Dextroamphetamine

For the racemic compound, see amphetamine.
Dexamfetamine (INN)
Systematic (IUPAC) name
(2S)-1-phenylpropan-2-amine
Clinical data
Trade names Dexedrine, Metamina, Zenzedi
AHFS/Drugs.com monograph
MedlinePlus a605027
Licence data US Daily Med:link
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
Legal status
Dependence
liability		 Physical: None
Psychological: Moderate
Addiction
liability		 Moderate
Routes of
administration		 oral
Pharmacokinetic data
Bioavailability Oral 75–100%[1]
Metabolism CYP2D6,[2] DBH,[3] FMO3,[4] XM-ligase,[5] and ACGNAT[6]
Onset of action IR dosing: 0.5-1.5 hours[7][8]
XR dosing: 1.5–2 hours[9][10]
Biological half-life 9–11 hours[2][11]
pH-dependent: 8–31 hours[12]
Duration of action IR dosing: 3–7 hours[9][13]
XR dosing: 12 hours[9][10][13]
Excretion Renal (45%);[14] urinary pH-dependent
Identifiers
CAS Number 51-64-9 YesY
ATC code N06BA02
PubChem CID 5826
IUPHAR/BPS 2147
DrugBank DB01576 YesY
ChemSpider 5621 YesY
UNII TZ47U051FI YesY
KEGG D03740 YesY
ChEBI CHEBI:4469 YesY
ChEMBL CHEMBL612 YesY
Chemical data
Formula C9H13N
Molar mass 135.20622
Physical data
Density 0.913 g/cm3
Boiling point 201.5 °C (394.7 °F)
Solubility in water 20 mg/mL (20 °C)
  (verify)

Dextroamphetamine[note 1] is a potent central nervous system (CNS) stimulant and amphetamine enantiomer that is prescribed for the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy.[15][16] It is also used as an athletic performance and cognitive enhancer, and recreationally as an aphrodisiac and euphoriant. Dextroamphetamine is also widely used by military air forces as a 'go-pill' during fatigue-inducing mission profiles such as night-time bombing missions. Preparations containing dextroamphetamine were also used in World War II as a treatment against fatigue.

The amphetamine molecule exists as two enantiomers (i.e., two different molecules that are mirror images of one another), levoamphetamine and dextroamphetamine. Dextroamphetamine is the more active dextrorotatory, or "right-handed", enantiomer of the amphetamine molecule. Pharmaceutical dextroamphetamine sulfate is available as both a brand name and generic drug in a variety of dosage forms. Dextroamphetamine is sometimes prescribed as the inactive prodrug lisdexamfetamine dimesylate, which is converted into dextroamphetamine after absorption.

Dextroamphetamine, like other amphetamines, elicits its stimulating effects via three distinct actions: first, it inhibits or reverses the transporter proteins for the monoamine neurotransmitters (namely the serotonin, norepinephrine and dopamine transporters) via trace amine-associated receptor 1 (TAAR1); second, it releases these neurotransmitters from synaptic vesicles via vesicular monoamine transporter 2; and third, it reduces the enzymatic breakdown of cytosolic dopamine, norepinephrine, serotonin and related trace amines via inhibition of monoamine oxidase, particularly at high concentrations of amphetamine and monoamine transmitters.[17][18][19] It also shares many chemical and pharmacological properties with human trace amines, particularly phenethylamine and N-methylphenethylamine, the latter being an isomer of amphetamine produced within the human body.

Uses

Part of this section is transcluded from Amphetamine. (edit | history)

Medical

Dexedrine Spansule 5, 10 and 15 mg capsules

Dextroamphetamine is used to treat attention deficit hyperactivity disorder (ADHD) and narcolepsy (a sleep disorder), and is sometimes prescribed off-label for its past medical indications, such as depression and obesity.[15][16] Long-term amphetamine exposure in some animal species is known to produce abnormal dopamine system development or nerve damage,[20][21] but, in humans with ADHD, pharmaceutical amphetamines appear to improve brain development and nerve growth.[22][23][24] 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.[22][23][24]

Reviews of clinical stimulant research have established the safety and effectiveness of long-term amphetamine use for ADHD.[25][26][27] Controlled trials spanning two years have demonstrated treatment effectiveness and safety.[25][27] One review highlighted a nine-month randomized controlled trial in children with ADHD that found an average increase of 4.5 IQ points, continued increases in attention, and continued decreases in disruptive behaviors and hyperactivity.[25]

Current models of ADHD suggest that it is associated with functional impairments in some of the brain's neurotransmitter systems;[28] these functional impairments involve impaired dopamine neurotransmission in the mesocorticolimbic projection and norepinephrine neurotransmission in the locus coeruleus and prefrontal cortex.[28] Psychostimulants like methylphenidate and amphetamine are effective in treating ADHD because they increase neurotransmitter activity in these systems.[29][28][30] Approximately 80% of those who use these stimulants see improvements in ADHD symptoms.[31] 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.[32][33] The Cochrane Collaboration's review[note 2] on the treatment of adult ADHD with pharmaceutical amphetamines stated that while these drugs improve short-term symptoms, they have higher discontinuation rates than non-stimulant medications due to their adverse side effects.[35] A Cochrane Collaboration review on the treatment of ADHD in children with tic disorders such as Tourette syndrome indicated that stimulants in general do not make tics worse, but high doses of dextroamphetamine could exacerbate tics in some individuals.[36]

