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Amphetamine

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This article is about mixtures of levoamphetamine and dextroamphetamine. For other uses, see Amphetamine (disambiguation).
Amphetamine
INN: Amfetamine
An image of the amphetamine compound
A 3d image of the D-amphetamine compound
Systematic (IUPAC) name
(RS)-1-phenylpropan-2-amine
Clinical data
Pronunciation Listeni/æmˈfɛtəmn/
Trade names Adderall, Dyanavel XR, Evekeo, others
AHFS/Drugs.com amphetamine
License data
Pregnancy
category
  • US: C (Risk not ruled out)
Dependence
liability
Physical: none[1]
Psychological: moderate
Addiction
liability
Moderate
Routes of
administration
Medical: oral (ingestion), nasal inhalation, intravenous[2]
Recreational: oral, nasal inhalation, insufflation, rectal, intravenous
Legal status
Legal status
Pharmacokinetic data
Bioavailability Oral 75–100%[3]
Protein binding 15–40%[4]
Metabolism CYP2D6,[5] DBH,[6][7][8] FMO3[6][9][10]
Metabolites 4-hydroxyamphetamine, 4-hydroxynorephedrine, 4-hydroxyphenylacetone, benzoic acid, hippuric acid, norephedrine, phenylacetone[5][11][12]
Onset of action IR dosing: 30–60 minutes[13]
XR dosing: 1.5–2 hours[14][15]
Biological half-life D-amph: 9–11 hours[5][16]
L-amph: 11–14 hours[5][16]
pH-dependent: 8–31 hours[17]
Duration of action IR dosing: 3–7 hours[14][18]
XR dosing: 12 hours[14][15][18]
Excretion Primarily renal;
pH-dependent range: 1–75%[5]
Identifiers
CAS Number 300-62-9 YesY
ATC code N06BA01 (WHO)
PubChem CID 3007
IUPHAR/BPS 4804
DrugBank DB00182 YesY
ChemSpider 13852819 YesY
UNII CK833KGX7E YesY
KEGG D07445 YesY
ChEBI CHEBI:2679 YesY
ChEMBL CHEMBL405 YesY
NIAID ChemDB 018564
Synonyms α-methylphenethylamine
PDB ligand ID FRD (PDBe, RCSB PDB)
Chemical data
Formula C9H13N
Molar mass 135.20622 g/mol[19]
Chirality Racemic mixture[20]
Physical data
Density 0.9±0.1 g/cm3
Melting point 11.3 °C (52.3 °F) (predicted)[21]
Boiling point 203 °C (397 °F) at 760 mmHg[22]
  (verify)

Amphetamine[note 1] (contracted from alphamethylphenethylamine) is a potent central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity. Amphetamine was discovered in 1887 and exists as two enantiomers:[note 2] levoamphetamine and dextroamphetamine. Amphetamine properly refers to a specific chemical, the racemic free base, which is equal parts of the two enantiomers, levoamphetamine and dextroamphetamine, in their pure amine forms. However, 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.[sources 1]

The first pharmaceutical amphetamine was Benzedrine, a brand which was used to treat a variety of conditions. Currently, pharmaceutical amphetamine is prescribed as racemic amphetamine, Adderall,[note 3] dextroamphetamine, or the inactive prodrug lisdexamfetamine. Amphetamine, through activation of a trace amine receptor, increases monoamine and excitatory neurotransmitter activity in the brain, with its most pronounced effects targeting the catecholamine neurotransmitters norepinephrine and dopamine.[sources 2]

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 decreased reaction time, fatigue resistance, and increased muscle strength. Larger doses of amphetamine may impair cognitive function and induce rapid muscle breakdown. Drug addiction is a serious risk with large recreational doses but is unlikely to arise from typical long-term medical use at therapeutic doses. Very high doses can result in psychosis (e.g., delusions and paranoia) which rarely occurs at therapeutic doses even during long-term use. Recreational doses are generally much larger than prescribed therapeutic doses and carry a far greater risk of serious side effects.[sources 3]

Amphetamine belongs to the phenethylamine class. It is also the parent compound of its own structural class, the substituted amphetamines,[note 4] which includes prominent substances such as bupropion, cathinone, MDMA (ecstasy), and methamphetamine. As a member of the phenethylamine class, amphetamine is also chemically related to the naturally occurring trace amine neuromodulators, specifically phenethylamine and N-methylphenethylamine, both of which are produced within the human body. Phenethylamine is the parent compound of amphetamine, while N-methylphenethylamine is a constitutional isomer that differs only in the placement of the methyl group.[sources 4]

Uses

Medical

Amphetamine is used to treat attention deficit hyperactivity disorder (ADHD), narcolepsy (a sleep disorder), and obesity, and is sometimes prescribed off-label for its past medical indications, such as depression.[2][16][35] Long-term amphetamine exposure at sufficiently high doses in some animal species is known to produce abnormal dopamine system development or nerve damage,[49][50] but, in humans with ADHD, pharmaceutical amphetamines appear to improve brain development and nerve growth.[51][52][53] 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.[51][52][53]

