athletic performance, such as rhabdomyolysis and hyperthermia.[18][22]

Contraindications

Amphetamine should not be used in individuals with a history of drug abuse, heart disease, or severe agitation or anxiety, or in individuals currently experiencing arteriosclerosis, glaucoma, hyperthyroidism, or severe hypertension.[45] Individuals who have experienced hypersensitivity reactions to other stimulants in the past or are currently taking monoamine oxidase inhibitors should not take amphetamine.[45] Individuals with a history of mild heart problems or those who currently have bipolar disorder, circulatory problems in the hands and feet (Raynaud's phenomenon), depression, elevated blood pressure, liver or kidney problems, mania, psychosis, seizures, tics or Tourette syndrome, or thyroid problems should be monitored while taking amphetamine.[45] Amphetamine is classified in US pregnancy category C.[45] This means that detriments to the fetus have been observed in animal studies, adequate human studies have not been conducted, and amphetamine may still be prescribed to pregnant women in some circumstances.[46] It has also been shown to pass through into breast milk, so mothers taking amphetamine are advised to avoid breastfeeding during their course of treatment.[45] Due to the potential for stunted growth, growing children and adolescents should have their height and weight monitored during treatment.[45]

Side effects

Side effects of amphetamine are many and varied, but the amount of amphetamine consumed is the primary factor in determining the likelihood and severity of side effects.[18][22][26] The therapeutic use of amphetamine is currently approved by the United States Food and Drug Administration for long-term pharmaceutical use.[22] Recreational use of amphetamine generally involves far larger doses and is therefore significantly more dangerous, involving a much greater risk of serious side effects.[26]

Physical

At normal therapeutic doses, the physical side effects of amphetamine vary widely by age and among individuals;[22] these side effects can include abdominal pain, acne, arrhythmias, blurred vision, bruxism, constipation or diarrhea, diaphoresis, dry skin, dry mouth, erectile dysfunction, fever, headache, hypertension or hypotension from a vasovagal response, indigestion, insomnia, loss of appetite, nausea, pallor, palpitations, Raynaud's phenomenon (secondary), reduced seizure threshold, tachycardia, tachypnea, tics, vomiting, and weight loss.[22][26][47] Dangerous physical side effects are quite rare in typical pharmaceutical doses.[26]

Amphetamine stimulates the medullary respiratory centers, which increases the rate of respiration and produces deeper breaths.[26] In a normal individual at therapeutic doses, amphetamine does not noticeably increase the rate of respiration or produce deeper breaths, but when respiration is already compromised, they may stimulate respiration.[26] Amphetamine also induces contraction in the urinary bladder sphincter, which can result in difficulty urinating; however, this effect also makes amphetamine useful in treating enuresis and incontinence.[26] In contrast, the effects of amphetamine on the gastrointestinal tract are unpredictable.[26] Amphetamine may reduce gastrointestinal motility if enteric activity is high, or increase motility if the smooth muscle of the tract are relaxed.[26] Amphetamine also has a slight analgesic effect and can further enhance the analgesia of opiates.[26]

Recent studies by the FDA indicate that, in children, young adults, and adults, there is no association between serious adverse cardiovascular events (sudden death, myocardial infarction, and stroke) and the medical use of amphetamine or other ADHD stimulants.[48][49][50][51]

Psychological

Common psychological effects of therapeutic doses can include alertness, apprehension, concentration, decreased sense of fatigue, mood swings (elevated mood or elation and euphoria followed by mild dysphoria), increased initiative, insomnia or wakefulness, self-confidence, and sociability.[22][26] Less common or rare psychological effects that depend on the user's personality and current mental state include anxiety, grandiosity, change in libido,[4] irritability, repetitive or obsessive behaviors, and restlessness.[15][22][26][52] When heavily abused, amphetamine psychosis can occur.[18][22][25] Although very rare, this psychosis can also occur at therapeutic doses during long-term therapy as a side effect.[18][22][52] According to the US Food and Drug Administration (FDA), "there is no systematic evidence that stimulants cause aggressive behavior or hostility."[22]

