Amphetamine

Template:Short description Template:About Template:Pp-semi-indef Template:Use dmy dates Template:Cs1 config Template:Main other {{#invoke:Infobox|infobox}}Template:Template other{{#invoke:TemplatePar |check |template=Template:Infobox_drug |all= |opt= pronounce= pronounce_ref= pronounce_comment= ATC_prefix= ATC_suffix= ATC_supplemental= ATCvet= biosimilars= CAS_number_Ref= CAS_number= CAS_supplemental= ChEBI= ChEBI_Ref= ChEMBL_Ref= ChEMBL= ChemSpiderID= ChemSpiderID_Ref= chirality= class= container_only= DailyMedID= data_page= DrugBank_Ref= DrugBank= Drugs.com= duration_of_action= INN= INN_EMA= IUPAC_name= IUPHAR_ligand= KEGG_Ref= KEGG= MedlinePlus= NIAID_ChemDB= PDB_ligand= PubChemSubstance= PubChem= StdInChIKey_Ref= StdInChIKey= StdInChI_Ref= StdInChI_comment= StdInChI= UNII_Ref= UNII= DTXSID= Verifiedfields= Watchedfields= addiction_liability= alt2= altL= altR= alt= bioavailability= boiling_high= boiling_notes= boiling_point= captionLR= caption= caption2= charge= chemical_formula= chemical_formula_ref= chemical_formula_comment= class1= class2= class3= class4= class5= class6= component1= component2= component3= component4= component5= component6= density= density_notes= dependency_liability= drug_name= elimination_half-life= engvar= excretion= image2= imageL= imageR= image= image_class= image_class2= image_classL= image_classR= Jmol= legal_AU= legal_BR= legal_CA= legal_DE= legal_EU= legal_NZ= legal_UK= legal_UN= legal_US= legal_AU_comment= legal_BR_comment= legal_CA_comment= legal_DE_comment= legal_UK_comment= legal_NZ_comment= legal_US_comment= legal_UN_comment= legal_EU_comment= legal_status= licence_CA= licence_EU= licence_US= license_CA= license_EU= license_US= mab_type= melting_high= melting_notes= melting_point= metabolism= metabolites= molecular_weight= molecular_weight_round= molecular_weight_unit= molecular_weight_ref= molecular_weight_comment= onset= pregnancy_AU= pregnancy_AU_comment= pregnancy_category= protein_bound= routes_of_administration= SMILES= smiles= solubility= sol_units= source= specific_rotation= synonyms= target= tradename= type= vaccine_type= verifiedrevid= width2= widthL= widthR= width= AAN= BAN= JAN= USAN= source_tissues= target_tissues= receptors= agonists= antagonists= precursor= biosynthesis= gt_target_gene= gt_vector= gt_nucleic_acid_type= gt_editing_method= gt_delivery_method= sec_combustion= Ac=Ag=Al=Am=Ar=As=At=Au=B=Ba=Be=Bh=Bi=Bk=Br=C=Ca=Cd=Ce=Cf=Cl=Cm=Cn=Co=Cr=Cs=Cu= D=Db=Ds=Dy=Er=Es=Eu=F=Fe=Fl=Fm=Fr=Ga=Gd=Ge=H=He=Hf=Hg=Ho=Hs=I=In=Ir=K=Kr=La=Li=Lr=Lu=Lv= Mc=Md=Mg=Mn=Mo=Mt=N=Na=Nb=Nd=Ne=Nh=Ni=No=Np=O=Og=Os=P=Pa=Pb=Pd=Pm=Po=Pr=Pt=Pu=Ra=Rb=Re=Rf=Rg=Rh=Rn=Ru=S=Sb=Sc=Se=Sg=Si=Sm=Sn=Sr=Ta=Tb=Tc=Te=Th=Ti=Tl=Tm=Ts=U=V=W=Xe=Y=Yb=Zn=Zr= index_label= index2_label= index_comment= index2_comment= CAS_number2= CAS_supplemental2= ATC_prefix2= ATC_suffix2= ATC_supplemental2= PubChem2= PubChemSubstance2= IUPHAR_ligand2= DrugBank2= ChemSpiderID2= UNII2= KEGG2= ChEBI2= ChEMBL2= PDB_ligand2= NIAID_ChemDB2= SMILES2= smiles2= StdInChI2= StdInChIKey2= CAS_number2_Ref= ChEBI2_Ref= ChEMBL2_Ref= ChemSpiderID2_Ref= DrugBank2_Ref= KEGG2_Ref= StdInChI2_Ref= StdInChIKey2_Ref= UNII2_Ref= DTXSID2= QID= QID2=PLLR= pregnancy_US= pregnancy_US_comment= |cat=Pages using infobox drug with unknown parameters |format=0|errNS=0

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Psychological: Moderate<ref name="Stahl's Essential Psychopharmacology" />Amphetamine Medical: Oral, intravenous<ref name="Amph Uses" />
Recreational: Oral, insufflation, rectal, intravenous, intramuscularEvekeo, Adderall,<ref name="AdderallDiff" group="note">Adderall and other mixed amphetamine salts products such as Mydayis are not racemic amphetamine – they are a mixture composed of equal parts racemate and dextroamphetamine.
See Mixed amphetamine salts for more information about the mixture, and this section for information about the various mixtures of amphetamine enantiomers marketed.</ref> othersTemplate:PlainlistN06Template:ATC Template:ATC | _legal_data=Schedule 8A3Schedule IAnlage IIIClass BClass BPsychotropic Schedule IISchedule II<ref name=":USAS2">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

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(RS)-1-phenylpropan-2-amine

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Amphetamine<ref group="note">Synonyms and alternate spellings include: Template:Nowrap (IUPAC name), Template:Nowrap, amfetamine (International Nonproprietary Name [INN]), Template:Nowrap, thyramine, and speed.<ref name="PubChem Header" /><ref name="Drugbank-amph" /><ref name="Acute amph toxicity" /></ref> (contracted from alpha-methylphenethylamine) is a central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity; it is also used to treat binge eating disorder in the form of its inactive prodrug lisdexamfetamine. 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:<ref group="note">Enantiomers are molecules that are mirror images of one another; they are structurally identical, but of the opposite orientation.<ref name="Enantiomers">Template:Cite book</ref>
Levoamphetamine and dextroamphetamine are also known as Template:Nowrap or levamfetamine (INN) and Template:Nowrap or dexamfetamine (INN) respectively.<ref name="PubChem Header" /></ref> levoamphetamine and dextroamphetamine. Amphetamine properly refers to a specific chemical, the racemic free base, which is equal parts of the two enantiomers in their pure amine forms. 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 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.<ref group="sources"><ref name="Amph Uses" /><ref>Template:Cite journal</ref><ref name="Proper definition">Template:Cite book</ref><ref name="Malenka_2009" /><ref name="Ergogenics" /><ref name="FDA" /><ref name="Benzedrine" /><ref name="UN Convention" /><ref name="Nonmedical" /><ref name="Libido" /><ref name="MeSHAmphetamine">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="WHO INN active moiety">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="Evekeo" /><ref name="BED rapid review" /></ref>

The first amphetamine pharmaceutical was Benzedrine, a brand which was used to treat a variety of conditions. Pharmaceutical amphetamine is prescribed as racemic amphetamine, Adderall,<ref name="UseOfAdderallName" group="note">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.<ref name="NDCD">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref></ref> dextroamphetamine, or the inactive prodrug lisdexamfetamine. Amphetamine increases monoamine and excitatory neurotransmission in the brain, with its most pronounced effects targeting the norepinephrine and dopamine neurotransmitter systems.<ref group="sources"><ref name="Amph Uses" /><ref name="Adderall IR" /><ref name="Malenka_2009" /><ref name="Benzedrine" /><ref name="Evekeo" /><ref name="Miller" /><ref name="Miller+Grandy 2016" /></ref>

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 (e.g., hallucinations, 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.<ref group="sources"><ref name="Adderall IR" /><ref name="Malenka_2009" /><ref name="Ergogenics" /><ref name="FDA" /><ref name="Libido" /><ref name="Westfall" /><ref name="Cochrane" /><ref name="Amphetamine-induced psychosis" /><ref name="Stimulant Misuse" /><ref name="Long-Term Outcomes Medications" /><ref name="NHMH_3e-Addiction doses" /><ref name="Addiction risk" /><ref name="narcolepsy addiction" /></ref>

Amphetamine belongs to the phenethylamine class. It is also the parent compound of its own structural class, the substituted amphetamines,<ref group="note">The term "amphetamines" also refers to a chemical class, but, unlike the class of substituted amphetamines,<ref name="Substituted amphetamines, FMO, and DBH" /> the "amphetamines" class does not have a standardized definition in academic literature.<ref name="Proper definition" /> One of the more restrictive definitions of this class includes only the racemate and enantiomers of amphetamine and methamphetamine.<ref name="Proper definition" /> The most general definition of the class encompasses a broad range of pharmacologically and structurally related compounds.<ref name="Proper definition" />
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.</ref> 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 Template:Nowrap, both of which are produced within the human body. Phenethylamine is the parent compound of amphetamine, while Template:Nowrap is a positional isomer of amphetamine that differs only in the placement of the methyl group.<ref group="sources"><ref name="Trace Amines" /><ref name="EMC">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="Amphetamine - a substituted amphetamine" /></ref>

Uses

Medical

Amphetamine is used to treat attention deficit hyperactivity disorder (ADHD), narcolepsy, obesity, and, in the form of lisdexamfetamine, binge eating disorder.<ref name="Stahl's Essential Psychopharmacology" /><ref name="Evekeo" /><ref name="BED rapid review" /> It is sometimes prescribed Template:Nowrap for its past medical indications, particularly for depression and chronic pain.<ref name="Stahl's Essential Psychopharmacology" /><ref name="Benzedrine sulfate"/>

ADHD

Long-term amphetamine exposure at sufficiently high doses in some animal species is known to produce abnormal dopamine system development or nerve damage,<ref name="pmid22392347">Template:Cite journal</ref><ref name="AbuseAndAbnormalities">Template:Cite journal</ref> but, in humans with ADHD, long-term use of pharmaceutical amphetamines at therapeutic doses appears to improve brain development and nerve growth.<ref name="Neuroplasticity 1">Template:Cite journal</ref><ref name="Neuroplasticity 2">Template:Cite journal</ref><ref name="Neuroplasticity 3">Template:Cite journal</ref> Reviews of magnetic resonance imaging (MRI) studies suggest that long-term treatment with amphetamine decreases abnormalities in brain structure and function found in subjects with ADHD, and improves function in several parts of the brain, such as the right caudate nucleus of the basal ganglia.<ref name="Neuroplasticity 1" /><ref name="Neuroplasticity 2" /><ref name="Neuroplasticity 3" />

Reviews of clinical stimulant research have established the safety and effectiveness of long-term continuous amphetamine use for the treatment of ADHD.<ref name="Long-Term Outcomes Medications">Template:Cite journal</ref><ref name="Millichap" /><ref name="Long-term 2015">Template:Cite journal
Figure 3: Treatment benefit by treatment type and outcome group</ref> Randomized controlled trials of continuous stimulant therapy for the treatment of ADHD spanning 2 years have demonstrated treatment effectiveness and safety.<ref name="Long-Term Outcomes Medications" /><ref name="Millichap" /> Two reviews have indicated that long-term continuous stimulant therapy for ADHD is effective for reducing the core symptoms of ADHD (i.e., hyperactivity, inattention, and impulsivity), enhancing quality of life and academic achievement, and producing improvements in a large number of functional outcomes<ref group="note">The ADHD-related outcome domains with the greatest proportion of significantly improved outcomes from long-term continuous stimulant therapy include academics (≈55% of academic outcomes improved), driving (100% of driving outcomes improved), non-medical drug use (47% of addiction-related outcomes improved), obesity (≈65% of obesity-related outcomes improved), self-esteem (50% of self-esteem outcomes improved), and social function (67% of social function outcomes improved).<ref name="Long-term 2015" />

The largest effect sizes for outcome improvements from long-term stimulant therapy occur in the domains involving academics (e.g., grade point average, achievement test scores, length of education, and education level), self-esteem (e.g., self-esteem questionnaire assessments, number of suicide attempts, and suicide rates), and social function (e.g., peer nomination scores, social skills, and quality of peer, family, and romantic relationships).<ref name="Long-term 2015" />