Performance-enhancing

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, unambiguous improvements in cognition, including working memory, episodic memory, and inhibitory control, in normal healthy adults;[37][38] the cognition-enhancing effects of amphetamine are known to occur through its indirect activation of both dopamine receptor D1 and adrenoceptor A2 in the prefrontal cortex.[37] Therapeutic doses of amphetamine also enhance cortical network efficiency, an effect which mediates improvements in working memory in all individuals.[29][39] Amphetamine and other ADHD stimulants also improve task saliency (motivation to perform a task) and increase arousal (wakefulness), in turn promoting goal-directed behavior.[29][40][41] 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.[29][41][42] Based upon studies of self-reported illicit stimulant use, 5–35% of college students use diverted ADHD stimulants, which are primarily used for performance enhancement rather than as recreational drugs.[43][44][45] However, high amphetamine doses that are above the therapeutic range can interfere with working memory and other aspects of cognitive control.[29][41]

Amphetamine is used by some athletes for its psychological and performance-enhancing effects, such as increased stamina and alertness;[46][47] however, non-medical amphetamine use is prohibited at sporting events that are regulated by collegiate, national, and international anti-doping agencies.[48][49] In healthy people at oral therapeutic doses, amphetamine has been shown to increase physical strength, acceleration, stamina, and endurance, while reducing reaction time.[46][50][51] Amphetamine improves stamina, endurance, and reaction time primarily through reuptake inhibition and effluxion of dopamine in the central nervous system.[50][51][52] At therapeutic doses, the adverse effects of amphetamine do not impede athletic performance;[46][50][51] however, at much higher doses, amphetamine can induce effects that severely impair performance, such as rapid muscle breakdown and elevated body temperature.[53][54][50]

Recreational

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.[55][56] Often taken in higher doses than those prescribed by doctors, Dextroamphetamine is considered to have a high potential for misuse in a recreational manner,[57][58] with users reporting feelings of elevated mood, increased alertness and energy after taking the drug. Adverse effects of recreational use include, but are not limited to, blurred vision, increase in body temperature, increased heart rate (tachycardia), impaired speech, and, usually only in very high doses, feelings of paranoia and psychotic episodes.[59][60] Dexedrine capsules can be opened and the contents crushed and snorted, or dissolved in water and injected.[61] Injection into the bloodstream can be dangerous because insoluble fillers within the tablets can block small blood vessels.[61] Abusing amphetamines over time can induce severe drug dependence.

Contraindications

This section is transcluded from Amphetamine. (edit | history)

According to the International Programme on Chemical Safety (IPCS) and United States Food and Drug Administration (USFDA),[note 3] amphetamine is contraindicated in people with a history of drug abuse,[note 4] the USFDA advises monitoring the height and weight of children and adolescents prescribed an amphetamine pharmaceutical.[63]

Side effects

This section is transcluded from Amphetamine. (edit | history)

Physical

At normal therapeutic doses, the physical side effects of amphetamine vary widely by age and from person to person.[54] Cardiovascular side effects can include hypertension or hypotension from a vasovagal response, Raynaud's phenomenon (reduced blood flow to extremities), and tachycardia (increased heart rate).[54][47][68] Sexual side effects in males may include erectile dysfunction, frequent erections, or prolonged erections.[54] Abdominal side effects may include abdominal pain, loss of appetite, nausea, and weight loss.[54][69] Other potential side effects include acne, blurred vision, dry mouth, excessive grinding of the teeth, nosebleed, profuse sweating, rhinitis medicamentosa (drug-induced nasal congestion), reduced seizure threshold, and tics (a type of movement disorder).[sources 1] Dangerous physical side effects are rare at typical pharmaceutical doses.[47]

Amphetamine stimulates the medullary respiratory centers, producing faster and deeper breaths.[47] In a normal person at therapeutic doses, this effect is usually not noticeable, but when respiration is already compromised, it may be evident.[47] Amphetamine also induces contraction in the urinary bladder sphincter, the muscle which controls urination, which can result in difficulty urinating. This effect can be useful in treating bed wetting and loss of bladder control.[47] The effects of amphetamine on the gastrointestinal tract are unpredictable.[47] If intestinal activity is high, amphetamine may reduce gastrointestinal motility (the rate at which content moves through the digestive system);[47] however, amphetamine may increase motility when the smooth muscle of the tract is relaxed.[47] Amphetamine also has a slight analgesic effect and can enhance the pain relieving effects of opioids.[47]

USFDA-commissioned studies from 2011 indicate that in children, young adults, and adults there is no association between serious adverse cardiovascular events (sudden death, heart attack, and stroke) and the medical use of amphetamine or other ADHD stimulants.[sources 2]