Overdose

An amphetamine overdose is rarely fatal with appropriate care,[53] but can lead to a number of different symptoms.[18][22] A moderate overdose may induce symptoms including: arrhythmia, confusion, dysuria, hypertension or hypotension, hyperthermia, hyperreflexia, myalgia, severe agitation, tachypnea, tremor, urinary hesitancy, and urinary retention.[18][22][26] An extremely large overdose may produce symptoms such as adrenergic storm, amphetamine psychosis, anuria, cardiogenic shock, circulatory collapse, cerebral hemorrhage, hyperpyrexia, pulmonary hypertension, renal failure, rhabdomyolysis, serotonin syndrome, and stereotypy.[note 4] Fatal amphetamine poisoning usually also involves convulsions and coma.[18][26]

Dependence, addiction and withdrawal

While addiction is a serious risk with heavy recreational amphetamine use, it is unlikely to arise from typical medical use.[18][24][26] Tolerance is developed rapidly in amphetamine abuse; therefore, periods of extended use require increasing amounts of the drug in order to achieve the same effect.[57] According to a Cochrane Collaboration review on withdrawal in highly dependent racemic amphetamine, dextroamphetamine, 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."[58] This review noted that withdrawal symptoms in chronic, high-dose users are frequent, occurring in up to 87.6% of cases, and persist for 3–4 weeks with a marked "crash" phase occurring during the first week.[58] Amphetamine withdrawal symptoms can include fatigue, dysphoric mood, increased appetite, vivid or lucid dreams, hypersomnia or insomnia, increased movement or decreased movement, anxiety, and drug craving.[58] The review suggested that withdrawal symptoms are associated with the degree of dependence, suggesting that therapeutic use would result in far milder discontinuation symptoms.[58] The FDA does not indicate the presence of withdrawal symptoms following discontinuation of amphetamine use after an extended period at therapeutic doses.[59][60][61]

Psychosis

Main article: Stimulant psychosis § Amphetamines

Abuse of amphetamine can result in a stimulant psychosis that may present with a variety of symptoms (e.g., paranoia, hallucinations, delusions).[25] 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.[25][62] The same review asserts that, based upon at least one trial, antipsychotic medications effectively resolve the symptoms of acute amphetamine psychosis.[25] Psychosis very rarely arises from therapeutic use.[45]

Toxicity

Studies conducted on rodents and primates consistently observe long-term dopaminergic neurotoxicity with sufficiently high doses of amphetamine.[63] The only proposed mechanism for neurotoxicity from high-dose amphetamine use in humans is indirect damage to dopamine terminals via autoxidation of dopamine, as opposed to direct toxicity from amphetamine.[26][64][65] Nonetheless, in part due to clinical research ethics, there is no evidence that amphetamine is neurotoxic, directly or indirectly, in humans even at high doses.[24][63][66][67] On the other hand, there is in vitro evidence that amphetamine is neurogenerative and neuroprotective from increasing the activity of cocaine and amphetamine regulated transcript.[68]

Interactions

Amphetamine interacts with many substances due to its effects and its the metabolic systems that break it down into its metabolites. Since amphetamine is metabolized by the liver enzyme CYP2D6, CYP2D6 inhibitors, such as SSRIs and bupropion, will prolong the elimination half-life of amphetamine.[69] Moreover, amphetamine also interacts with monoamine oxidase inhibitors (MAOIs), since both MAOIs and amphetamine increase plasma catecholamines; therefore, concurrent use of both is dangerous.[69] Amphetamine will modulate the activity of most psychoactive drugs. In particular, amphetamine may mitigate the effects of sedatives and depressants and potentiate the effects of stimulants and antidepressants.[69] Amphetamine may also mitigate the effects of antihypertensives and antipsychotics due to its effects on blood pressure and dopamine respectively.[69] While there is no significant effect on consuming amphetamine with food in general, the pH of gastrointestinal and urine content affects the absorption and excretion of amphetamine, respectively.[69] Specifically, acidic substances will reduce the absorption of amphetamine and increase urinary excretion, while alkaline substances do the opposite.[69] Due to the effect pH has on absorption, amphetamine also interacts with gastric acid reducers such as proton pump inhibitors and H2 antihistamines, which decrease gastrointestinal pH.[69]

Pharmacology

An image of amphetamine freebase
A vial containing the colorless amphetamine free base
Graphical representation of Amphetamine stereoisomers
The skeletal structure of L-amph and D-amph respectively