Long-term combination therapy for ADHD (i.e., treatment with both a stimulant and behavioral therapy) produces even larger effect sizes for outcome improvements and improves a larger proportion of outcomes across each domain compared to long-term stimulant therapy alone.<ref name="Long-term 2015" /> These findings were further supported by a 2025 review of interventions for adolescents, which concluded that medications and cognitive-behavioral treatments (CBT) provide complementary benefits. Medications demonstrated strong short-term efficacy on core symptoms, while CBT contributed modest to strong, and sometimes long-lasting, improvements in functional impairments and executive skills when used as part of combination therapy.<ref>Template:Cite journal</ref></ref> across 9 categories of outcomes related to academics, antisocial behavior, driving, non-medicinal drug use, obesity, occupation, self-esteem, service use (i.e., academic, occupational, health, financial, and legal services), and social function.<ref name="Long-Term Outcomes Medications" /><ref name="Long-term 2015" /> Additionally, a 2024 meta-analytic systematic review reported moderate improvements in quality of life when amphetamine treatment is used for ADHD.<ref name="2024 QOL meta-analysis">Template:Cite journal</ref> One review highlighted a nine-month randomized controlled trial of amphetamine treatment for ADHD in children that found an average increase of 4.5 IQ points, continued increases in attention, and continued decreases in disruptive behaviors and hyperactivity.<ref name="Millichap">Template:Cite book</ref> Another review indicated that, based upon the longest follow-up studies conducted to date, lifetime stimulant therapy that begins during childhood is continuously effective for controlling ADHD symptoms and reduces the risk of developing a substance use disorder as an adult.<ref name="Long-Term Outcomes Medications" />

Models of ADHD suggest that it is associated with functional impairments in some of the brain's neurotransmitter systems;<ref name="Malenka_2009_03" /> these functional impairments involve impaired dopamine neurotransmission in the mesocorticolimbic projection and norepinephrine neurotransmission in the noradrenergic projections from the locus coeruleus to the prefrontal cortex.<ref name="Malenka_2009_03" /> Stimulants like methylphenidate and amphetamine are effective in treating ADHD because they increase neurotransmitter activity in these systems.<ref name="Malenka_2009" /><ref name="Malenka_2009_03">Template:Cite book</ref><ref name="cognition enhancers">Template:Cite journal</ref> Approximately 80% of those who use these stimulants see improvements in ADHD symptoms.<ref name="Long-term 36">Template:Cite journal</ref> Children with ADHD who use stimulant medications generally have better relationships with peers and family members, perform better in school, are less distractible and impulsive, and have longer attention spans.<ref name="Millichap_3">Template:Cite book</ref><ref name="ADHD">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> The Cochrane reviews<ref group="note">Cochrane reviews are high quality meta-analytic systematic reviews of randomized controlled trials.<ref name="pmid16052183">Template:Cite journal</ref></ref> on the treatment of ADHD in children, adolescents, and adults with pharmaceutical amphetamines stated that short-term studies have demonstrated that these drugs decrease the severity of symptoms, but they have higher discontinuation rates than non-stimulant medications due to their adverse side effects.<ref name="Cochrane Amphetamines ADHD">Template:Cite journal</ref><ref name="pmid26844979">Template:Cite journal</ref> However, a 2025 meta-analytic systematic review of 113 randomized controlled trials found that stimulant medications were the only intervention with robust short-term efficacy, and were associated with lower all-cause treatment discontinuation rates than non-stimulant medications (e.g., atomoxetine).<ref name="all-cause discontinuation" group="note">In contrast to the Cochrane reviews that observed higher treatment discontinuation from adverse effects alone, this figure represents any cause of discontinuation (e.g., insufficient perceived treatment benefit).<ref name="2025_113_RCTs" /> </ref><ref name="2025_113_RCTs">Template:Cite journal</ref> A Cochrane review on the treatment of ADHD in children with tic disorders such as Tourette syndrome indicated that stimulants in general do not make tics worse, but high doses of dextroamphetamine could exacerbate tics in some individuals.<ref name="pmid29944175">Template:Cite journal</ref>

Binge eating disorder

Binge eating disorder (BED) is characterized by recurrent and persistent episodes of compulsive binge eating.<ref name="BED definition">Template:Cite journal</ref> These episodes are often accompanied by marked distress and a feeling of loss of control over eating.<ref name="BED definition" /> The pathophysiology of BED is not fully understood, but it is believed to involve dysfunctional dopaminergic reward circuitry along the cortico-striatal-thalamic-cortical loop.<ref name="BED ADHD overlap">Template:Cite journal</ref><ref name="BED secondary outcomes">Template:Cite journal</ref> As of July 2024, lisdexamfetamine is the only USFDA- and TGA-approved pharmacotherapy for BED.<ref name="BED rapid review">Template:Cite journal</ref><ref name="BED neuroplasticity">Template:Cite journal</ref> Evidence suggests that lisdexamfetamine's treatment efficacy in BED is underpinned at least in part by a psychopathological overlap between BED and ADHD, with the latter conceptualized as a cognitive control disorder that also benefits from treatment with lisdexamfetamine.<ref name="BED ADHD overlap" /><ref name="BED secondary outcomes" />

File:TAAR1 organ-specific expression and function.jpg

This diagram illustrates how TAAR1 activation induces incretin-like effects through the release of gastrointestinal hormones and influences food intake, blood glucose levels, and insulin release.<ref name="Berry hTAAR pharmacology December 2017 review" /> TAAR1 expression in the periphery is indicated with "x".<ref name="Berry hTAAR pharmacology December 2017 review" />

Lisdexamfetamine's therapeutic effects for BED primarily involve direct action in the central nervous system after conversion to its pharmacologically active metabolite, dextroamphetamine.<ref name="BED neuroplasticity" /> Centrally, dextroamphetamine increases neurotransmitter activity of dopamine and norepinephrine in prefrontal cortical regions that regulate cognitive control of behavior.<ref name="BED ADHD overlap" /><ref name="BED neuroplasticity" /> Similar to its therapeutic effect in ADHD, dextroamphetamine enhances cognitive control and may reduce impulsivity in patients with BED by enhancing the cognitive processes responsible for overriding prepotent feeding responses that precede binge eating episodes.<ref name="BED ADHD overlap" /><ref>Template:Cite book</ref><ref name="BED systematic review">Template:Cite journal</ref> In addition, dextroamphetamine's actions outside of the central nervous system may also contribute to its treatment effects in BED. Peripherally, dextroamphetamine triggers lipolysis through noradrenergic signaling in adipose fat cells, leading to the release of triglycerides into blood plasma to be utilized as a fuel substrate.<ref name="BED secondary outcomes" /><ref>Template:Cite journal</ref> Dextroamphetamine also activates TAAR1 in peripheral organs along the gastrointestinal tract that are involved in the regulation of food intake and body weight.<ref name="Berry hTAAR pharmacology December 2017 review">Template:Cite journal</ref> Together, these actions confer an anorexigenic effect that promotes satiety in response to feeding and may decrease binge eating as a secondary effect.<ref name="BED systematic review" /><ref name="Berry hTAAR pharmacology December 2017 review" /> While lisdexamfetamine's anorexigenic effects contribute to its efficacy in BED, evidence indicates that the enhancement of cognitive control is necessary and sufficient for addressing the disorder's underlying psychopathology.<ref name="BED ADHD overlap"/><ref name="Heal 2024 BED">Template:Cite book</ref> This view is supported by the failure of anti-obesity medications and other appetite suppressants to significantly reduce BED symptom severity, despite their capacity to induce weight loss.<ref name="Heal 2024 BED"/>

Medical reviews of randomized controlled trials have demonstrated that lisdexamfetamine, at doses between 50–70 mg, is safe and effective for the treatment of moderate-to-severe BED in adults.<ref group="sources" name="BED efficacy"><ref name="BED secondary outcomes" /><ref name="BED rapid review" /><ref name="BED systematic review" /><ref name="BED neuroplasticity" /><ref name="BED review">Template:Cite journal</ref></ref> These reviews suggest that lisdexamfetamine is persistently effective at treating BED and is associated with significant reductions in the number of binge eating days and binge eating episodes per week.<ref name="BED efficacy" group="sources" /> Furthermore, a meta-analytic systematic review highlighted an open-label, 12-month extension safety and tolerability study that reported lisdexamfetamine remained effective at reducing the number of binge eating days for the duration of the study.<ref name="BED systematic review" /> In addition, both a review and a meta-analytic systematic review found lisdexamfetamine to be superior to placebo in several secondary outcome measures, including persistent binge eating cessation, reduction of obsessive-compulsive related binge eating symptoms, reduction of body-weight, and reduction of triglycerides.<ref name="BED secondary outcomes" /><ref name="BED systematic review" /> Lisdexamfetamine, like all pharmaceutical amphetamines, has direct appetite suppressant effects that may be therapeutically useful in both BED and its comorbidities.<ref name="BED rapid review" /><ref name="BED systematic review" /> Based on reviews of neuroimaging studies involving BED-diagnosed participants, therapeautic neuroplasticity in dopaminergic and noradrenergic pathways from long-term use of lisdexamfetamine may be implicated in lasting improvements in the regulation of eating behaviors that are observed.<ref name="BED rapid review" /><ref name="BED neuroplasticity" /><ref name="BED systematic review" />

Narcolepsy

Narcolepsy is a chronic sleep-wake disorder that is associated with excessive daytime sleepiness, cataplexy, and sleep paralysis.<ref name="Autoimmune basis review">Template:Cite journal</ref> Patients with narcolepsy are diagnosed as either type 1 or type 2, with only the former presenting cataplexy symptoms.<ref name="Barateau_2022">Template:Cite journal</ref> Type 1 narcolepsy results from the loss of approximately 70,000 orexin-releasing neurons in the lateral hypothalamus, leading to significantly reduced cerebrospinal orexin levels;<ref name="Narcolepsy guide">Template:Cite journal</ref><ref name="Malenka_2015b">Template:Cite book</ref> this reduction is a diagnostic biomarker for type 1 narcolepsy.<ref name="Barateau_2022" /> Lateral hypothalamic orexin neurons innervate every component of the ascending reticular activating system (ARAS), which includes noradrenergic, dopaminergic, histaminergic, and serotonergic nuclei that promote wakefulness.<ref name="Malenka_2015b" /><ref name="Malenka_2015a">Template:Cite book</ref>

Amphetamine’s therapeutic mode of action in narcolepsy primarily involves increasing monoamine neurotransmitter activity in the ARAS.<ref name="Narcolepsy guide" /><ref name="Amphetamine ARAS textbook">Template:Cite book</ref><ref name="Narcolepsy - Amphetamine and the ARAS" /> This includes noradrenergic neurons in the locus coeruleus, dopaminergic neurons in the ventral tegmental area, histaminergic neurons in the tuberomammillary nucleus, and serotonergic neurons in the dorsal raphe nucleus.<ref name="Malenka_2015a" /><ref name="Narcolepsy - Amphetamine and the ARAS">Template:Cite journal</ref> Dextroamphetamine, the more dopaminergic enantiomer of amphetamine, is particularly effective at promoting wakefulness because dopamine release has the greatest influence on cortical activation and cognitive arousal, relative to other monoamines.<ref name="Narcolepsy guide" /> In contrast, levoamphetamine may have a greater effect on cataplexy, a symptom more sensitive to the effects of norepinephrine and serotonin.<ref name="Narcolepsy guide" /> Noradrenergic and serotonergic nuclei in the ARAS are involved in the regulation of the REM sleep cycle and function as "REM-off" cells, with amphetamine's effect on norepinephrine and serotonin contributing to the suppression of REM sleep and a possible reduction of cataplexy at high doses.<ref name="Narcolepsy guide" /><ref name="Barateau_2022" /><ref name="Malenka_2015a" />