Psychological

Common psychological effects of therapeutic doses can include increased alertness, apprehension, concentration, decreased sense of fatigue, mood swings (elated mood followed by mildly depressed mood), increased initiative, insomnia or wakefulness, self-confidence, and sociability.[54][47] Less common side effects include anxiety, change in libido, grandiosity, irritability, repetitive or obsessive behaviors, and restlessness;[sources 3] these effects depend on the user's personality and current mental state.[47] Amphetamine psychosis (e.g., delusions and paranoia) can occur in heavy users.[53][54][77] Although very rare, this psychosis can also occur at therapeutic doses during long-term therapy.[53][54][78] According to the USFDA, "there is no systematic evidence" that stimulants produce aggressive behavior or hostility.[54]

Amphetamine has also been shown to produce a conditioned place preference in humans taking therapeutic doses,[35][79] meaning that individuals acquire a preference for spending time in places where they have previously used amphetamine.[79][80]

Overdose

This section is transcluded from Amphetamine. (edit | history)

An amphetamine overdose can lead to many different symptoms, but is rarely fatal with appropriate care.[64][81] The severity of overdose symptoms increases with dosage and decreases with drug tolerance to amphetamine.[47][64] 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.[64] Symptoms of a moderate and extremely large overdose are listed below; fatal amphetamine poisoning usually also involves convulsions and coma.[53][47] In 2013, overdose on amphetamine, methamphetamine, and other compounds implicated in an "amphetamine use disorder" resulted in an estimated 3,788 deaths worldwide (3,425–4,145 deaths, 95% confidence).[note 5][82]

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.[83][84] Individuals who frequently overdose on amphetamine during recreational use have a high risk of developing an amphetamine addiction, since repeated overdoses gradually increase the level of accumbal ΔFosB, a "molecular switch" and "master control protein" for addiction.[85][86][87] 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.[85][88] 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.[89] Sustained aerobic exercise on a regular basis also appears to be an effective treatment for amphetamine addiction;[88][89][90] exercise therapy improves clinical treatment outcomes and may be used as a combination therapy with cognitive behavioral therapy, which is currently the best clinical treatment available.[89][90][91]

Overdose symptoms by system
System Minor or moderate overdose[53][47][64] Severe overdose[sources 4]
Cardiovascular
Central nervous
system
Musculoskeletal
Respiratory
  • Rapid breathing
Urinary
Other

Addiction

Addiction and dependence glossary[80][86][94]
• addiction – a state characterized by compulsive engagement in rewarding stimuli despite adverse consequences
• addictive behavior – a behavior that is both rewarding and reinforcing
• addictive drug – a drug that is both rewarding and reinforcing
• dependence – an adaptive state associated with a withdrawal syndrome upon cessation of repeated exposure to a stimulus (e.g., drug intake)
• drug sensitization or reverse tolerance – the escalating effect of a drug resulting from repeated administration at a given dose
• drug withdrawal – symptoms that occur upon cessation of repeated drug use
• physical dependence – dependence that involves persistent physical–somatic withdrawal symptoms (e.g., fatigue and delirium tremens)
• psychological dependence – dependence that involves emotional–motivational withdrawal symptoms (e.g., dysphoria and anhedonia)
• reinforcing stimuli – stimuli that increase the probability of repeating behaviors paired with them
• rewarding stimuli – stimuli that the brain interprets as intrinsically positive or as something to be approached
• sensitization – an amplified response to a stimulus resulting from repeated exposure to it
• tolerance – the diminishing effect of a drug resulting from repeated administration at a given dose

Addiction is a serious risk with heavy recreational amphetamine use but is unlikely to arise from typical medical use at therapeutic doses.[47][95][96] Drug tolerance develops rapidly in amphetamine abuse (i.e., a recreational amphetamine overdose), so periods of extended use require increasingly larger doses of the drug in order to achieve the same effect.[97][98]

Biomolecular mechanisms

Current models of addiction from chronic drug use involve alterations in gene expression in certain parts of the brain, particularly the nucleus accumbens.[99][100][101] The most important transcription factors[note 6] that produce these alterations are ΔFosB, cAMP response element binding protein (CREB), and nuclear factor kappa B (NF-κB).[100] ΔFosB plays a crucial role in the development of drug addictions, since its overexpression in D1-type medium spiny neurons in the nucleus accumbens is necessary and sufficient[note 7] for most of the behavioral and neural adaptations that arise from addiction.[85][86][100] Once ΔFosB is sufficiently overexpressed, it induces an addictive state that becomes increasingly more severe with further increases in ΔFosB expression.[85][86] It has been implicated in addictions to alcohol, cannabinoids, cocaine, methylphenidate, nicotine, opioids, phencyclidine, propofol, and substituted amphetamines, among others.[sources 5]