Chemical properties

Amphetamine is a chiral compound and homologue of phenethylamine.[8] Physically, at room temperature, the freebase of amphetamine is a mobile, colorless, and volatile liquid with a characteristically strong amine odor, and acrid, burning taste.[70] The racemic mixture can be divided into its optical isomers: levoamphetamine and dextroamphetamine.[8] Some of the salts of amphetamine include amphetamine aspartate,[18] hydrochloride,[71] phosphate,[72] saccharate,[18] and sulfate,[18] the last of which is the most common amphetamine salt.[27] Amphetamine is also the parent compound of its own structural class, which includes a number of psychoactive derivatives.[8] In organic chemistry, amphetamine is an excellent chiral ligand for the stereoselective synthesis of 1,1'-bi-2-naphthol.[73]

Derivatives

Main article: Substituted amphetamine

Amphetamine derivatives, often referred to as "amphetamines" or "substituted amphetamines", are a broad range of chemicals that contain amphetamine as a "backbone".[74][75] The class includes stimulants like methamphetamine, serotonergic empathogens like MDMA (ecstasy), and decongestants like ephedrine, among other subgroups.[74][75] This class of chemicals is sometimes referred to collectively as the "amphetamine family."[76]

Synthesis

Amphetamine can be synthesized by Knoevenagel condensation of benzaldehyde with nitroethane, which is subsequently reduced by hydrogenation of the double bond and reduction of the nitro group using hydrogen over a palladium catalyst or lithium aluminum hydride.[77][78] Another method is the reaction of phenylacetone with hydroxylamine, producing an imine intermediate that is reduced to the primary amine using hydrogen over a palladium catalyst or lithium aluminum hydride.[78] A third method, commonly used in the illicit manufacture of amphetamine, employs a non-metal reduction known as the "Leuckart" reaction. In the first step, an Eschweiler–Clarke reaction between phenylacetone and formamide using formic acid as a reducing agent yields the synthetic intermediate N-formylamphetamine.[78] This intermediate is then hydrolysed 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.[78]

Amphetamine synthesis routes
Diagram of amphetamine synthesis by Knoevenagel condensation
Method 1: Amphetamine synthesis by Knoevenagel condensation
Diagram of amphetamine synthesis from phenylacetone and hydroxylamine
Method 2: Amphetamine synthesis using phenylacetone and hydroxylamine
Diagram of amphetamine synthesis by the Leuckart reaction
Method 3: Amphetamine synthesis by the Leuckart reaction

Pharmacodynamics

Amphetamine has been identified as a potent agonist of trace amine-associated receptor 1 (TAAR1), a G protein-coupled receptor (GPCR) discovered in 2001, which is important for regulation of brain monoamines.[21][68][79][80] Activation of TAAR1 increases cyclic adenosine monophosphate (cAMP) production via adenylyl cyclase activation and inhibits monoamine transporter function.[21][79] Monoamine autoreceptors, such as D2 short, have the opposite effect of TAAR1, and together these receptors provide a regulatory system for monoamines.[21] Notably, both amphetamine and the endogenous trace amines activate TAAR1, but not monoamine autoreceptors.[21] Other transporters that amphetamine is known to inhibit are vesicular monoamine transporter 2 (VMAT2), SLC22A3, and SLC22A5.[68][81] SLC22A3 is an extraneuronal monoamine transporter that is present in astrocytes and SLC22A5 is a high-affinity carnitine transporter.[68][82] Amphetamine also mildly inhibits both the CYP2A6 and CYP2D6 liver enzymes.[80] There is evidence that amphetamine is an agonist of cocaine and amphetamine regulated transcript (CART),[68][80] a neuropeptide involved in feeding behavior, stress, and reward, which induces observable increases in neuronal development and survival in vitro.[68][83] A receptor for the CART neuropeptide has yet to be identified, but significant evidence of a CART binding site at a GPCR exists.[83][84] At high doses, amphetamine inhibits monoamine oxidase as well, which results in less monoamine metabolism and consequently higher concentrations of synaptic monoamines.[4][85]

Amphetamine primarily exerts its behavioral effects by modulating monoamine neurotransmitters in the brain,[21][80] through mechanisms primarily involving catecholamine neurotransmitters.[21][80][86] Beyond this, amphetamine has broader influence on the brain neurotransmission and the central nervous system, including but not limited to effects on dopamine,[21] serotonin,[21] norepinephrine,[21] acetylcholine,[87][88] glutamate,[89][90] and histamine,[91] through various mechanisms.