The American Academy of Sleep Medicine (AASM) 2021 clinical practice guideline conditionally recommends dextroamphetamine for the treatment of both type 1 and type 2 narcolepsy.<ref name="narcolepsy efficacy">Template:Cite journal</ref> Treatment with pharmaceutical amphetamines is generally less preferred relative to other stimulants (e.g., modafinil) and is considered a third-line treatment option.<ref name="narcolepsy addiction">Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Medical reviews indicate that amphetamine is safe and effective for the treatment of narcolepsy.<ref name="Narcolepsy guide" /><ref name="narcolepsy addiction" /><ref name="narcolepsy efficacy" /> Amphetamine appears to be most effective at improving symptoms associated with hypersomnolence, with three reviews finding clinically significant reductions in daytime sleepiness in patients with narcolepsy.<ref name="Narcolepsy guide" /><ref name="narcolepsy addiction" /><ref name="narcolepsy efficacy" /> Additionally, these reviews suggest that amphetamine may dose-dependently improve cataplexy symptoms.<ref name="Narcolepsy guide" /><ref name="narcolepsy addiction" /><ref name="narcolepsy efficacy" /> However, the quality of evidence for these findings is low and is consequently reflected in the AASM's conditional recommendation for dextroamphetamine as a treatment option for narcolepsy.<ref name="narcolepsy efficacy" />

Enhancing performance

Cognitive performance

In 2015, a systematic review and a meta-analysis of high quality clinical trials found that, when used at low (therapeutic) doses, amphetamine produces modest yet unambiguous improvements in cognition, including working memory, long-term episodic memory, inhibitory control, and some aspects of attention, in normal healthy adults;<ref name="Unambiguous PFC D1 A2">Template:Cite journal</ref><ref name="Cognitive and motivational effects">Template:Cite journal</ref> these cognition-enhancing effects of amphetamine are known to be partially mediated through the indirect activation of both dopamine D₁ receptor and α₂-adrenergic receptor in the prefrontal cortex.<ref name="Malenka_2009" /><ref name="Unambiguous PFC D1 A2" /> A systematic review from 2014 found that low doses of amphetamine also improve memory consolidation, in turn leading to improved recall of information.<ref name="Cognition enhancement 2014 systematic review">Template:Cite journal</ref> Therapeutic doses of amphetamine also enhance cortical network efficiency, an effect which mediates improvements in working memory in all individuals.<ref name="Malenka_2009" /><ref name="pmid11337538">Template:Cite journal</ref> Amphetamine and other ADHD stimulants also improve task saliency (motivation to perform a task) and increase arousal (wakefulness), in turn promoting goal-directed behavior.<ref name="Malenka_2009" /><ref name="Malenka NAcc">Template:Cite book</ref><ref name="Continuum">Template:Cite journal</ref> Stimulants such as amphetamine can improve performance on difficult and boring tasks and are used by some students as a study and test-taking aid.<ref name="Malenka_2009">Template:Cite book</ref><ref name="Continuum" /><ref name="Test taking aid">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Based upon studies of self-reported illicit stimulant use, Template:Nowrap of college students use diverted ADHD stimulants, which are primarily used for enhancement of academic performance rather than as recreational drugs.<ref name="pmid16999660">Template:Cite journal</ref><ref name="Diversion prevalence 1">Template:Cite journal</ref><ref name="Diversion prevalence 2">Template:Cite journal</ref> However, high amphetamine doses that are above the therapeutic range can interfere with working memory and other aspects of cognitive control.<ref name="Malenka_2009" /><ref name="Continuum" />

Physical performance

Amphetamine is used by some athletes for its psychological and athletic performance-enhancing effects, such as increased endurance and alertness;<ref name="Ergogenics">Template:Cite journal</ref><ref name="Westfall">Template:Cite book</ref> however, non-medical amphetamine use is prohibited at sporting events that are regulated by collegiate, national, and international anti-doping agencies.<ref name="NCAA">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="WADA & AD regulation">Template:Cite journal</ref> In healthy people at oral therapeutic doses, amphetamine has been shown to increase muscle strength, acceleration, athletic performance in anaerobic conditions, and endurance (i.e., it delays the onset of fatigue), while improving reaction time.<ref name="Ergogenics" /><ref name="Ergogenics2" /><ref name="Roelands_2013" /> Amphetamine improves endurance and reaction time primarily through reuptake inhibition and release of dopamine in the central nervous system.<ref name="Ergogenics2" /><ref name="Roelands_2013">Template:Cite journal</ref><ref name="Amph-DA reaction time">Template:Cite journal</ref> Amphetamine and other dopaminergic drugs also increase power output at fixed levels of perceived exertion by overriding a "safety switch", allowing the core temperature limit to increase in order to access a reserve capacity that is normally off-limits.<ref name="Roelands_2013" /><ref name="Central mechanisms affecting exertion">Template:Cite journal</ref><ref name="Monoamine+drug effects on exercise - fatigue and heat">Template:Cite journal</ref> At therapeutic doses, the adverse effects of amphetamine do not impede athletic performance;<ref name="Ergogenics" /><ref name="Ergogenics2" /> however, at much higher doses, amphetamine can induce effects that severely impair performance, such as rapid muscle breakdown and elevated body temperature.<ref name="FDA">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="Ergogenics2">Template:Cite journal</ref>

Recreational

Amphetamine, specifically the more dopaminergic dextrorotatory enantiomer (dextroamphetamine), is also used recreationally as a euphoriant and aphrodisiac, and like other amphetamines; is used as a club drug for its energetic and euphoric high. Dextroamphetamine (d-amphetamine) is considered to have a high potential for misuse in a recreational manner since individuals typically report feeling euphoric, more alert, and more energetic after taking the drug.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="NIDA ADHD stimulants" /> A notable part of the 1960s mod subculture in the UK was recreational amphetamine use, which was used to fuel all-night dances at clubs like Manchester's Twisted Wheel. Newspaper reports described dancers emerging from clubs at 5 a.m. with dilated pupils.<ref name="mixing the medicine">Template:Cite journal</ref> Mods used the drug for stimulation and alertness, which they viewed as different from the intoxication caused by alcohol and other drugs.<ref name="mixing the medicine" /> Dr. Andrew Wilson argues that for a significant minority, "amphetamines symbolised the smart, on-the-ball, cool image" and that they sought "stimulation not intoxication [...] greater awareness, not escape" and "confidence and articulacy" rather than the "drunken rowdiness of previous generations."<ref name="mixing the medicine" /> Dextroamphetamine's dopaminergic (rewarding) properties affect the mesocorticolimbic circuit; a group of neural structures responsible for incentive salience (i.e., "wanting"; desire or craving for a reward and motivation), positive reinforcement and positively-valenced emotions, particularly ones involving pleasure.<ref name=Schultz>Template:Cite journal</ref> Large recreational doses of dextroamphetamine may produce symptoms of dextroamphetamine overdose.<ref name="NIDA ADHD stimulants" /> Recreational users sometimes open dexedrine capsules and crush the contents in order to insufflate (snort) it or subsequently dissolve it in water and inject it.<ref name="NIDA ADHD stimulants">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Immediate-release formulations have higher potential for abuse via insufflation (snorting) or intravenous injection due to a more favorable pharmacokinetic profile and easy crushability (especially tablets).<ref name="CADDRA_2018">Template:Cite book</ref><ref name="Bright2008">Template:Cite journal</ref> Injection into the bloodstream can be dangerous because insoluble fillers within the tablets can block small blood vessels.<ref name="NIDA ADHD stimulants" /> Chronic overuse of dextroamphetamine can lead to severe drug dependence, resulting in withdrawal symptoms when drug use stops.<ref name="NIDA ADHD stimulants" />

Contraindications

Template:See also According to the International Programme on Chemical Safety (IPCS) and the U.S. Food and Drug Administration (FDA),<ref group="note">The statements supported by the USFDA come from prescribing information, which is the copyrighted intellectual property of the manufacturer and approved by the USFDA. USFDA contraindications are not necessarily intended to limit medical practice but limit claims by pharmaceutical companies.<ref name="pmid8545689">Template:Cite journal</ref></ref> amphetamine is contraindicated in people with a history of drug abuse,<ref group="note">According to one review, amphetamine can be prescribed to individuals with a history of abuse provided that appropriate medication controls are employed, such as requiring daily pick-ups of the medication from the prescribing physician.<ref name="Amph Uses" /></ref> cardiovascular disease, severe agitation, or severe anxiety.<ref name="Evekeo">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="FDA"/><ref name="International" /> It is also contraindicated in individuals with advanced arteriosclerosis (hardening of the arteries), glaucoma (increased eye pressure), hyperthyroidism (excessive production of thyroid hormone), or moderate to severe hypertension.<ref name="Evekeo" /><ref name="FDA" /><ref name="International"/> These agencies indicate that people who have experienced allergic reactions to other stimulants or who are taking monoamine oxidase inhibitors (MAOIs) should not take amphetamine,<ref name="Evekeo" /><ref name="FDA" /><ref name="International" /> although safe concurrent use of amphetamine and monoamine oxidase inhibitors has been documented.<ref name="Review MAOI-amph">Template:Cite journal</ref><ref name="Primary MAOI-amph">Template:Cite journal</ref> These agencies also state that anyone with anorexia nervosa, bipolar disorder, depression, hypertension, liver or kidney problems, mania, psychosis, Raynaud's phenomenon, seizures, thyroid problems, tics, or Tourette syndrome should monitor their symptoms while taking amphetamine.<ref name="FDA" /><ref name="International" /> 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.<ref name="International" /> Amphetamine has also been shown to pass into breast milk, so the IPCS and the FDA advise mothers to avoid breastfeeding when using it.<ref name="FDA" /><ref name="International" /> Due to the potential for reversible growth impairments,<ref group="note">In individuals who experience sub-normal height and weight gains, a rebound to normal levels is expected to occur if stimulant therapy is briefly interrupted.<ref name="Long-Term Outcomes Medications" /><ref name="Millichap" /><ref name="pmid18295156" /> The average reduction in final adult height from 3 years of continuous stimulant therapy is 2 cm.<ref name="pmid18295156" /></ref> the FDA advises monitoring the height and weight of children and adolescents prescribed an amphetamine pharmaceutical.<ref name="FDA" />

Adverse effects

The adverse side effects of amphetamine are many and varied, and the amount of amphetamine used is the primary factor in determining the likelihood and severity of adverse effects.<ref name="FDA" /><ref name="Westfall" /> Amphetamine products such as Adderall, Dexedrine, and their generic equivalents are currently approved by the U.S. FDA for long-term therapeutic use.<ref name="NDCD" /><ref name="FDA" /> Recreational use of amphetamine generally involves much larger doses, which have a greater risk of serious adverse drug effects than dosages used for therapeutic purposes.<ref name="Westfall" />

Physical

Cardiovascular side effects can include hypertension or hypotension from a vasovagal response, Raynaud's phenomenon (reduced blood flow to the hands and feet), and tachycardia (increased heart rate).<ref name="FDA" /><ref name="Westfall" /><ref name="pmid18295156">Template:Cite journal</ref> Sexual side effects in males may include erectile dysfunction, frequent erections, or prolonged erections.<ref name="FDA" /> Gastrointestinal side effects may include abdominal pain, constipation, diarrhea, and nausea.<ref name="Stahl's Essential Psychopharmacology" /><ref name="FDA" /><ref name="Dyanavel">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Other potential physical side effects include appetite loss, blurred vision, dry mouth, excessive grinding of the teeth, nosebleed, profuse sweating, rhinitis medicamentosa (drug-induced nasal congestion), reduced seizure threshold, tics (a type of movement disorder), and weight loss.<ref group="sources"><ref name="Stahl's Essential Psychopharmacology" /><ref name="FDA" /><ref name="Westfall" /><ref name="pmid18295156" /><ref name="Dyanavel" /><ref name="rhinitis">Template:Cite journal</ref></ref> Dangerous physical side effects are rare at typical pharmaceutical doses.<ref name="Westfall" />

Amphetamine stimulates the medullary respiratory centers, producing faster and deeper breaths.<ref name="Westfall"/> In a normal person at therapeutic doses, this effect is usually not noticeable, but when respiration is already compromised, it may be evident.<ref name="Westfall" /> Amphetamine also induces contraction in the urinary bladder sphincter, the muscle which controls urination, which can result in difficulty urinating.<ref name="Westfall" /> This effect can be useful in treating bed wetting and loss of bladder control.<ref name="Westfall" /> The effects of amphetamine on the gastrointestinal tract are unpredictable.<ref name="Westfall" /> If intestinal activity is high, amphetamine may reduce gastrointestinal motility (the rate at which content moves through the digestive system);<ref name="Westfall" /> however, amphetamine may increase motility when the smooth muscle of the tract is relaxed.<ref name="Westfall" /> Amphetamine also has a slight analgesic effect and can enhance the pain relieving effects of opioids.<ref name="Stahl's Essential Psychopharmacology">Template:Cite book</ref><ref name="Westfall" />