ΔJunD, a transcription factor, and G9a, a histone methyltransferase enzyme, both directly oppose the induction of ΔFosB in the nucleus accumbens (i.e., they oppose increases in its expression).[86][100][105] 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).[100] ΔFosB also plays an important role in regulating behavioral responses to natural rewards, such as palatable food, sex, and exercise.[88][100][106] Since both natural rewards and addictive drugs induce expression of ΔFosB (i.e., they cause the brain to produce more of it), chronic acquisition of these rewards can result in a similar pathological state of addiction.[88][100] Consequently, ΔFosB is the most significant factor involved in both amphetamine addiction and amphetamine-induced sex addictions, which are compulsive sexual behaviors that result from excessive sexual activity and amphetamine use.[88][107][108] These sex addictions are associated with a dopamine dysregulation syndrome which occurs in some patients taking dopaminergic drugs.[88][106]

The effects of amphetamine on gene regulation are both dose- and route-dependent.[101] Most of the research on gene regulation and addiction is based upon animal studies with intravenous amphetamine administration at very high doses.[101] 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.[101] This suggests that medical use of amphetamine does not significantly affect gene regulation.[101]

Pharmacological treatments

As of May 2014, there is no effective pharmacotherapy for amphetamine addiction.[109][110][111] Reviews from 2015 and 2016 indicated that TAAR1-selective agonists have significant therapeutic potential as a treatment for psychostimulant addictions;[112][113] however, as of February 2016, the only compounds which are known to function as TAAR1-selective agonists are experimental drugs.[112][113] Amphetamine addiction is largely mediated through increased activation of dopamine receptors and co-localized NMDA receptors[note 8] in the nucleus accumbens;[84] magnesium ions inhibit NMDA receptors by blocking the receptor calcium channel.[84][114] One review suggested that, based upon animal testing, pathological (addiction-inducing) amphetamine use significantly reduces the level of intracellular magnesium throughout the brain.[84] Supplemental magnesium[note 9]

Pharmacology

Pharmacodynamics

The main section for this topic is on the page Amphetamine, in the section Pharmacodynamics.
Pharmacodynamics of amphetamine in a dopamine neuron
A pharmacodynamic model of amphetamine and TAAR1

via AADC

The image above contains clickable links
Amphetamine enters the presynaptic neuron across the neuronal membrane or through DAT. Once inside, it binds to TAAR1 or enters synaptic vesicles through VMAT2. When amphetamine enters the synaptic vesicles through VMAT2, dopamine is released into the cytosol (yellow-orange area). When amphetamine binds to TAAR1, it reduces postsynaptic dopamine neuron firing rate via potassium channels and triggers protein kinase A (PKA) and protein kinase C (PKC) signaling, resulting in DAT phosphorylation. PKA-phosphorylation causes DAT to withdraw into the presynaptic neuron (internalize) and cease transport. PKC-phosphorylated DAT may either operate in reverse or, like PKA-phosphorylated DAT, internalize and cease transport. Amphetamine is also known to increase intracellular calcium, an effect which is associated with DAT phosphorylation through a CAMKIIα-dependent pathway, in turn producing dopamine efflux.

Amphetamine and its enantiomers have been identified as potent full agonists of trace amine-associated receptor 1 (TAAR1), a GPCR, discovered in 2001, that is important for regulation of monoaminergic systems in the brain.[124][125] Activation of TAAR1 increases cAMP production via adenylyl cyclase activation and inhibits the function of the dopamine transporter, norepinephrine transporter, and serotonin transporter, as well as inducing the release of these monoamine neurotransmitters (effluxion).[124][126][127] Amphetamine enantiomers are also substrates for a specific neuronal synaptic vesicle uptake transporter called VMAT2.[128] When amphetamine is taken up by VMAT2, the vesicle releases (effluxes) dopamine, norepinephrine, and serotonin, among other monoamines, into the cytosol in exchange.[128]

Dextroamphetamine (the dextrorotary enantiomer) and levoamphetamine (the levorotary enantiomer) have identical pharmacodynamics, but their binding affinities to their biomolecular targets vary.[125][129] Dextroamphetamine is a more potent agonist of TAAR1 than levoamphetamine.[125] Consequently, dextroamphetamine produces roughly three to four times more central nervous system (CNS) stimulation than levoamphetamine;[125][129] however, levoamphetamine has slightly greater cardiovascular and peripheral effects.[129]

Related endogenous compounds

For more details on related compounds, see Trace amine.

Amphetamine has a very similar structure and function to the endogenous trace amines, which are naturally occurring neurotransmitter molecules produced in the human body and brain.[127][130] Among this group, the most closely related compounds are phenethylamine, the parent compound of amphetamine, and N-methylphenethylamine, an isomer of amphetamine (i.e., it has an identical molecular formula).[127][130][131] In humans, phenethylamine is produced directly from L-phenylalanine by the aromatic amino acid decarboxylase (AADC) enzyme, which converts L-DOPA into dopamine as well.[130][131] In turn, N‑methylphenethylamine is metabolized from phenethylamine by phenylethanolamine N-methyltransferase, the same enzyme that metabolizes norepinephrine into epinephrine.[130][131] Like amphetamine, both phenethylamine and N‑methylphenethylamine regulate monoamine neurotransmission via TAAR1;[127][131] unlike amphetamine, both of these substances are broken down by monoamine oxidase B, and therefore have a shorter half-life than amphetamine.[130][131]