The activity of amphetamine on monoamine transporters in the brain also appears to be site-specific.[21] Specifically, it has been observed that non-competitive inhibition of monoamine transporters by amphetamine and trace amines is dependent upon the presence of TAAR1 co-localization in the associated monoamine neurons.[21] 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 mRNA expression.[21] The major neural systems affected by amphetamine are largely implicated in the reward and executive function pathways of the brain, collectively known as the mesocorticolimbic projection.[86] In particular, the concentrations of the primary neurotransmitters involved in reward circuitry and executive functioning, dopamine and norepinephrine, are markedly increased in a dose-dependent manner by amphetamine due to its effects on monoamine transporters.[21][86][91] The reinforcing and task saliency effects of amphetamine, however, are mostly due to enhanced dopaminergic activity in the mesolimbic pathway.[14]

As a CNS stimulant, dextroamphetamine is roughly three to four times more potent than levoamphetamine, but levoamphetamine has stronger cardiovascular and peripheral effects.[26][85]

Dopamine

The most widely studied neurotransmitter with regard to amphetamine action in the central nervous system is dopamine.[21] Studies have shown that, in certain brain regions, amphetamine increases the concentrations of dopamine in the synaptic cleft, thereby heightening the response of the post-synaptic neuron.[21] The various mechanisms by which amphetamine affects dopamine concentrations have been studied extensively, and are known to involve both DAT and VMAT2.[21][80][91] Amphetamine is similar in structure to dopamine and trace amines; consequently, it can enter the presynaptic neuron via DAT as well as by diffusing through the neural membrane directly.[21] Upon entering the presynaptic neuron, amphetamine activates TAAR1 which, through protein kinase signaling, induces dopamine efflux, phosphorylation-dependent DAT internalization, and non-competitive reuptake inhibition.[21][92] Because of the similarity between amphetamine and trace amines, it is also a substrate for monoamine transporters; consequently, it (competitively) inhibits the reuptake of dopamine and other monoamines by competing with them for uptake as well.[21]

In addition, amphetamine is a substrate for the neuronal vesicular monoamine transporter, VMAT2.[91] When amphetamine is taken up by VMAT2, the vesicle releases (effluxes) dopamine molecules into the cytosol in exchange.[91] At high doses, amphetamine inhibits monoamine oxidase which results in less conversion of dopamine into dihydroxyphenylacetic acid, and therefore higher concentrations of synaptic dopamine.[4][85]

Norepinephrine

It is well-established that amphetamine causes increased brain and blood levels of norepinephrine,[86] the direct precursor of adrenaline. Based upon the effects of co-localized TAAR1 with NET in animals and presence of its mRNA in humans, this is thought to occur analogously to its effect on dopamine.[21][92] In other words, amphetamine causes norepinephrine efflux and reuptake inhibition through TAAR1 effects on NET, competitive reuptake inhibition at NET, and norepinephrine efflux from VMAT2.[21][91]

Serotonin

Amphetamine has been found to exert similar effects on serotonin as on dopamine.[21][92] Like DAT, SERT, can be induced to operate in reverse upon amphetamine stimulation, via TAAR1 that are co-localized with SERT.[21][92] The serotonin effluxion and reuptake inhibition effects of amphetamine are not present in SERT cells that lack TAAR1.[21] The effect of amphetamine on serotonin through VMAT2 is also similar to dopamine and norepinephrine.[91]

Acetylcholine

While amphetamine has no direct effect on acetylcholine, several studies have noted that it increases acetylcholine release after use.[87][88] In a study on rats, amphetamine, administered at high therapeutic (1 mg/kg) and supratherapeutic (2 mg/kg) doses, greatly increased acetylcholine levels in many areas of the brain, including the hippocampus, caudate nucleus, prefrontal cortex, nucleus accumbens, and basal ganglia.[87] In humans, this is thought to occur via a cholinergic–dopaminergic link, mediated by a neuropeptide, ghrelin, in the ventral tegmentum.[88] This heightened cholinergic activity leads to heightened activation of nicotinic receptors. This likely contributes to the nootropic effects of amphetamine.[93]