Reviews of clinical stimulant research have established the safety and effectiveness of long-term amphetamine use for ADHD.[54][55][56] Controlled trials spanning two years have demonstrated treatment effectiveness and safety.[54][56] 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.[54]

Current models of ADHD suggest that it is associated with functional impairments in some of the brain's neurotransmitter systems;[57] these functional impairments involve impaired dopamine neurotransmission in the mesocorticolimbic projection and norepinephrine neurotransmission in the locus coeruleus and prefrontal cortex.[57] Psychostimulants like methylphenidate and amphetamine are effective in treating ADHD because they increase neurotransmitter activity in these systems.[26][57][58] Approximately 80% of those who use these stimulants see improvements in ADHD symptoms.[59] 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.[60][61] The Cochrane Collaboration's reviews[note 5] on the treatment of ADHD in children, adolescents, and adults 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.[63][64] 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.[65]

Enhancing 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, unambiguous improvements in cognition, including working memory, episodic memory, inhibitory control and some aspects of attention, in normal healthy adults;[66][67] the cognition-enhancing effects of amphetamine are known to occur through its indirect activation of both dopamine receptor D1 and adrenoceptor α2 in the prefrontal cortex.[26][66] A systematic review from 2014 noted that low doses of amphetamine also improve memory consolidation, in turn leading to improved recall of information.[68] Therapeutic doses of amphetamine also enhance cortical network efficiency, an effect which mediates improvements in working memory in all individuals.[26][69] Amphetamine and other ADHD stimulants also improve task saliency (motivation to perform a task) and increase arousal (wakefulness), in turn promoting goal-directed behavior.[26][70][71] 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.[26][71][72] 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.[73][74][75] However, high amphetamine doses that are above the therapeutic range can interfere with working memory and other aspects of cognitive control.[26][71]

Amphetamine is used by some athletes for its psychological and athletic performance-enhancing effects, such as increased endurance and alertness;[27][40] however, non-medical amphetamine use is prohibited at sporting events that are regulated by collegiate, national, and international anti-doping agencies.[76][77] 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.[27][78][79] Amphetamine improves endurance and reaction time primarily through reuptake inhibition and effluxion of dopamine in the central nervous system.[78][79][80] Amphetamine and other dopaminergic drugs also increase power output at fixed levels of perceived exertion by overriding a "safety switch" that allows the core temperature limit to increase in order to access a reserve capacity that is normally off-limits.[79][81][82] At therapeutic doses, the adverse effects of amphetamine do not impede athletic performance;[27][78] however, at much higher doses, amphetamine can induce effects that severely impair performance, such as rapid muscle breakdown and elevated body temperature.[28][39][78]

Contraindications

According to the International Programme on Chemical Safety (IPCS) and United States Food and Drug Administration (USFDA),[note 6] amphetamine is contraindicated in people with a history of drug abuse,[note 7] heart disease, severe agitation, or severe anxiety.[84][85] 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.[84][85][86] 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,[84][85] although safe concurrent use of amphetamine and monoamine oxidase inhibitors has been documented.[87][88] 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.[84][85] 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.[85] Amphetamine has also been shown to pass into breast milk, so the IPCS and USFDA advise mothers to avoid breastfeeding when using it.[84][85] Due to the potential for reversible growth impairments,[note 8] the USFDA advises monitoring the height and weight of children and adolescents prescribed an amphetamine pharmaceutical.[84]

Side effects

The side effects of amphetamine are varied, and the amount of amphetamine used is the primary factor in determining the likelihood and severity of side effects.[28][39][40] Amphetamine products such as Adderall, Dexedrine, and their generic equivalents are currently approved by the USFDA for long-term therapeutic use.[36][39] Recreational use of amphetamine generally involves much larger doses, which have a greater risk of serious side effects than dosages used for therapeutic reasons.[40]

Physical

At normal therapeutic doses, the physical side effects of amphetamine vary widely by age and from person to person.[39] 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).[39][40][89] Sexual side effects in males may include erectile dysfunction, frequent erections, or prolonged erections.[39] Abdominal side effects may include abdominal pain, appetite loss, nausea, and weight loss.[39][90] Other potential side effects include 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 5] Dangerous physical side effects are rare at typical pharmaceutical doses.[40]

Amphetamine stimulates the medullary respiratory centers, producing faster and deeper breaths.[40] In a normal person at therapeutic doses, this effect is usually not noticeable, but when respiration is already compromised, it may be evident.[40] Amphetamine also induces contraction in the urinary bladder sphincter, the muscle which controls urination, which can result in difficulty urinating.[40] This effect can be useful in treating bed wetting and loss of bladder control.[40] The effects of amphetamine on the gastrointestinal tract are unpredictable.[40] If intestinal activity is high, amphetamine may reduce gastrointestinal motility (the rate at which content moves through the digestive system);[40] however, amphetamine may increase motility when the smooth muscle of the tract is relaxed.[40] Amphetamine also has a slight analgesic effect and can enhance the pain relieving effects of opioids.[40]