Pharmacokinetics

Amphetamine is well absorbed from the gut, and bioavailability is typically over 75% for dextroamphetamine.[132] However, oral availability varies with gastrointestinal pH.[133] Dextroamphetamine is a weak base with a pKa of 9–10;[2] 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.[2][133] Conversely, an acidic pH means the drug is predominantly in its water-soluble cationic form, and less is absorbed.[2][133]

Approximately 15–40% of dextroamphetamine circulating in the bloodstream is bound to plasma proteins.[134]

The half-life of dextroamphetamine varies with urine pH.[2] At normal urine pH, the half-life of dextroamphetamine is 9–11 hours.[2] An acidic diet will reduce the half-life to 8–11 hours, while an alkaline diet will increase the range to 16–31 hours.[135][136] The immediate-release and extended release variants of dextroamphetamine salts reach peak plasma concentrations at 3 hours and 7 hours post-dose respectively.[2] Dextromphetamine is eliminated via the kidneys, with 30–40% of the drug being excreted unchanged at normal urinary pH.[2] When the urinary pH is basic, more of the drug is in its poorly water-soluble free base form, and less is excreted.[2] When urine pH is abnormal, the urinary recovery of amphetamine may range from a low of 1% to as much as 75%, depending mostly upon whether urine is too basic or acidic, respectively.[2] Amphetamine is usually eliminated within two days of the last oral dose.[135] Apparent half-life and duration of effect increase with repeated use and accumulation of the drug.[137]

CYP2D6, dopamine β-hydroxylase, flavin-containing monooxygenase, butyrate-CoA ligase, and glycine N-acyltransferase are the enzymes known to metabolize amphetamine or its metabolites in humans.[2][3][4][5][6][138] Amphetamine has a variety of excreted metabolic products, including 4-hydroxyamfetamine, 4-hydroxynorephedrine, 4-hydroxyphenylacetone, benzoic acid, hippuric acid, norephedrine, and phenylacetone.[2][135][139] Among these metabolites, the active sympathomimetics are 4‑hydroxyamphetamine,[140] 4‑hydroxynorephedrine,[141] and norephedrine.[142]

The main metabolic pathways involve aromatic para-hydroxylation, aliphatic alpha- and beta-hydroxylation, N-oxidation, N-dealkylation, and deamination.[2][135] The known pathways include:[2][4][139]

Metabolic pathways of amphetamine
Graphic of several routes of amphetamine metabolism

Para-
Hydroxylation
Para-
Hydroxylation
Para-
Hydroxylation
Beta-
Hydroxylation
Beta-
Hydroxylation
Oxidative
Deamination
Oxidation
Glycine
Conjugation

The image above contains clickable links
The primary active metabolites of amphetamine are 4-hydroxyamphetamine and norephedrine;[139] however, most of an administered dose is excreted as amphetamine itself and the inactive metabolites.[2] Benzoic acid is metabolized by butyrate-CoA ligase into an intermediate product, benzoyl-CoA,[5] which is then metabolized by glycine N-acyltransferase into hippuric acid.[6]

History, society, and culture

Racemic amphetamine was first synthesized under the chemical name "phenylisopropylamine" in Berlin, 1887 by the Romanian chemist Lazar Edeleanu.[143] It was not widely marketed until 1932, when the pharmaceutical company Smith, Kline & French (now known as GlaxoSmithKline) introduced it in the form of the Benzedrine inhaler for use as a bronchodilator. Notably, the amphetamine contained in the Benzedrine inhaler was the liquid free-base,[note 10] not a chloride or sulfate salt.

Three years later, in 1935, the medical community became aware of the stimulant properties of amphetamine, specifically dextroamphetamine, and in 1937 Smith, Kline, and French introduced tablets under the tradename Dexedrine.[144] In the United States, Dexedrine was approved to treat narcolepsy, attention disorders, and obesity. In Canada indications once included epilepsy and parkinsonism.[145] Dextroamphetamine was marketed in various other forms in the following decades, primarily by Smith, Kline, and French, such as several combination medications including a mixture of dextroamphetamine and amobarbital (a barbiturate) sold under the tradename Dexamyl and, in the 1950s, an extended release capsule (the "Spansule").[146] Preparations containing dextroamphetamine were also used in World War II as a treatment against fatigue.[147]

It quickly became apparent that dextroamphetamine and other amphetamines had a high potential for misuse, although they were not heavily controlled until 1970, when the Comprehensive Drug Abuse Prevention and Control Act was passed by the United States Congress. Dextroamphetamine, along with other sympathomimetics, was eventually classified as Schedule II, the most restrictive category possible for a drug with a government-sanctioned, recognized medical use.[148] Internationally, it has been available under the names AmfeDyn (Italy), Curban (US), Obetrol (Switzerland), Simpamina (Italy), Dexedrine/GSK (US & Canada), Dexedrine/UCB (United Kingdom), Dextropa (Portugal), and Stild (Spain).[149]

In October 2010, GlaxoSmithKline sold the rights for Dexedrine Spansule to Amedra Pharmaceuticals (a subsidiary of CorePharma).[150]