FDA-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.<ref group="sources"><ref name="FDA - cardiovascular effects in young individuals">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="pmid22043968">Template:Cite journal</ref><ref name="FDA - cardiovascular effects in adults">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="pmid22161946">Template:Cite journal</ref></ref> However, amphetamine pharmaceuticals are contraindicated in individuals with cardiovascular disease.<ref group="sources"><ref name="FDA" /><ref name="International">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="FDA - cardiovascular effects in young individuals" /><ref name="FDA - cardiovascular effects in adults" /></ref>

Psychological

At normal therapeutic doses, the most common psychological side effects of amphetamine include increased alertness, apprehension, concentration, initiative, self-confidence and sociability, mood swings (elated mood followed by mildly depressed mood), insomnia or wakefulness, and decreased sense of fatigue.<ref name="FDA" /><ref name="Westfall" /> Less common side effects include anxiety, change in libido, grandiosity, irritability, repetitive or obsessive behaviors, and restlessness;<ref group="sources"><ref name="Libido">Template:Cite journal</ref><ref name="FDA" /><ref name="Westfall" /><ref name="Merck_Manual_Amphetamines">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref></ref> these effects depend on the user's personality and current mental state.<ref name="Westfall" /> Amphetamine psychosis (e.g., delusions and paranoia) can occur in heavy users.<ref name="FDA" /><ref name="Cochrane">Template:Cite journal</ref><ref name="Amphetamine-induced psychosis">Template:Cite journal</ref> Although very rare, this psychosis can also occur at therapeutic doses during long-term therapy.<ref name="FDA" /><ref name="Amphetamine-induced psychosis" /><ref name="Stimulant Misuse">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> According to the FDA, "there is no systematic evidence" that stimulants produce aggressive behavior or hostility.<ref name="FDA" />

Amphetamine has also been shown to produce a conditioned place preference in humans taking therapeutic doses,<ref name="Cochrane Amphetamines ADHD" /><ref name="Human CPP">Template:Cite journal</ref> meaning that individuals acquire a preference for spending time in places where they have previously used amphetamine.<ref name="Human CPP" /><ref name="Addiction glossary" />

Reinforcement disorders

Addiction

Template:Addiction glossary Template:Transcription factor glossary Template:Psychostimulant addiction Addiction is a serious risk with heavy recreational amphetamine use, but is unlikely to occur from long-term medical use at therapeutic doses;<ref name="NHMH_3e-Addiction doses">Template:Cite book</ref><ref name="Addiction risk">Template:Cite journal</ref><ref name="narcolepsy addiction" /> in fact, lifetime stimulant therapy for ADHD that begins during childhood reduces the risk of developing substance use disorders as an adult.<ref name="Long-Term Outcomes Medications" /> Template:If pagename Pathological overactivation of the mesolimbic pathway, a dopamine pathway that connects the ventral tegmental area to the nucleus accumbens, plays a central role in amphetamine addiction.<ref name="Amphetamine KEGG – ΔFosB">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="Magnesium" /> Individuals who frequently self-administer high doses of amphetamine have a high risk of developing an amphetamine addiction, since chronic use at high doses gradually increases the level of accumbal ΔFosB, a "molecular switch" and "master control protein" for addiction.<ref name="Cellular basis" /><ref name="What the ΔFosB?" /><ref name="Nestler" /> Once nucleus accumbens ΔFosB is sufficiently overexpressed, it begins to increase the severity of addictive behavior (i.e., compulsive drug-seeking) with further increases in its expression.<ref name="What the ΔFosB?">Template:Cite journal</ref><ref name="Natural and drug addictions" /> While there are currently no effective drugs for treating amphetamine addiction, regularly engaging in sustained aerobic exercise appears to reduce the risk of developing such an addiction.<ref name="Running vs addiction" /><ref name="Exercise, addiction prevention, and ΔFosB">Template:Cite journal</ref> Exercise therapy improves clinical treatment outcomes and may be used as an adjunct therapy with behavioral therapies for addiction.<ref name="Running vs addiction" /><ref name="Exercise Rev 3" /><ref name="Exercise therapy" group="sources" />

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.<ref name="Nestler" /><ref name="Nestler, Hyman, and Malenka 2">Template:Cite journal</ref><ref name="Addiction genetics" /> The most important transcription factors<ref group="note">Transcription factors are proteins that increase or decrease the expression of specific genes.<ref name="NHM-Transcription factor">Template:Cite book</ref></ref> 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).<ref name="Nestler" /> 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<ref group="note">In simpler terms, this necessary and sufficient relationship means that ΔFosB overexpression in the nucleus accumbens and addiction-related behavioral and neural adaptations always occur together and never occur alone.</ref> for many of the neural adaptations and regulates multiple behavioral effects (e.g., reward sensitization and escalating drug self-administration) involved in addiction.<ref name="Cellular basis" /><ref name="What the ΔFosB?" /><ref name="Nestler" /> Once ΔFosB is sufficiently overexpressed, it induces an addictive state that becomes increasingly more severe with further increases in ΔFosB expression.<ref name="Cellular basis" /><ref name="What the ΔFosB?" /> It has been implicated in addictions to alcohol, cannabinoids, cocaine, methylphenidate, nicotine, opioids, phencyclidine, propofol, and substituted amphetamines, among others.<ref group="sources"><ref name="What the ΔFosB?" /><ref name="Natural and drug addictions" /><ref name="Nestler" /><ref name="Alcoholism ΔFosB">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="MPH ΔFosB">Template:Cite journal</ref></ref>

ΔJunD, a transcription factor, and G9a, a histone methyltransferase enzyme, both oppose the function of ΔFosB and inhibit increases in its expression.<ref name="Cellular basis" /><ref name="Nestler" /><ref name="Nestler 2014 epigenetics">Template:Cite journal</ref> 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).<ref name="Nestler" /> 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,<ref group="sources"><ref name="Nestler" /><ref name="G9a reverses ΔFosB plasticity">Template:Cite journal</ref><ref name="HDACi-induced G9a+H3K9me2 primary source">Template:Cite journal</ref><ref name="A feat of epigenetic engineering">Template:Cite journal</ref></ref> which occurs via H3K9me2-mediated repression of transcription factors for ΔFosB and H3K9me2-mediated repression of various ΔFosB transcriptional targets (e.g., CDK5).<ref name="Nestler" /><ref name="Nestler 2014 epigenetics" /><ref name="G9a reverses ΔFosB plasticity" /> ΔFosB also plays an important role in regulating behavioral responses to natural rewards, such as palatable food, sex, and exercise.<ref name="Natural and drug addictions" /><ref name="Nestler" /><ref name="ΔFosB reward">Template:Cite journal</ref> 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.<ref name="Natural and drug addictions" /><ref name="Nestler">Template:Cite journal</ref> 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.<ref name="Natural and drug addictions" /><ref name="Amph-Sex X-sensitization through D1 signaling">Template:Cite journal</ref><ref name="Amph-Sex X-sensitization through NMDA signaling">Template:Cite journal</ref> These sexual addictions are associated with a dopamine dysregulation syndrome which occurs in some patients taking dopaminergic drugs.<ref name="Natural and drug addictions" /><ref name="ΔFosB reward" />

The effects of amphetamine on gene regulation are both dose- and route-dependent.<ref name="Addiction genetics">Template:Cite journal</ref> Most of the research on gene regulation and addiction is based upon animal studies with intravenous amphetamine administration at very high doses.<ref name="Addiction genetics" /> The few studies that have used equivalent (weight-adjusted) human therapeutic doses and oral administration show that these changes, if they occur, are relatively minor.<ref name="Addiction genetics" /> This suggests that medical use of amphetamine does not significantly affect gene regulation.<ref name="Addiction genetics" />

Pharmacological treatments

Template:Further Template:As of there is no effective pharmacotherapy for amphetamine addiction.<ref name="NHMH_3e-Physical dependence + psychostimulant addiction treatment">Template:Cite book</ref><ref name="SystRev-Meta analysis amphetamine addiction pharmacotherapy" /><ref name="pmid24716825">Template:Cite journal</ref> Reviews from 2015 and 2016 indicated that TAAR1-selective agonists have significant therapeutic potential as a treatment for psychostimulant addictions;<ref name="Miller+Grandy 2016" /><ref name="TAAR1 addiction 2015" /> however, Template:As of the only compounds which are known to function as TAAR1-selective agonists are experimental drugs.<ref name="Miller+Grandy 2016">Template:Cite journal</ref><ref name="TAAR1 addiction 2015">Template:Cite journal</ref> Amphetamine addiction is largely mediated through increased activation of dopamine receptors and Template:Nowrap NMDA receptors<ref group="note">NMDA receptors are voltage-dependent ligand-gated ion channels that requires simultaneous binding of glutamate and a co-agonist (Template:Nowrap or glycine) to open the ion channel.<ref name="NHM-NMDA">Template:Cite book</ref></ref> in the nucleus accumbens;<ref name="Magnesium" /> magnesium ions inhibit NMDA receptors by blocking the receptor calcium channel.<ref name="Magnesium" /><ref name="NHM-NMDA" /> One review suggested that, based upon animal testing, pathological (addiction-inducing) psychostimulant use significantly reduces the level of intracellular magnesium throughout the brain.<ref name="Magnesium" /> Supplemental magnesium<ref group="note">The review indicated that [[magnesium aspartate|magnesium Template:Nowrap]] and magnesium chloride produce significant changes in addictive behavior;<ref name="Magnesium" /> other forms of magnesium were not mentioned.</ref> treatment has been shown to reduce amphetamine self-administration (i.e., doses given to oneself) in humans, but it is not an effective monotherapy for amphetamine addiction.<ref name="Magnesium">Template:Cite journal</ref>

A systematic review and meta-analysis from 2019 assessed the efficacy of 17 different pharmacotherapies used in randomized controlled trials (RCTs) for amphetamine and methamphetamine addiction;<ref name="SystRev-Meta analysis amphetamine addiction pharmacotherapy" /> it found only low-strength evidence that methylphenidate might reduce amphetamine or methamphetamine self-administration.<ref name="SystRev-Meta analysis amphetamine addiction pharmacotherapy">Template:Cite journal</ref> There was low- to moderate-strength evidence of no benefit for most of the other medications used in RCTs, which included antidepressants (bupropion, mirtazapine, sertraline), antipsychotics (aripiprazole), anticonvulsants (topiramate, baclofen, gabapentin), naltrexone, varenicline, citicoline, ondansetron, prometa, riluzole, atomoxetine, dextroamphetamine, and modafinil.<ref name="SystRev-Meta analysis amphetamine addiction pharmacotherapy" />

Behavioral treatments

A 2018 systematic review and network meta-analysis of 50 trials involving 12 different psychosocial interventions for amphetamine, methamphetamine, or cocaine addiction found that combination therapy with both contingency management and community reinforcement approach had the highest efficacy (i.e., abstinence rate) and acceptability (i.e., lowest dropout rate).<ref name="Psychosocial interventions network meta-analysis">Template:Cite journal</ref> Other treatment modalities examined in the analysis included monotherapy with contingency management or community reinforcement approach, cognitive behavioral therapy, 12-step programs, non-contingent reward-based therapies, psychodynamic therapy, and other combination therapies involving these.<ref name="Psychosocial interventions network meta-analysis" />

Additionally, research on the neurobiological effects of physical exercise suggests that daily aerobic exercise, especially endurance exercise (e.g., marathon running), prevents the development of drug addiction and is an effective adjunct therapy (i.e., a supplemental treatment) for amphetamine addiction.<ref group="sources" name="Exercise therapy"><ref name="Natural and drug addictions" /><ref name="Running vs addiction" /><ref name="Exercise, addiction prevention, and ΔFosB" /><ref name="Exercise Rev 3" /><ref name="Addiction review 2016" /></ref> Exercise leads to better treatment outcomes when used as an adjunct treatment, particularly for psychostimulant addictions.<ref name="Running vs addiction">Template:Cite journal</ref><ref name="Exercise Rev 3">Template:Cite journal</ref><ref name="Addiction review 2016">Template:Cite journal</ref> In particular, aerobic exercise decreases psychostimulant self-administration, reduces the reinstatement (i.e., relapse) of drug-seeking, and induces increased dopamine receptor D₂ (DRD2) density in the striatum.<ref name="Natural and drug addictions" /><ref name="Addiction review 2016" /> This is the opposite of pathological stimulant use, which induces decreased striatal DRD2 density.<ref name="Natural and drug addictions">Template:Cite journal</ref> One review noted that exercise may also prevent the development of a drug addiction by altering ΔFosB or Template:Nowrap immunoreactivity in the striatum or other parts of the reward system.<ref name="Exercise, addiction prevention, and ΔFosB" /> Template:FOSB addiction table