Other relevant activity

In addition, extracellular levels of glutamate, the primary excitatory neurotransmitter in the brain, have been shown to increase upon exposure to amphetamine.[89][90] Consistent with other findings, this effect was found in the mesolimbic pathway, an area of the brain implicated in reward.[89][90] Amphetamine also induces effluxion of histamine, another monoamine, via a VMAT2-mediated mechanism.[91]

Pharmacokinetics

The half-lives of amphetamine varies with age and stereochemistry.[4] The half life for dextroamphetamine is 9 hours for children of ages 6–12, 11 hours in adolescents aged 13–17, and 10 hours in adults.[4] For levoamphetamine, the half-life is 11 hours for children of ages 6–12, 13–14 hours in adolescents aged 13–17, and 13 hours in adults.[4] 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 renally with 30–40% of the drug being excreted unchanged at normal urinary pH.[4] Amphetamine is a weak base with a pKa of 9–10; consequently, when the urinary pH is basic, more of the drug is in its free base form and less is excreted.[4] When urine pH is abnormal, the urinary recovery of amphetamine may range from 1–75%, depending on whether urine is too alkaline or acidic respectively.[4] Amphetamine is usually eliminated within 2 days of the last oral dose.[94] Apparent half-life and duration of effect increase with repeated use and accumulation of drug.[95]

Metabolism occurs mostly in the liver by the cytochrome P450 (CYP) detoxification system. CYP2D6 and flavin-containing monooxygenase are the only enzymes currently known to metabolize amphetamine in humans.[4][5][74] Amphetamine has a variety of excreted metabolic products, including 4-hydroxyamfetamine, 4-hydroxynorephedrine, 4-hydroxyphenylacetone, benzoic acid, hippuric acid, norephedrine, and phenylacetone.[4][94][96] Among these metabolites, the active sympathomimetics are 4‑hydroxyamphetamine,[97] 4‑hydroxynorephedrine,[98] and norephedrine.[99]

The main metabolic pathways involve aromatic para-hydroxylation, aliphatic alpha- and beta-hydroxylation, N-oxidation, N-dealkylation, and deamination.[4][94] The known pathways include:[4][5][96]

Graphic of several routes of amphetamine metabolism
The primary active metabolites of amphetamine are 4-hydroxyamphetamine and norephedrine.[96]

Amphetamine has a very similar structure and function to the endogenous trace amines, which are naturally occurring molecules produced in the human body and brain.[21][28] Among this group, the most closely related compounds are phenethylamine, the parent compound of amphetamine, and N-methylphenethylamine, an isomer of amphetamine (i.e., identical molecular formula).[21][28] In humans, phenethylamine is produced in the body directly from phenylalanine by the same enzyme that converts L-DOPA into dopamine, aromatic amino acid decarboxylase.[28] In turn, N‑methylphenethylamine is metabolized from phenethylamine by phenylethanolamine N-methyltransferase, which the same enzyme that metabolizes norepinephrine into adrenaline.[28] Like amphetamine, both phenethylamine and N‑methylphenethylamine regulate monoamine neurotransmission via TAAR1;[21] however, unlike amphetamine, both of these substances are broken down by monoamine oxidase, and therefore have a shorter half-life than amphetamine.[28]

Detection in body fluids

Amphetamine is frequently measured in urine or blood as part of a drug test in sports or employment, in plasma or serum to confirm a diagnosis of poisoning in hospitalized victims, or to assist in the forensic investigation of a traffic or other criminal violation or a case of sudden death.[13][100][101][102] Techniques such as immunoassay, which is the most common form of amphetamine test, may cross-react with a number of sympathomimetic drugs.[103] Chromatographic methods specific for amphetamine are employed to prevent false positive results.[104] Chiral-separation techniques may be employed to help distinguish the source of the drug, whether obtained legally from prescription amphetamine itself, prescription amphetamine prodrugs, (e.g., selegiline), and over-the-counter drug products (e.g., Vicks Vapoinhaler) or from illicitly obtained substituted amphetamines.[104][105][106]

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.[103]