The U.S. Air Force uses dextroamphetamine as one of its "go pills", given to pilots on long missions to help them remain focused and alert. Conversely, "no-go pills" are used after the mission is completed, to combat the effects of the mission and "go-pills".[151][152][153][154] The Tarnak Farm incident was linked by media reports to the use of this drug on long term fatigued pilots. The military did not accept this explanation, citing the lack of similar incidents. Newer stimulant medications or awakeness promoting agents with different side effect profiles, such as modafinil, are being investigated and sometimes issued for this reason.[152]

Formulations

Dextroamphetamine pharmaceuticals and prodrugs[note 11]
Brand
name		 United States
Adopted Name		 (D:L) ratio Dosage
form		 Marketing
start date		 Sources
Adderall – 3:1 (salts) tablet 1996 [16][162]
Adderall XR – 3:1 (salts) capsule 2001 [16][162]
Dyanavel XR amphetamine 3.2:1 (base)suspension 2015 [69][163]
Evekeo amphetamine sulfate 1:1 (salts) tablet 2012 [164][165]
Dexedrine dextroamphetamine sulfate 1:0 (salts) capsule 1976 [16][162]
ProCentra dextroamphetamine sulfate 1:0 (salts) liquid 2010 [162]
Zenzedi dextroamphetamine sulfate 1:0 (salts) tablet 2013 [162]
Vyvanse lisdexamfetamine dimesylate 1:0 (salts) capsule 2007 [16][166]
 
An image of the lisdexamfetamine compound
The skeletal structure of lisdexamfetamine

Dextroamphetamine sulfate

Dexamphetamine 5 mg generic name tablets

In the United States, immediate release (IR) formulations of dextroamphetamine sulfate are available generically as 5 mg and 10 mg tablets, marketed by Barr (Teva Pharmaceutical Industries), Mallinckrodt Pharmaceuticals, Wilshire Pharmaceuticals, Aurobindo Pharmaceutical USA and CorePharma. Previous IR tablets sold by the brand names of Dexedrine and Dextrostat have been discontinued but in 2015 IR tablets became available by the brand name Zenzedi, offered as 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg and 30 mg tablets.[167] Dextroamphetamine sulfate is also available as a controlled-release (CR) capsule preparation in strengths of 5 mg, 10 mg, and 15 mg under the brand name Dexedrine Spansule, with generic versions marketed by Barr and Mallinckrodt. A bubblegum flavored oral solution is available under the brand name ProCentra, manufactured by FSC Pediatrics, which is designed to be an easier method of administration in children who have difficulty swallowing tablets, each 5 mL contains 5 mg dextroamphetamine.[168] The conversion rate between dextroamphetamine sulfate to amphetamine free base is .728.[169]

In Australia, dexamphetamine is available in bottles of 100 instant release 5 mg tablets as a generic drug.[170] or slow release dextroamphetamine preparations may be compounded by individual chemists.[171] Similarly, in the United Kingdom it is only available in 5 mg instant release sulfate tablets under the generic name dextroamphetamine sulphate having had been available under the brand name Dexedrine prior to UCB Pharma disinvesting the product to another pharmaceutical company (Auden Mckenzie).[172]

Lisdexamfetamine

Main article: Lisdexamfetamine

Dextroamphetamine is the active metabolite of the prodrug lisdexamfetamine (L-lysine-dextroamphetamine), available by the brand name Vyvanse (lisdexamfetamine dimesylate). Dextroamphetamine is liberated from lisdexamfetamine enzymatically following contact with red blood cells. The conversion is rate-limited by the enzyme, which prevents high blood concentrations of dextroamphetamine and reduces lisdexamfetamine's drug liking and abuse potential at clinical doses.[173][174] Vyvanse is marketed as once-a-day dosing as it provides a slow release of dextroamphetamine into the body. Vyvanse is available as capsules, and in six strengths; 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, and 70 mg. The conversion rate between lisdexamfetamine dimesylate (Vyvanse) to dextroamphetamine base is 29.5%.[175][176][177]

Adderall

Adderall tablets
Adderall 20 mg tablets, some broken in half, with a lengthwise-folded US dollar bill along the bottom
Main article: Adderall

Another pharmaceutical that contains dextroamphetamine is commonly known by the brand name Adderall. It is available as immediate release (IR) tablets and extended release (XR) capsules. Adderall contains equal amounts of four amphetamine salts:

One-quarter racemic (d,l-)amphetamine aspartate monohydrate
One-quarter dextroamphetamine saccharate
One-quarter dextroamphetamine sulfate
One-quarter racemic (d,l-)amphetamine sulfate

Adderall has a total amphetamine base equivalence of 63%.[178] While the enantiomer ratio by dextroamphetamine salts to levoamphetamine salts is 3:1, the amphetamine base content is 75.9% dextroamphetamine, 24.1% levoamphetamine. [note 12]