Dependence and withdrawal

Drug tolerance develops rapidly in amphetamine abuse (i.e., recreational amphetamine use), so periods of extended abuse require increasingly larger doses of the drug in order to achieve the same effect.<ref name="Cochrane 2013 treatments">Template:Cite journal</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> According to a Cochrane review on withdrawal in individuals who compulsively use amphetamine and methamphetamine, "when chronic heavy users abruptly discontinue amphetamine use, many report a time-limited withdrawal syndrome that occurs within 24 hours of their last dose."<ref name="Cochrane Withdrawal">Template:Cite journal</ref> This review noted that withdrawal symptoms in chronic, high-dose users are frequent, occurring in roughly 88% of cases, and persist for Template:Nowrap weeks with a marked "crash" phase occurring during the first week.<ref name="Cochrane Withdrawal" /> 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.<ref name="Cochrane Withdrawal" /> The review indicated that the severity of withdrawal symptoms is positively correlated with the age of the individual and the extent of their dependence.<ref name="Cochrane Withdrawal" /> Mild withdrawal symptoms from the discontinuation of amphetamine treatment at therapeutic doses can be avoided by tapering the dose.<ref name="Stahl's Essential Psychopharmacology" />

Overdose

An amphetamine overdose can lead to many different symptoms, but is rarely fatal with appropriate care.<ref name="Stahl's Essential Psychopharmacology" /><ref name="International" /><ref name="Amphetamine toxidrome">Template:Cite journal</ref> The severity of overdose symptoms increases with dosage and decreases with drug tolerance to amphetamine.<ref name="Westfall" /><ref name="International" /> Tolerant individuals have been known to take as much as 5 grams of amphetamine in a day, which is roughly 100 times the maximum daily therapeutic dose.<ref name="International" /> Symptoms of a moderate and extremely large overdose are listed below; fatal amphetamine poisoning usually also involves convulsions and coma.<ref name="FDA" /><ref name="Westfall" /> In 2013, overdose on amphetamine, methamphetamine, and other compounds implicated in an "amphetamine use disorder" resulted in an estimated 3,788 deaths worldwide (Template:Nowrap deaths, 95% confidence).<ref group="note">The 95% confidence interval indicates that there is a 95% probability that the true number of deaths lies between 3,425 and 4,145.</ref><ref name=GDB2013>Template:Cite journal</ref>

Overdose symptoms by system

System	Minor or moderate overdose<ref name="FDA" /><ref name="Westfall" /><ref name="International" />	Severe overdose<ref group="sources"><ref name="Acute amph toxicity">Template:Cite journal</ref><ref name="FDA" /><ref name="Westfall" /><ref name="Amphetamine toxidrome" /><ref name="Albertson_2011">Template:Cite book</ref></ref>
Cardiovascular	Abnormal heartbeat High or low blood pressure	Cardiogenic shock (heart not pumping enough blood) Cerebral hemorrhage (bleeding in the brain) Circulatory collapse (partial or complete failure of the circulatory system)
Central nervous system	Confusion Abnormally fast reflexes Severe agitation Tremor (involuntary muscle twitching)	Acute amphetamine psychosis (e.g., delusions and paranoia) Compulsive and repetitive movement Serotonin syndrome (excessive serotonergic nerve activity) Sympathomimetic toxidrome (excessive adrenergic nerve activity)
Musculoskeletal	Muscle pain	Rhabdomyolysis (rapid muscle breakdown)
Respiratory	Rapid breathing	Pulmonary edema (fluid accumulation in the lungs) Pulmonary hypertension (high blood pressure in the arteries of the lung) Respiratory alkalosis (reduced blood CO2)
Urinary	Painful urination Urinary retention (inability to urinate)	No urine production Kidney failure
Other	Elevated body temperature Mydriasis (dilated pupils)	Elevated or low blood potassium Hyperpyrexia (extremely elevated core body temperature) Metabolic acidosis (excessively acidic bodily fluids)

Toxicity

In rodents and primates, sufficiently high doses of amphetamine cause dopaminergic neurotoxicity, or damage to dopamine neurons, which is characterized by dopamine terminal degeneration and reduced transporter and receptor function.<ref name="Humans&Animals">Template:Cite journal</ref><ref name="Amph-induced hyperthermia and neurotoxicity review" /> There is no evidence that amphetamine is directly neurotoxic in humans.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name = "Malenka_2009_02">Template:Cite book</ref> However, large doses of amphetamine may indirectly cause dopaminergic neurotoxicity as a result of hyperpyrexia, the excessive formation of reactive oxygen species, and increased autoxidation of dopamine.<ref group="sources"><ref name="pmid22392347"/><ref name="Amph-induced hyperthermia and neurotoxicity review" /><ref name="Autoxidation1">Template:Cite journal</ref><ref name="Autoxidation2">Template:Cite journal</ref></ref> Animal models of neurotoxicity from high-dose amphetamine exposure indicate that the occurrence of hyperpyrexia (i.e., core body temperature ≥ 40 °C) is necessary for the development of amphetamine-induced neurotoxicity.<ref name="Amph-induced hyperthermia and neurotoxicity review">Template:Cite journal</ref> Prolonged elevations of brain temperature above 40 °C likely promote the development of amphetamine-induced neurotoxicity in laboratory animals by facilitating the production of reactive oxygen species, disrupting cellular protein function, and transiently increasing blood–brain barrier permeability.<ref name="Amph-induced hyperthermia and neurotoxicity review" />

Psychosis

Template:See also An amphetamine overdose can result in a stimulant psychosis that may involve a variety of symptoms, such as delusions and paranoia.<ref name="Cochrane" /><ref name="Amphetamine-induced psychosis"/> A Cochrane review on treatment for amphetamine, dextroamphetamine, and methamphetamine psychosis states that about Template:Nowrap of users fail to recover completely.<ref name="Cochrane"/><ref name="Hofmann">Template:Cite book</ref> According to the same review, there is at least one trial that shows antipsychotic medications effectively resolve the symptoms of acute amphetamine psychosis.<ref name="Cochrane"/> Psychosis rarely arises from therapeutic use.<ref name="FDA" /><ref name="Amphetamine-induced psychosis" /><ref name="Stimulant Misuse" />

Drug interactionsTemplate:Anchor

Template:See also Many types of substances are known to interact with amphetamine, resulting in altered drug action or metabolism of amphetamine, the interacting substance, or both.<ref name="FDA" /> Inhibitors of enzymes that metabolize amphetamine (e.g., CYP2D6 and FMO3) will prolong its elimination half-life, meaning that its effects will last longer.<ref name="FMO" /><ref name="FDA"/> Amphetamine also interacts with Template:Abbr, particularly monoamine oxidase A inhibitors, since both MAOIs and amphetamine increase plasma catecholamines (i.e., norepinephrine and dopamine);<ref name="FDA" /> therefore, concurrent use of both is dangerous.<ref name="FDA" /> Amphetamine modulates 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.<ref name="FDA" /> Amphetamine may also decrease the effects of antihypertensives and antipsychotics due to its effects on blood pressure and dopamine respectively.<ref name="FDA" /> Zinc supplementation may reduce the minimum effective dose of amphetamine when it is used for the treatment of ADHD.<ref name="zinc" group="note">The human dopamine transporter (hDAT) contains a high-affinity, extracellular, and allosteric Zn²⁺ (zinc ion) binding site which, upon zinc binding, inhibits dopamine reuptake, inhibits amphetamine-induced hDAT internalization, and amplifies amphetamine-induced dopamine efflux.<ref name="Allosteric Zn2+ regulation of hDAT 2019 Review">Template:Cite journal</ref><ref name="Zinc binding sites + ADHD review">Template:Cite journal</ref><ref name="Primary 2002 amph-zinc study">Template:Cite journal</ref><ref name="pmid16684900">Template:Cite journal</ref> The human serotonin transporter and norepinephrine transporter do not contain zinc binding sites.<ref name="Primary 2002 amph-zinc study" /></ref><ref name="Zinc and PEA">Template:Cite journal</ref> Norepinephrine reuptake inhibitors (NRIs) like atomoxetine prevent norepinephrine release induced by amphetamines and have been found to reduce the stimulant, euphoriant, and sympathomimetic effects of dextroamphetamine in humans.<ref name="TreuerGauMéndez2013">Template:Cite journal</ref><ref name="HealSmithFindling2012">Template:Cite book</ref><ref name="SofuogluPolingHill2009">Template:Cite journal</ref>

In general, there is no significant interaction when consuming amphetamine with food, but the pH of gastrointestinal content and urine affects the absorption and excretion of amphetamine, respectively.<ref name="FDA" /> Acidic substances reduce the absorption of amphetamine and increase urinary excretion, and alkaline substances do the opposite.<ref name="FDA" /> 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 (i.e., make it less acidic).<ref name="FDA" />

Pharmacology

Pharmacodynamics

Template:For Template:Amphetamine 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.<ref name="Miller" /><ref name="cognition enhancers" /> 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.<ref name="Miller" /><ref name="cognition enhancers" /><ref name="E Weihe" /> The reinforcing and motivational salience-promoting effects of amphetamine are due mostly to enhanced dopaminergic activity in the mesolimbic pathway.<ref name="Malenka_2009" /> 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.<ref name="Amph Uses" />

Amphetamine potentiates monoaminergic neurotransmission by entering the presynaptic neuron both as a substrate for monoamine transporters (DAT, NET, and, SERT) and by passive diffusion across the neuronal membrane.<ref name="Stahl2021">Template:Cite book</ref><ref name="handbook2022_DAT">Template:Cite book</ref> Transporter-mediated uptake competes with reabsorption of endogenous neurotransmitters from the synaptic cleft and produces competitive reuptake inhibition as a consequence.<ref name="Stahl2021" /> Once inside the neuronal cytosol, amphetamine initiates intracellular signaling cascades that activate protein kinase C (PKC), leading to phosphorylation of DAT, NET, and SERT.<ref name="handbook2022_DAT" /> PKC-dependent phosphorylation of monoamine transporters can either reverse their direction to induce efflux of cytosolic neurotransmitters into the synaptic cleft, or trigger the withdrawal of transporters into the presynaptic neuron (internalization), thereby ceasing their reuptake function in a non-competitive manner.<ref name="handbook2022_DAT" /><ref name="Kinase-dependent transporter regulation review">Template:Cite journal</ref> Amphetamine also causes a rise in intracellular calcium, an effect associated with transporter phosphorylation through a Ca²⁺/calmodulin-dependent protein kinase II alpha (CaMKIIα) signaling cascade.<ref name="handbook2022_DAT" /> Unlike PKC, CaMKIIα-mediated transporter phosphorylation appears to reverse the direction of DAT and NET without triggering internalization.<ref name="handbook2022_DAT" /><ref name="2020_Reith">Template:Cite journal</ref>

Amphetamine has been identified as a full agonist of trace amine-associated receptor 1 (TAAR1), a Template:Nowrap and Template:Nowrap G protein-coupled receptor (GPCR) discovered in 2001, which is important for regulation of brain monoamines.<ref name="Miller" /> 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.<ref group="sources" name="TAAR1 phosphorylation"><ref name="Miller" /><ref name="handbook2022_DAT" /><ref name="2022 T1 LDX">Template:Cite journal</ref><ref>Template:Cite journal</ref><ref name="TAAR1_cAMP2025">Template:Cite journal</ref></ref> Activation of Template:Abbr increases Template:Abbrlink production via adenylyl cyclase activation, which triggers protein kinase A (PKA)- and PKC-mediated transporter phosphorylation.<ref name="Miller" /><ref name="2022 T1 LDX" /><ref name="pmid114599292">Template:Cite journal</ref> Monoamine autoreceptors (e.g., D₂ short, presynaptic α₂, and presynaptic 5-HT_1A) have the opposite effect of TAAR1, and together these receptors provide a regulatory system for monoamines.<ref name="Miller" /><ref name="Miller+Grandy 2016" /><ref name="handbook2022_TAAR1">Template:Cite book</ref> Notably, amphetamine and trace amines possess high binding affinities for TAAR1, but not for monoamine autoreceptors.<ref name="Miller" /><ref name="Miller+Grandy 2016" /> Although TAAR1 is implicated in amphetamine-induced transporter phosphorylation, the magnitude of TAAR1-mediated monoamine release in humans remains unclear.<ref name="TAAR1 phosphorylation" group="sources" /><ref name="handbook2022_TAAR1" /> Findings from studies using TAAR1 gene knockout models suggest that, despite facilitating monoamine release through reverse transport, TAAR1 activation may paradoxically attenuate amphetamine’s psychostimulant effects in part by opening G protein-coupled inwardly rectifying potassium channels, an action that reduces neuronal firing.<ref name="Miller" /><ref name="handbook2022_TAAR1" />