For the assays, a study noted that an enzyme multiplied immunoassay technique (EMIT) assay[note 5] for amphetamine and methamphetamine may produce a large number of false positives when compared with samples confirmed by liquid chromatography–tandem mass spectrometry.[105] Moreover, 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.[104] In comparison, GC–MS of amphetamine and methamphetamine with the chiral derivatizing agent Mosher's acid chloride[note 6] allows for the detection both of dextroamphetamine and dextromethamphetamine in urine.[104] Hence, the latter method may be used to on samples that test positive using other methods to help distinguish between the aforementioned forms of legal and illicit drug use.[104]

History, society, and culture

Main article: History and culture of amphetamines

Amphetamine was first synthesized in 1887 in Germany by Romanian chemist Lazăr Edeleanu who named it phenylisopropylamine.[107][108] Amphetamine had no pharmacological use until 1934, when Smith, Kline and French began selling it as an inhaler under trade name Benzedrine as a decongestant.[11] During World War II, amphetamines were used extensively by the allied forces and axis forces for their stimulant and performance-enhancing effects.[108][109][110] Eventually, as the addictive properties of the drug became known, governments began to place strict controls on the sale of amphetamine.[108] For example, during the early 1970s in the United States, amphetamine became a schedule II controlled substance under the Controlled Substances Act.[111] In spite of strict government controls, amphetamine has still been used legally or illicitly by individuals from a variety of backgrounds, including authors,[112] musicians,[113] mathematicians,[114] and athletes.[13]

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.[17] Consequently, it is heavily regulated in most countries.[115][116] Some countries, such as South Korea and Japan, have banned substituted amphetamines even for medical use.[117][118] In other nations, such as Canada (schedule I drug),[119] the United States (schedule II drug),[18] Thailand (category 1 narcotic),[120] and United Kingdom (class B drug)[121] amphetamine is in a restrictive national drug schedule which allows for its use as a medical treatment.

Prodrugs

A number of substances have been shown to produce amphetamine and methamphetamine as metabolites, including amphetaminil, benzphetamine, clobenzorex, dimethylamphetamine, ethylamphetamine, famprofazone, fencamine, fenethylline, fenproporex, furfenorex, lisdexamfetamine, mefenorex, mesocarb, prenylamine, propylamphetamine, and selegiline, among others.[10][122][123] These compounds may produce positive results for amphetamine on drug tests.[122][123]

Pharmaceutical products

A commonly prescribed mixture of amphetamine isomers is referred to as amphetamine mixed salts, or by the brand name Adderall.[8] It is also prescribed in enantiopure and prodrug form respectively as dextroamphetamine and lisdexamfetamine.[66][124] Lisdexamfetamine is structurally different from amphetamine, but is inactive until it metabolizes into dextroamphetamine.[124] Brand names of medications that contain, or are inactive and metabolize into, amphetamine include:

  • Adderall (25% levoamphetamine 75% dextroamphetamine)[8]
  • Dexacaps (dextroamphetamine)[66]
  • Dexedrine (dextroamphetamine)[66]
  • ProCentra (dextroamphetamine)[125]
  • Vyvanse (lisdexamfetamine)[124]

Benzedrine and Psychedrine are examples of past pharmaceutical amphetamine formulations.[8]

Notes

  1. ^ Synonyms and alternate spellings include: α-methylphenethylamine, amfetamine (International Nonproprietary Name (INN)), β-phenylisopropylamine, speed, 1-phenylpropan-2-amine, α-methylbenzeneethanamine, C9H13N, and desoxynorephedrine.[8][9]
  2. ^ Levoamphetamine and dextroamphetamine are also known as L-amph or levamfetamine (INN) and D-amph or dexamfetamine (INN) respectively.
  3. ^ Due to confusion that may arise from use of the plural form, this article will only use the term "amphetamines" to refer to racemic amphetamine, levoamphetamine, and dextroamphetamine and reserve the term "substituted amphetamines" for the class.
  4. ^ [18][22][26][52][54][55][56]
  5. ^ The study specified the EMIT II Plus Monoclonal Amphetamine/Metamphetamine assay.
  6. ^ Mosher's acid chloride is also known as (S)-(+)-α-methoxy-α-(trifluoromethy)phenylacetyl chloride.

References

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