Amphetamine base in marketed amphetamine medications
drug formula molecular mass
[note 13]		 amphetamine base
[note 14]		 amphetamine base
in equal doses		 doses with
equal base
content
[note 15]
(g/mol) (percent) (30 mg dose)
total base total dextro- levo- dextro- levo-
dextroamphetamine sulfate[180][181] (C9H13N)2•H2SO4
368.49
270.41
73.38%
73.38%
—
22.0 mg
—
30.0 mg
amphetamine sulfate[182] (C9H13N)2•H2SO4
368.49
270.41
73.38%
36.69%
36.69%
11.0 mg
11.0 mg
30.0 mg
Adderall
62.57%
47.49%
15.08%
14.2 mg
4.5 mg
35.2 mg
25% dextroamphetamine sulfate[180][181] (C9H13N)2•H2SO4
368.49
270.41
73.38%
73.38%
—
25% amphetamine sulfate[182] (C9H13N)2•H2SO4
368.49
270.41
73.38%
36.69%
36.69%
25% dextroamphetamine saccharate[183] (C9H13N)2•C6H10O8
480.55
270.41
56.27%
56.27%
—
25% amphetamine aspartate monohydrate[184] (C9H13N)•C4H7NO4•H2O
286.32
135.21
47.22%
23.61%
23.61%
lisdexamfetamine dimesylate[185] C15H25N3O•(CH4O3S)2
455.49
135.21
29.68%
29.68%
—
8.9 mg
—
74.2 mg
amphetamine base suspension[note 16][69] C9H13N
135.21
135.21
100%
76.19%
23.81%
22.9 mg
7.1 mg
22.0 mg

Notes

  1. ↑ Synonyms and alternate spellings include dexamphetamine (AAN) and dexamfetamine (INN and BAN).
  2. ↑ Cochrane Collaboration reviews are high quality meta-analytic systematic reviews of randomized controlled trials.[34]
  3. ↑ 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.[62]
  4. ↑ 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.[16]</ref> heart disease, severe agitation, or severe anxiety.[63][64] It is also contraindicated in people currently experiencing arteriosclerosis (hardening of the arteries), glaucoma (increased eye pressure), hyperthyroidism (excessive production of thyroid hormone), or moderate to severe hypertension.[63][64][65] People who have experienced allergic reactions to other stimulants in the past or who are taking monoamine oxidase inhibitors (MAOIs) are advised not to take amphetamine,[63][64] although safe concurrent use of amphetamine and monoamine oxidase inhibitors has been documented.[66][67] 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.[63][64] 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.[64] Amphetamine has also been shown to pass into breast milk, so the IPCS and USFDA advise mothers to avoid breastfeeding when using it.[63][64] 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.[25][27][68] The average reduction in final adult height from continuous stimulant therapy over a 3 year period is 2 cm.[68]
  5. ↑ The 95% confidence interval indicates that there is a 95% probability that the true number of deaths lies between 3,425 and 4,145.
  6. ↑ Transcription factors are proteins that increase or decrease the expression of specific genes.[102]
  7. ↑ 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.
  8. ↑ NMDA receptors are voltage-dependent ligand-gated ion channels that requires simultaneous binding of glutamate and a co-agonist (D-serine or glycine) to open the ion channel.[114]
  9. ↑ The review indicated that magnesium L-aspartate and magnesium chloride produce significant changes in addictive behavior;[84] 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.[84]

    Behavioral treatments

    Cognitive behavioral therapy is currently the most effective clinical treatment for psychostimulant addictions.[91] 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.[88][89][90] Exercise leads to better treatment outcomes when used as an adjunct treatment, particularly for psychostimulant addictions.[89][90] 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.[88] This is the opposite of pathological stimulant use, which induces decreased striatal DRD2 density.[88]
    Summary of addiction-related plasticity
    Form of neural or behavioral plasticity Type of reinforcer Sources
    Opiates Psychostimulants High fat or sugar food Sexual intercourse Physical exercise
    (aerobic)    		 Environmental
    enrichment
    ΔFosB expression in
    nucleus accumbens D1-type MSNs    		 ↑ ↑ ↑ ↑ ↑ ↑ [88]
    Behavioral plasticity
    Escalation of intake Yes Yes Yes [88]
    Psychostimulant
    cross-sensitization     		Yes Not applicable Yes Yes Attenuated Attenuated [88]
    Psychostimulant
    self-administration    		 ↑ ↑ ↓ ↓ ↓ [88]
    Psychostimulant
    conditioned place preference    		 ↑ ↑ ↓ ↑ ↓ ↑ [88]
    Reinstatement of drug-seeking behavior ↑ ↑ ↓ ↓ [88]
    Neurochemical plasticity
    CREB phosphorylation
    in the nucleus accumbens    		 ↓ ↓ ↓ ↓ ↓ [88]
    Sensitized dopamine response
    in the nucleus accumbens    		 No Yes No Yes [88]
    Altered striatal dopamine signaling ↓DRD2, ↑DRD3 ↑DRD1, ↓DRD2, ↑DRD3 ↑DRD1, ↓DRD2, ↑DRD3 ↑DRD2 ↑DRD2 [88]
    Altered striatal opioid signaling ↑μ-opioid receptors ↑μ-opioid receptors
    ↑κ-opioid receptors     		↑μ-opioid receptors ↑μ-opioid receptors No change No change [88]
    Changes in striatal opioid peptides ↑dynorphin ↑dynorphin ↓enkephalin ↑dynorphin ↑dynorphin [88]
    Mesocorticolimbic synaptic plasticity
    Number of dendrites in the nucleus accumbens ↓ ↑ ↑ [88]
    Dendritic spine density in
    the nucleus accumbens    		 ↓ ↑ ↑ [88]