Amphetamine is also a substrate for the vesicular monoamine transporters VMAT1 and VMAT2.<ref name="Amphetamine VMAT2 pH gradient">Template:Cite journal</ref><ref name="VMAT2ADHD">Template:Cite journal</ref> 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.<ref name="Amphetamine VMAT2 pH gradient" /><ref name="VMAT2ADHD" /> 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.<ref name="2020_Reith" /><ref name="VMAT2ADHD" /> 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.<ref name="Stahl2021" /><ref name="2020_Reith" /><ref name="VMAT2ADHD" />

In addition to membrane and vesicular monoamine transporters, amphetamine also inhibits SLC1A1, SLC22A3, and SLC22A5.<ref group="sources" name="Reuptake inhibition"><ref name="E Weihe" /><ref name="EAAT3">Template:Cite journal</ref><ref name="IUPHAR VMATs">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="SLC1A1">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="SLC22A3">Template:Cite journal</ref><ref name="SLC22A5">Template:Cite journal</ref><ref name="pmid13677912">Template:Cite journal</ref></ref> 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.<ref name="Reuptake inhibition" group="sources" /> Amphetamine is known to strongly induce cocaine- and amphetamine-regulated transcript (CART) gene expression,<ref name="Drugbank-amph" /><ref name="CART NAcc">Template:Cite journal</ref> a neuropeptide involved in feeding behavior, stress, and reward, which induces observable increases in neuronal development and survival in vitro.<ref name="Drugbank-amph" /><ref name="CART functions">Template:Cite journal</ref><ref name="CART">Template:Cite journal</ref> The CART receptor has yet to be identified, but there is significant evidence that CART binds to a unique Template:Nowrap Template:Abbr.<ref name="CART" /><ref name="pmid21855138">Template:Cite journal</ref> Amphetamine also inhibits monoamine oxidases at very high doses, resulting in less monoamine and trace amine metabolism and consequently higher concentrations of synaptic monoamines.<ref name="PubChem Header">Template:Cite encyclopedia</ref><ref name="BRENDA MAO Homo sapiens">Template:Cite encyclopedia</ref> In humans, the only post-synaptic receptor at which amphetamine is known to bind is the [[5-HT1A receptor|Template:Nowrap receptor]], where it acts as an agonist with low micromolar affinity.<ref name="5HT1A secondary">Template:Cite encyclopedia</ref><ref name="5HT1A Primary">Template:Cite journal</ref>

The full profile of amphetamine's short-term drug effects in humans is mostly derived through increased cellular communication or neurotransmission of dopamine,<ref name="Miller">Template:Cite journal</ref> serotonin,<ref name="Miller" /> norepinephrine,<ref name="Miller" /> epinephrine,<ref name="E Weihe">Template:Cite journal</ref> histamine,<ref name="E Weihe" /> CART peptides,<ref name="Drugbank-amph" /><ref name="CART NAcc" /> endogenous opioids,<ref name="Amphetamine-induced endogenous opioid release review">Template:Cite journal</ref><ref name="Opioids">Template:Cite journal</ref><ref name="Opioids cited primary source">Template:Cite journal</ref> adrenocorticotropic hormone,<ref name="Human amph effects" /><ref name="Primary: Human HPA axis" /> corticosteroids,<ref name="Human amph effects" /><ref name="Primary: Human HPA axis" /> and glutamate,<ref name="EAAT3" /><ref name="SLC1A1" /> which it affects through interactions with Template:Abbr, Template:Nowrap, Template:Abbr, Template:Abbr, Template:Abbr, Template:Abbr, and possibly other biological targets.<ref group="sources"><ref name="Miller" /><ref name="E Weihe" /><ref name="IUPHAR VMATs" /><ref name="SLC1A1" /><ref name="CART NAcc" /><ref name="5HT1A secondary" /></ref> Amphetamine also activates seven human carbonic anhydrase enzymes, several of which are expressed in the human brain.<ref name="Amphetamine-induced activation of 7 hCA isoforms" />

Dextroamphetamine displays higher binding affinity for DAT than levoamphetamine, whereas both enantiomers share comparable affinity at NET;<ref name="Stahl2021" /> Consequently, dextroamphetamine produces greater Template:Abbr stimulation than levoamphetamine, roughly three to four times more, but levoamphetamine has slightly stronger cardiovascular and peripheral effects.<ref name="Stahl2021" /><ref name="Westfall" /> Dextroamphetamine is also a more potent agonist of Template:Abbr than levoamphetamine.<ref name="TAAR1 stereoselective">Template:Cite journal</ref>

Dopamine

In certain brain regions, amphetamine increases the concentration of dopamine in the synaptic cleft by modulating Template:Abbr through several overlapping processes.<ref name="2020_Reith" /><ref name="handbook2022_DAT">Template:Cite book</ref><ref name="2022 T1 LDX" /> Amphetamine can enter the presynaptic neuron either through Template:Abbr or by diffusing across the neuronal membrane directly.<ref name="Miller" /><ref name="handbook2022_DAT" /> As a consequence of DAT uptake, amphetamine produces competitive reuptake inhibition at the transporter.<ref name="Miller" /><ref name="Amph Uses" /> 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.<ref name="Kinase-dependent transporter regulation review" /><ref name="2020_Reith" /> Subsequently, amphetamine initiates kinase-dependent signaling cascades that activate both protein kinase A (PKA) and protein kinase C (PKC).<ref name="handbook2022_DAT" /><ref name="2022 T1 LDX" /> Phosphorylation of DAT by either kinase induces transporter internalization (Template:Nowrap reuptake inhibition), but Template:Nowrap phosphorylation alone induces the reversal of dopamine transport through DAT (i.e., dopamine efflux).<ref name="handbook2022_DAT" /><ref name="Kinase-dependent transporter regulation review" />

Template:Abbr is a biomolecular target of amphetamine that can trigger the activation of PKA- and PKC-dependent pathways.<ref name="Miller" /><ref name="handbook2022_DAT" /><ref name="2022 T1 LDX" /> TAAR1 agonism also activates Ras homolog A (RhoA) and its downstream effector, Rho-associated coiled-coil kinase (ROCK), which results in transient internalization of DAT and EAAT3;<ref name="mesolimbic EAAT3" group="note">Mesolimbic dopamine neurons co-express the glutamate transporter EAAT3 alongside DAT, permitting amphetamine-induced EAAT3 internalization to influence glutamatergic signaling in the mesolimbic pathway.<ref name="EAAT3" /><ref name="handbook2022_DAT" /></ref><ref name="Amphetamine signaling through ROCKs" /><ref name="handbook2022_DAT" /> as intracellular Template:Abbrlink accumulates, PKA is activated and inhibits RhoA activity, thereby terminating ROCK-mediated transporter internalization.<ref name="Amphetamine signaling through ROCKs">Template:Cite journal</ref><ref name="handbook2022_DAT" /> Importantly, TAAR1 has been demonstrated to also produce inhibitory effects on dopamine release that may attenuate amphetamine's psychostimulant effects.<ref name="handbook2022_TAAR1" /> Through direct activation of G protein-coupled inwardly-rectifying potassium channels, Template:Abbr reduces the firing rate of dopamine neurons, preventing a hyper-dopaminergic state.<ref name="GIRK">Template:Cite journal</ref><ref name="Genatlas TAAR1">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

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.<ref name="handbook2022_DAT" /><ref name="Kinase-dependent transporter regulation review" /><ref name="DAT regulation review">Template:Cite journal</ref> Notably, because conventional PKC isoforms can be activated by calcium ions, the rise in intracellular calcium can also promote PKC activation and subsequent DAT phosphorylation independent of TAAR1.<ref name="2020_Reith" />

Effects of amphetamine on membrane transport proteins in dopamine neurons<ref name="DAT table" group="note">Amphetamine interacts with its receptor protein target(s), TAAR1 and an as-yet-unidentified biomolecular target, which initiates signaling cascades that generate second messengers and activate protein kinases. The activated kinases then phosphorylate their respective transporter(s), which in turn causes a conformational change in transporter protein, thereby altering its function and affecting dopaminergic/glutamatergic neurotransmission at dopaminergic synapses.<ref name="handbook2022_DAT" /><ref name="Kinase-dependent transporter regulation review" /></ref>

Biological target of amphetamine	Initial effector / G-protein	Second messenger(s)	Secondary effector protein kinase	Phosphorylated transporter	Effect on transporter function	Effect on neurotransmission	Sources
Unidentified	Unidentified intracellular effector	IP₃-mediated intracellular Ca²⁺ release	Template:Abbrlink	Template:Abbrlink	Reverse transport of dopamine	Dopamine efflux into synaptic cleft	<ref name="2020_Reith" /><ref name="Kinase-dependent transporter regulation review" />
Template:Abbrlink	G13	RhoA–GTP	ROCK†	DAT	Transporter internalization	Dopamine reuptake inhibition	<ref name="handbook2022_DAT" /><ref name="Amph RhoA+ROCK signaling to DAT - primary">Template:Cite journal</ref><ref name="Amphetamine signaling through ROCKs" />
Template:Abbrlink	G13	RhoA–GTP	ROCK†	Template:Abbrlink	Transporter internalization	Glutamate reuptake inhibition	<ref name="handbook2022_DAT" /><ref name="handbook2022_TAAR1" /><ref name="Amphetamine signaling through ROCKs" />
Template:Abbrlink	Gs	↑ Template:Abbrlink	Template:Abbrlink	DAT	Transporter internalization	Dopamine reuptake inhibition	<ref name="Miller" /><ref name="handbook2022_DAT" /><ref name="2022 T1 LDX" />
Template:Abbrlink	Gs	↑ Template:Abr	Template:Abbrlink	DAT	Reverse transport of dopamine Transporter internalization	Dopamine efflux into synaptic cleft Dopamine reuptake inhibition	<ref name="Miller" /><ref name="2022 T1 LDX" /><ref name="TAAR1_cAMP2025" />
Unidentified	Unidentified intracellular effector	IP₃/DAG pathway‡	Template:Abbrlink	DAT	Reverse transport of dopamine Transporter internalization	Dopamine efflux into synaptic cleft Dopamine reuptake inhibition	<ref name="2020_Reith" /><ref name="Kinase-dependent transporter regulation review" />
†ROCK-mediated transporter internalization is transient due to the inactivation of RhoA (which activates ROCK) by PKA. ‡IP₃ binds to its receptors on the endoplasmic reticulum to release intracellular Ca²⁺ stores, and together with diacylglycerol activates conventional PKC isoforms.							<ref name="handbook2022_DAT" /><ref name="Kinase-dependent transporter regulation review" /><ref name="Amphetamine signaling through ROCKs" />

Amphetamine is also a substrate for the presynaptic vesicular monoamine transporter, Template:Abbr.<ref name="Amphetamine VMAT2 pH gradient" /> 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.<ref name="Amphetamine VMAT2 pH gradient" /><ref name="VMAT2ADHD2">Template:Cite journal</ref> Subsequently, the cytosolic dopamine molecules are released from the presynaptic neuron into the synaptic cleft via reverse transport at Template:Abbr.<ref name="Amphetamine VMAT2 pH gradient" /><ref name="VMAT2ADHD2" />

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.<ref name="handbook2022_DAT" /><ref name="2020_Reith" /><ref name="2022 T1 LDX" /> In other words, amphetamine induces competitive Template:Abbr reuptake inhibition, non-competitive reuptake inhibition and efflux at phosphorylated NET via PKC activation, CAMKIIα-mediated NET efflux without internalization, and norepinephrine release from Template:Abbr.<ref name="handbook2022_DAT" /><ref name="2020_Reith" /><ref name="2022 T1 LDX" />

Serotonin

Amphetamine exerts analogous, yet less pronounced, effects on serotonin as on dopamine and norepinephrine.<ref name="Miller" /> Amphetamine affects serotonin via Template:Abbr and is thought to phosphorylate Template:Abbr via a PKC-dependent signaling cascade.<ref name="2022 T1 LDX" /> Like dopamine, amphetamine has low, micromolar affinity at the human 5-HT1A receptor.<ref name="5HT1A secondary2">Template:Cite encyclopedia</ref><ref name="5HT1A Primary" />

Other neurotransmitters, peptides, hormones, and enzymes

Human carbonic anhydrase
activation potency

Enzyme	KA (Template:Abbrlink)	Sources
hCA4	94	<ref name="Amphetamine-induced activation of 7 hCA isoforms" />
hCA5A	810	<ref name="Amphetamine-induced activation of 7 hCA isoforms">Template:Cite journal</ref><ref name="IUPHAR Amphetamine">{{#invoke:citation/CS1|citation	CitationClass=web }}</ref>
hCA5B	2560	<ref name="Amphetamine-induced activation of 7 hCA isoforms" />
hCA7	910	<ref name="Amphetamine-induced activation of 7 hCA isoforms" /><ref name="IUPHAR Amphetamine" />
hCA12	640	<ref name="Amphetamine-induced activation of 7 hCA isoforms" />
hCA13	24100	<ref name="Amphetamine-induced activation of 7 hCA isoforms" />
hCA14	9150	<ref name="Amphetamine-induced activation of 7 hCA isoforms" />

Acute amphetamine administration in humans increases endogenous opioid release in several brain structures in the reward system.<ref name="Amphetamine-induced endogenous opioid release review" /><ref name="Opioids" /><ref name="Opioids cited primary source" /> Extracellular levels of glutamate, the primary excitatory neurotransmitter in the brain, have been shown to increase in the striatum following exposure to amphetamine.<ref name="EAAT3" /> This increase in extracellular glutamate presumably occurs via the amphetamine-induced internalization of EAAT3, a glutamate reuptake transporter, in dopamine neurons.<ref name="EAAT3" /><ref name="SLC1A1" /> This internalization is mediated by RhoA activation and its downstream effector ROCK.<ref name="handbook2022_DAT" /><ref name="EAAT3 review">Template:Cite journal</ref> Amphetamine also induces the selective release of histamine from mast cells and efflux from histaminergic neurons through Template:Abbr.<ref name="E Weihe" /> Acute amphetamine administration can also increase adrenocorticotropic hormone and corticosteroid levels in blood plasma by stimulating the hypothalamic–pituitary–adrenal axis.<ref name="Evekeo" /><ref name="Human amph effects">Template:Cite book</ref><ref name="Primary: Human HPA axis">Template:Cite journal</ref>

In December 2017, the first study assessing the interaction between amphetamine and human carbonic anhydrase enzymes was published;<ref name="Amphetamine-induced activation of 7 hCA isoforms" /> 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.<ref name="Amphetamine-induced activation of 7 hCA isoforms" /> Based upon preclinical research, cerebral carbonic anhydrase activation has cognition-enhancing effects;<ref name="Carbonic anhydrase modulators 2019 Review" /> 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.<ref name="Carbonic anhydrase modulators 2019 Review">Template:Cite journal</ref>

Pharmacokinetics

The oral bioavailability of amphetamine varies with gastrointestinal pH;<ref name="FDA" /> it is well absorbed from the gut, and bioavailability is typically 90%.<ref name="handbook2022">Template:Cite book</ref> Amphetamine is a weak base with a pK_a of 9.9;<ref name="FDA Pharmacokinetics" /> 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.<ref name="FDA Pharmacokinetics" /><ref name="FDA" /> Conversely, an acidic pH means the drug is predominantly in a water-soluble cationic (salt) form, and less is absorbed.<ref name="FDA Pharmacokinetics" /> Approximately Template:Nowrap of amphetamine circulating in the bloodstream is bound to plasma proteins.<ref name="Drugbank-amph">Template:Cite DrugBank</ref> Following absorption, amphetamine readily distributes into most tissues in the body, with high concentrations occurring in cerebrospinal fluid and brain tissue.<ref name="HSDB Toxnet October 2017 Full archived record">Template:Cite encyclopedia</ref>

The half-lives of amphetamine enantiomers differ and vary with urine pH.<ref name="FDA Pharmacokinetics" /> At normal urine pH, the half-lives of dextroamphetamine and levoamphetamine are Template:Nowrap hours and Template:Nowrap hours, respectively.<ref name="FDA Pharmacokinetics" /> Highly acidic urine will reduce the enantiomer half-lives to 7 hours;<ref name="HSDB Toxnet October 2017 Full archived record" /> highly alkaline urine will increase the half-lives up to 34 hours.<ref name="HSDB Toxnet October 2017 Full archived record" /> 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.<ref name="FDA Pharmacokinetics" /> Amphetamine is eliminated via the kidneys, with Template:Nowrap of the drug being excreted unchanged at normal urinary pH.<ref name="FDA Pharmacokinetics" /> When the urinary pH is basic, amphetamine is in its free base form, so less is excreted.<ref name="FDA Pharmacokinetics" /> 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.<ref name="FDA Pharmacokinetics" /> Following oral administration, amphetamine appears in urine within 3 hours.<ref name="HSDB Toxnet October 2017 Full archived record" /> Roughly 90% of ingested amphetamine is eliminated 3 days after the last oral dose.<ref name="HSDB Toxnet October 2017 Full archived record" />Template:If pagename

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.<ref name="amphetamine metabolism" group = "sources" /> Amphetamine has a variety of excreted metabolic products, including Template:Nowrap, Template:Nowrap, Template:Nowrap, benzoic acid, hippuric acid, norephedrine, and phenylacetone.<ref name="FDA Pharmacokinetics" /><ref name="Metabolites" /> Among these metabolites, the active sympathomimetics are Template:Nowrap,<ref>Template:Cite encyclopedia</ref> Template:Nowrap,<ref>Template:Cite encyclopedia</ref> and norephedrine.<ref>Template:Cite encyclopedia</ref> The main metabolic pathways involve aromatic para-hydroxylation, aliphatic alpha- and beta-hydroxylation, N-oxidation, N-dealkylation, and deamination.<ref name="FDA Pharmacokinetics" /><ref name="Pubchem Kinetics">Template:Cite encyclopedia</ref> The known metabolic pathways, detectable metabolites, and metabolizing enzymes in humans include the following: Template:Amphetamine pharmacokinetics

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.<ref name="Pharmacomicrobiomics">Template:Cite journal</ref><ref name="Human microbiome">Template:Cite journal</ref> Since the total number of microbial and viral cells in the human body (over 100 trillion) greatly outnumbers human cells (tens of trillions),<ref group="note">There is substantial variation in microbiome composition and microbial concentrations by anatomical site.<ref name="Pharmacomicrobiomics" /><ref name="Human microbiome" /> Fluid from the human colon – which contains the highest concentration of microbes of any anatomical site – contains approximately one trillion (10^12) bacterial cells/ml.<ref name="Pharmacomicrobiomics" /></ref><ref name="Pharmacomicrobiomics" /><ref name="Gut feeling">Template:Cite journal</ref> 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.<ref name="Pharmacomicrobiomics" /><ref name="Human microbiome" /><ref name="Microbial amphetamine metabolism - E. coli" /> The field that studies these interactions is known as pharmacomicrobiomics.<ref name="Pharmacomicrobiomics" />

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.<ref name="Microbial amphetamine metabolism - E. coli" /> The first amphetamine-metabolizing microbial enzyme, tyramine oxidase from a strain of E. coli commonly found in the human gut, was identified in 2019.<ref name="Microbial amphetamine metabolism - E. coli" /> This enzyme was found to metabolize amphetamine, tyramine, and phenethylamine with roughly the same binding affinity for all three compounds.<ref name="Microbial amphetamine metabolism - E. coli">Template:Cite journal</ref>

Related endogenous compounds

Template:Further 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.<ref name="Miller" /><ref name="Trace Amines" /><ref name="Human trace amines and hTAARs October 2016 review">Template:Cite journal</ref> Among this group, the most closely related compounds are phenethylamine, the parent compound of amphetamine, and Template:Nowrap, a structural isomer of amphetamine (i.e., it has an identical molecular formula).<ref name="Miller" /><ref name="Trace Amines" /><ref name="Renaissance GPCR">Template:Cite journal</ref> In humans, phenethylamine is produced directly from Template:Nowrap by the aromatic amino acid decarboxylase (AADC) enzyme, which converts Template:Nowrap into dopamine as well.<ref name="Trace Amines" /><ref name="Renaissance GPCR" /> In turn, Template:Nowrap is metabolized from phenethylamine by phenylethanolamine N-methyltransferase, the same enzyme that metabolizes norepinephrine into epinephrine.<ref name="Trace Amines">Template:Cite journal</ref><ref name="Renaissance GPCR" /> Like amphetamine, both phenethylamine and Template:Nowrap regulate monoamine neurotransmission via Template:Abbr;<ref name="Miller" /><ref name="Human trace amines and hTAARs October 2016 review" /><ref name="Renaissance GPCR" /> unlike amphetamine, both of these substances are broken down by monoamine oxidase B, and therefore have a shorter half-life than amphetamine.<ref name="Trace Amines" /><ref name="Renaissance GPCR" />

Chemistry

Template:Annotated image 4

Template:Multiple image Amphetamine is a methyl homolog of the mammalian neurotransmitter phenethylamine with the chemical formula Template:Chem2. The carbon atom adjacent to the primary amine is a stereogenic center, and amphetamine is composed of a racemic 1:1 mixture of two enantiomers.<ref name="Drugbank-amph" /> This racemic mixture can be separated into its optical isomers:<ref group="note">Enantiomers are molecules that are mirror images of one another; they are structurally identical, but of the opposite orientation.<ref name="Enantiomers" /></ref> levoamphetamine and dextroamphetamine.<ref name="Drugbank-amph" /> 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.<ref name="Properties">Template:Cite encyclopedia</ref> Frequently prepared solid salts of amphetamine include amphetamine adipate,<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> aspartate,<ref name="FDA" /> hydrochloride,<ref>Template:Cite encyclopedia</ref> phosphate,<ref>Template:Cite encyclopedia</ref> saccharate,<ref name="FDA" /> sulfate,<ref name="FDA" /> and tannate.<ref>Template:Cite journal</ref> Dextroamphetamine sulfate is the most common enantiopure salt.<ref name="EMC" /> Amphetamine is also the parent compound of its own structural class, which includes a number of psychoactive derivatives.<ref name="Substituted amphetamines, FMO, and DBH" /><ref name="Drugbank-amph" /> In organic chemistry, amphetamine is an excellent chiral ligand for the stereoselective synthesis of Template:Nowrap.<ref name="Chiral Ligand">Template:Cite journal</ref>

Substituted derivatives

Template:Main list The substituted derivatives of amphetamine, or "substituted amphetamines", are a broad range of chemicals that contain amphetamine as a "backbone";<ref name="Substituted amphetamines, FMO, and DBH" /><ref name="Amphetamine - a substituted amphetamine">Template:Cite journal</ref><ref name="Schep">Template:Cite journal</ref> specifically, this chemical class includes derivative compounds that are formed by replacing one or more hydrogen atoms in the amphetamine core structure with substituents.<ref name="Substituted amphetamines, FMO, and DBH" /><ref name="Amphetamine - a substituted amphetamine" /><ref name="pmid1855720">Template:Cite journal</ref> The class includes amphetamine itself, stimulants like methamphetamine, serotonergic empathogens like MDMA, and decongestants like ephedrine, among other subgroups.<ref name="Substituted amphetamines, FMO, and DBH" /><ref name="Amphetamine - a substituted amphetamine" /><ref name="Schep" />

Synthesis

Template:Further Since the first preparation was reported in 1887,<ref name="Vermont"/> numerous synthetic routes to amphetamine have been developed.<ref name="Allen_Ely_2009">Template:Cite journal</ref><ref name="Allen_Cantrell_1989">Template:Cite journal</ref> The most common route of both legal and illicit amphetamine synthesis employs a non-metal reduction known as the Leuckart reaction (method 1).<ref name="EMC"/><ref name="Amph Synth" /> In the first step, a reaction between phenylacetone and formamide, either using additional formic acid or formamide itself as a reducing agent, yields Template:Nowrap. This intermediate is then hydrolyzed using hydrochloric acid, and subsequently basified, extracted with organic solvent, concentrated, and distilled to yield the free base. The free base is then dissolved in an organic solvent, sulfuric acid added, and amphetamine precipitates out as the sulfate salt.<ref name="Amph Synth" /><ref>Template:Cite journal</ref>