    Dependence and withdrawal

    According to another Cochrane Collaboration 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."[115] This review noted that withdrawal symptoms in chronic, high-dose users are frequent, occurring in up to 87.6% of cases, and persist for three to four weeks with a marked "crash" phase occurring during the first week.[115] 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.[115] The review indicated that withdrawal symptoms are associated with the degree of dependence, suggesting that therapeutic use would result in far milder discontinuation symptoms.[115] Manufacturer prescribing information does not indicate the presence of withdrawal symptoms following discontinuation of amphetamine use after an extended period at therapeutic doses.[65][116][117]

    Toxicity and psychosis

    In rodents and primates, sufficiently high doses of amphetamine cause dopaminergic neurotoxicity, or damage to dopamine neurons, which is characterized by reduced transporter and receptor function.[118] There is no evidence that amphetamine is directly neurotoxic in humans.[119][120] However, large doses of amphetamine may cause indirect neurotoxicity as a result of increased oxidative stress from reactive oxygen species and autoxidation of dopamine.[20][121][122] A severe amphetamine overdose can result in a stimulant psychosis that may involve a variety of symptoms, such as paranoia and delusions.[77] A Cochrane Collaboration review on treatment for amphetamine, dextroamphetamine, and methamphetamine psychosis states that about 5–15% of users fail to recover completely.[77][123] According to the same review, there is at least one trial that shows antipsychotic medications effectively resolve the symptoms of acute amphetamine psychosis.[77] Psychosis very rarely arises from therapeutic use.[78]<ref name='FDA Contra Warnings'>"Adderall XR Prescribing Information" (PDF). United States Food and Drug Administration. Shire US Inc. December 2013. pp. 4–6. Retrieved 30 December 2013.
  10. ↑ Free-base form amphetamine is a volatile oil, hence the efficacy of the inhalers.
  11. ↑ These represent the current brands in the United States, except Dexedrine instant release tablets. Dexedrine tablets, introduced in 1937, is discontinued but available as Zenzedi and generically;[155][156] Dexedrine listed here represents the extended release "Spansule" capsule which was approved in 1976.[157][158] Amphetamine sulfate tablets, now sold as Evekeo (brand), were originally sold as Benzedrine (brand) sulfate in 1935[159][160] and discontinued sometime after 1976.[161] Vyvanse and Dyanavel are only available as brand pharmaceuticals, due to the patented mechanisms used to release the active amphetamine ingredient.
  12. ↑ Calculated by dextroamphetamine base percent / total amphetamine base percent = 47.49/62.57 = 75.90% from table: Amphetamine base in marketed amphetamine medications. The remainder is levoamphetamine.
  13. ↑ For uniformity, molecular masses were calculated using the Lenntech Molecular Weight Calculator.[179] and were within 0.01g/mol of published pharmaceutical values.
  14. ↑ Amphetamine base percentage = molecular massbase / molecular masstotal. Amphetamine base percentage for Adderall = sum of component percentages / 4.
  15. ↑ dose = (1 / amphetamine base percentage) × scaling factor = (molecular masstotal / molecular massbase) × scaling factor. The values in this column were scaled to a 30 mg dose of dextroamphetamine. Due to pharmacological differences between these medications (e.g., differences in the release, absorption, conversion, concentration, differing effects of enantiomers, half-life, etc), the listed values should not be considered equipotent doses.
  16. ↑ This product (Dyanavel XR) is an oral suspension (i.e., a drug that is suspended in a liquid and taken by mouth) that contains 2.5 mg/mL of amphetamine base.[69] The product uses an ion exchange resin to achieve extended release of the amphetamine base.[69]

Reference notes

  1. ↑ [54][47][68][69][70]
  2. ↑ [71][72][73][74]
  3. ↑ [75][54][47][76]
  4. ↑ [92][53][47][81][93]
  5. ↑ [85][88][100][103][104]

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    Table 9.2 Dextroamphetamine formulations of stimulant medication
    Dexedrine [Peak:2–3 h] [Duration:5–6 h] ...
    Adderall [Peak:2–3 h] [Duration:5–7 h]
    Dexedrine spansules [Peak:7–8 h] [Duration:12 h] ...
    Adderall XR [Peak:7–8 h] [Duration:12 h]
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    Physiologic and performance effects
     • Amphetamines increase dopamine/norepinephrine release and inhibit their reuptake, leading to central nervous system (CNS) stimulation
     • Amphetamines seem to enhance athletic performance in anaerobic conditions 39 40
     • Improved reaction time
     • Increased muscle strength and delayed muscle fatigue
     • Increased acceleration
     • Increased alertness and attention to task
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