A number of chiral resolutions have been developed to separate the two enantiomers of amphetamine.<ref name = "Allen_Ely_2009"/> For example, racemic amphetamine can be treated with Template:Nowrap to form a diastereoisomeric salt which is fractionally crystallized to yield dextroamphetamine.<ref name = "US2276508">Template:Cite patent</ref> Chiral resolution remains the most economical method for obtaining optically pure amphetamine on a large scale.<ref name = "Gray_2007"/> In addition, several enantioselective syntheses of amphetamine have been developed. In one example, optically pure Template:Nowrap is condensed with phenylacetone to yield a chiral Schiff base. In the key step, this intermediate is reduced by catalytic hydrogenation with a transfer of chirality to the carbon atom alpha to the amino group. Cleavage of the benzylic amine bond by hydrogenation yields optically pure dextroamphetamine.<ref name = "Gray_2007">Template:Cite book</ref>

A large number of alternative synthetic routes to amphetamine have been developed based on classic organic reactions.<ref name="Allen_Ely_2009"/><ref name="Allen_Cantrell_1989"/> One example is the Friedel–Crafts alkylation of benzene by allyl chloride to yield beta chloropropylbenzene which is then reacted with ammonia to produce racemic amphetamine (method 2).<ref name="pmid20985610">Template:Cite journal</ref> Another example employs the Ritter reaction (method 3). In this route, allylbenzene is reacted acetonitrile in sulfuric acid to yield an organosulfate which in turn is treated with sodium hydroxide to give amphetamine via an acetamide intermediate.<ref name="pmid18105933">Template:Cite journal</ref><ref name=Krimen_Cota_1969>Template:Cite book</ref> A third route starts with Template:Nowrap which through a double alkylation with methyl iodide followed by benzyl chloride can be converted into Template:Nowrap acid. This synthetic intermediate can be transformed into amphetamine using either a Hofmann or Curtius rearrangement (method 4).<ref name = "US2413493">Template:Cite patent</ref>

A significant number of amphetamine syntheses feature a reduction of a nitro, imine, oxime, or other nitrogen-containing functional groups.<ref name = "Allen_Cantrell_1989"/> In one such example, a Knoevenagel condensation of benzaldehyde with nitroethane yields Template:Nowrap. The double bond and nitro group of this intermediate is reduced using either catalytic hydrogenation or by treatment with lithium aluminium hydride (method 5).<ref name="Amph Synth">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="Delta Isotope">Template:Cite journal</ref> Another method is the reaction of phenylacetone with ammonia, producing an imine intermediate that is reduced to the primary amine using hydrogen over a palladium catalyst or lithium aluminum hydride (method 6).<ref name="Amph Synth" />

Amphetamine synthetic routes

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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.<ref group="sources"><ref name="Ergogenics" /><ref name="pmid9700558">Template:Cite journal</ref><ref name="pmid17468860">Template:Cite journal</ref><ref name="pmid8075776">Template:Cite journal</ref></ref> Techniques such as immunoassay, which is the most common form of amphetamine test, may cross-react with a number of sympathomimetic drugs.<ref name="NAHMSA_testing" /> Chromatographic methods specific for amphetamine are employed to prevent false positive results.<ref name="pmid15516295" /> 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,<ref name="OTC levmetamfetamine" group="note">The active ingredient in some OTC inhalers in the United States is listed as levmetamfetamine, the INN and USAN of levomethamphetamine.<ref name="FDA levmetamfetamine">Template:Cite encyclopedia</ref><ref>Template:Cite encyclopedia</ref></ref> or illicitly obtained substituted amphetamines.<ref name="pmid15516295">Template:Cite journal</ref><ref name="pmid16105261">Template:Cite journal</ref><ref name="Baselt_2011">Template:Cite book</ref> Several prescription drugs produce amphetamine as a metabolite, including benzphetamine, clobenzorex, famprofazone, fenproporex, lisdexamfetamine, mesocarb, methamphetamine, prenylamine, and selegiline, among others.<ref name="Amph Uses" /><ref name="pmid10711406">Template:Cite journal</ref><ref name="pmid12024689">Template:Cite journal</ref> These compounds may produce positive results for amphetamine on drug tests.<ref name="pmid10711406" /><ref name="pmid12024689" /> Amphetamine is generally only detectable by a standard drug test for approximately 24 hours, although a high dose may be detectable for Template:Nowrap days.<ref name="NAHMSA_testing">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

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.<ref name="pmid16105261" /> Gas chromatography–mass spectrometry (GC–MS) of amphetamine and methamphetamine with the derivatizing agent Template:Nowrap chloride allows for the detection of methamphetamine in urine.<ref name="pmid15516295" /> 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.<ref name="pmid15516295" /> 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.<ref name="pmid15516295" />

History, society, and culture

{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}} Template:Global estimates of illegal drug users

Amphetamine was first synthesized in 1887 in Germany by Romanian chemist Lazăr Edeleanu who named it phenylisopropylamine;<ref name="Vermont">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>Template:Cite book</ref><ref name="SynthHistory" /> its stimulant effects remained unknown until 1927, when it was independently resynthesized by Gordon Alles and reported to have sympathomimetic properties.<ref name="SynthHistory">Template:Cite journal</ref> Amphetamine had no medical use until late 1933, when Smith, Kline and French began selling it as an inhaler under the brand name Benzedrine as a decongestant.<ref name="Benzedrine">Template:Cite journal</ref> Benzedrine sulfate was introduced 3 years later and was used to treat a wide variety of medical conditions, including narcolepsy, obesity, low blood pressure, low libido, and chronic pain, among others.<ref name="Benzedrine sulfate">Template:Cite journal</ref><ref name="Benzedrine" /> During World War II, amphetamine and methamphetamine were used extensively by both the Allied and Axis forces for their stimulant and performance-enhancing effects.<ref name="Vermont" /><ref>Template:Cite journal</ref><ref name="pmid22849208">Template:Cite journal</ref> As the addictive properties of the drug became known, governments began to place strict controls on the sale of amphetamine.<ref name="Vermont" /> For example, during the early 1970s in the United States, amphetamine became a schedule II controlled substance under the Controlled Substances Act.<ref name=":USAS2" /> In spite of strict government controls, amphetamine has been used legally or illicitly by people from a variety of backgrounds, including authors,<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> musicians,<ref>Template:Cite journal</ref> mathematicians,<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> and athletes.<ref name="Ergogenics" />

Amphetamine is illegally synthesized in clandestine labs and sold on the black market, primarily in European countries.<ref name="WDR2014">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Among European Union (EU) member states Template:As of 11.9 million adults of ages Template:Nowrap have used amphetamine or methamphetamine at least once in their lives and 1.7 million have used either in the last year.<ref name="Bulletin2018">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> During 2012, approximately 5.9 metric tons of illicit amphetamine were seized within EU member states;<ref name="EMCDDA 2014">Template:Cite report</ref> the "street price" of illicit amphetamine within the EU ranged from Template:Nowrap per gram during the same period.<ref name="EMCDDA 2014" /> Outside Europe, the illicit market for amphetamine is much smaller than the market for methamphetamine and MDMA.<ref name="WDR2014" />

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.<ref name="UN Convention">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Consequently, it is heavily regulated in most countries.<ref name="UNODC2007">Template:Cite book</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Some countries, such as South Korea and Japan, have banned substituted amphetamines even for medical use.<ref name="urlMoving to Korea brings medical, social changes">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> In other nations, such as Brazil (class A3),<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Canada (schedule I drug),<ref name="Canada Control">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> the Netherlands (List I drug),<ref name="Opiumwet">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> the United States (schedule II drug),<ref name=":USAS2" /> Australia (schedule 8),<ref>Template:Cite encyclopedia</ref> Thailand (category 1 narcotic),<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> and United Kingdom (class B drug),<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> amphetamine is in a restrictive national drug schedule that allows for its use as a medical treatment.<ref name="WDR2014" /><ref name="Nonmedical">Template:Cite journal</ref>

Pharmaceutical products

Several currently marketed amphetamine formulations contain both enantiomers, including those marketed under the brand names Adderall, Adderall XR, Mydayis,<ref group=note name=AdderallDiff /> Adzenys ER, Template:Nowrap, Dyanavel XR, Evekeo, and Evekeo ODT. Of those, Evekeo (including Evekeo ODT) is the only product containing only racemic amphetamine (as amphetamine sulfate), and is therefore the only one whose active moiety can be accurately referred to simply as "amphetamine".<ref name="Stahl's Essential Psychopharmacology" /><ref name="Evekeo" /><ref name="Dyanavel" /> Dextroamphetamine, marketed under the brand names Dexedrine and Zenzedi, is the only enantiopure amphetamine product currently available. A prodrug form of dextroamphetamine, lisdexamfetamine, is also available and is marketed under the brand name Vyvanse. As it is a prodrug, lisdexamfetamine is structurally different from dextroamphetamine, and is inactive until it metabolizes into dextroamphetamine.<ref name="NDCD" /><ref name=USVyvanselabel/> The free base of racemic amphetamine was previously available as Benzedrine, Psychedrine, and Sympatedrine.<ref name="Amph Uses" /> Levoamphetamine was previously available as Cydril.<ref name="Amph Uses" /> Many current amphetamine pharmaceuticals are salts due to the comparatively high volatility of the free base.<ref name="Amph Uses" /><ref name="NDCD" /><ref name="EMC" /> However, oral suspension and orally disintegrating tablet (ODT) dosage forms composed of the free base were introduced in 2015 and 2016, respectively.<ref name="Dyanavel" /><ref name="FDA Dyanavel approval date" /><ref name="Adzenys" /> Some of the current brands and their generic equivalents are listed below.

Amphetamine pharmaceuticals

Brand name	United States Adopted Name	(D:L) ratio	Dosage form	Marketing start date	Sources
Adderall	–	3:1 (salts)	tablet	1996	<ref name="Amph Uses" /><ref name="NDCD" />
Adderall XR	–	3:1 (salts)	capsule	2001	<ref name="Amph Uses" /><ref name="NDCD" />
Mydayis	–	3:1 (salts)	capsule	2017	citation	CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation	CitationClass=web }}</ref>
Adzenys ER	amphetamine	3:1 (base)	suspension	2017	citation	CitationClass=web }}</ref>
Template:Nowrap	amphetamine	3:1 (base)	ODT	2016	citation	CitationClass=web }}</ref><ref name="FDA Adzenys approval date">{{#invoke:citation/CS1|citation	CitationClass=web }}</ref>
Dyanavel XR	amphetamine	3.2:1 (base)	suspension	2015	citation	CitationClass=web }}</ref>
Evekeo	amphetamine sulfate	1:1 (salts)	tablet	2012	citation	CitationClass=web }}</ref>
Evekeo ODT	amphetamine sulfate	1:1 (salts)	ODT	2019	citation	CitationClass=web }}</ref>
Dexedrine	dextroamphetamine sulfate	1:0 (salts)	capsule	1976	<ref name="Amph Uses" /><ref name="NDCD" />
Zenzedi	dextroamphetamine sulfate	1:0 (salts)	tablet	2013	citation	CitationClass=web }}</ref>
Vyvanse	lisdexamfetamine dimesylate	1:0 (prodrug)	capsule	2007	<ref name="Amph Uses">Template:Cite journal</ref><ref name=USVyvanselabel/><ref>{{#invoke:citation/CS1|citation	CitationClass=web }}</ref>
			tablet
Xelstrym	dextroamphetamine	1:0 (base)	patch	2022	citation	CitationClass=web }}</ref>

Notes

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External links

• {{#invoke:citation/CS1|citation

|CitationClass=web }}

• Template:PubChem – Dextroamphetamine
• Template:PubChem – Levoamphetamine
• Comparative Toxicogenomics Database entry: Amphetamine
• Comparative Toxicogenomics Database entry: CARTPT

Template:Amphetamine Template:ADHD pharmacotherapies Template:TAAR ligands Template:Monoamine releasing agents {{#invoke:Navbox|navbox}} Template:Drug use Template:Chemical classes of psychoactive drugs Template:Portal bar Template:Authority control