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 6]

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.[39][40] Less common side effects include anxiety, change in libido, grandiosity, irritability, repetitive or obsessive behaviors, and restlessness;[sources 7] these effects depend on the user's personality and current mental state.[40] Amphetamine psychosis (e.g., delusions and paranoia) can occur in heavy users.[28][39][41] Although very rare, this psychosis can also occur at therapeutic doses during long-term therapy.[28][39][42] According to the USFDA, "there is no systematic evidence" that stimulants produce aggressive behavior or hostility.[39]

Amphetamine has also been shown to produce a conditioned place preference in humans taking therapeutic doses,[63][97] meaning that individuals acquire a preference for spending time in places where they have previously used amphetamine.[97][98]

Overdose

An amphetamine overdose can lead to many different symptoms, but is rarely fatal with appropriate care.[85][99] The severity of overdose symptoms increases with dosage and decreases with drug tolerance to amphetamine.[40][85] 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.[85] Symptoms of a moderate and extremely large overdose are listed below; fatal amphetamine poisoning usually also involves convulsions and coma.[28][40] 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 9][100]

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.[101][102] 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.[103][104][105] 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.[103][106] 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.[107][108] Sustained aerobic exercise on a regular basis also appears to be an effective treatment for amphetamine addiction;[106][107][109] 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.[107][109][110]

Overdose symptoms by system
System Minor or moderate overdose[28][40][85] Severe overdose[sources 8]
Cardiovascular
Central nervous
system
Musculoskeletal
Respiratory
  • Rapid breathing
Urinary
Other

Addiction

Addiction and dependence glossary[98][104][112][113]
addiction – a medical condition 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
substance use disorder - a condition in which the use of substances leads to clinically and functionally significant impairment or distress
tolerance – the diminishing effect of a drug resulting from repeated administration at a given dose
(edit | history)
Signaling cascade in the nucleus accumbens that results in amphetamine addiction
v · t · e
The image above contains clickable links
This diagram depicts the signaling events in the brain's reward center that are induced by chronic high-dose exposure to psychostimulants that increase the concentration of synaptic dopamine, like amphetamine, methamphetamine, and phenethylamine. Following presynaptic dopamine and glutamate co-release by such psychostimulants,[114][115] postsynaptic receptors for these neurotransmitters trigger internal signaling events through a cAMP pathway and calcium-dependent pathway that ultimately result in increased CREB phosphorylation.[116][117] Phosphorylated CREB increases levels of ΔFosB, which in turn represses the c-Fos gene with the help of corepressors;[117] c-Fos repression acts as a molecular switch that enables the accumulation of ΔFosB in the neuron.[118] A highly stable (phosphorylated) form of ΔFosB, one that persists in neurons for one or two months, slowly accumulates following repeated high-dose exposure to stimulants through this process.[119][120] ΔFosB functions as "one of the master control proteins" that produces addiction-related structural changes in the brain, and upon sufficient accumulation, with the help of its downstream targets (e.g., nuclear factor kappa B), it induces an addictive state.[119][120]

Addiction is a serious risk with heavy recreational amphetamine use but is unlikely to arise from typical long-term medical use at therapeutic doses.[43][44][45] 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.[121][122]

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.[123][124][125] The most important transcription factors[note 10] that produce these alterations are ΔFosB, cAMP response element binding protein (CREB), and nuclear factor kappa B (NF-κB).[124] 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 11] for most of the behavioral and neural adaptations that arise from addiction.[103][104][124] Once ΔFosB is sufficiently overexpressed, it induces an addictive state that becomes increasingly more severe with further increases in ΔFosB expression.[103][104] It has been implicated in addictions to alcohol, cannabinoids, cocaine, methylphenidate, nicotine, opioids, phencyclidine, propofol, and substituted amphetamines, among others.[sources 9]

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).[104][124][129] 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).[124] ΔFosB also plays an important role in regulating behavioral responses to natural rewards, such as palatable food, sex, and exercise.[106][124][130] 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.[106][124] 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.[106][131][132] These sex addictions are associated with a dopamine dysregulation syndrome which occurs in some patients taking dopaminergic drugs.[106][130]

The effects of amphetamine on gene regulation are both dose- and route-dependent.[125] Most of the research on gene regulation and addiction is based upon animal studies with intravenous amphetamine administration at very high doses.[125] 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.[125] This suggests that medical use of amphetamine does not significantly affect gene regulation.[125]

Pharmacological treatments

Further information: Addiction § Research

As of May 2014, there is no effective pharmacotherapy for amphetamine addiction.[133][134][135] Reviews from 2015 and 2016 indicated that TAAR1-selective agonists have significant therapeutic potential as a treatment for psychostimulant addictions;[38][136] however, as of February 2016, the only compounds which are known to function as TAAR1-selective agonists are experimental drugs.[38][136] Amphetamine addiction is largely mediated through increased activation of dopamine receptors and co-localized NMDA receptors[note 12] in the nucleus accumbens;[102] magnesium ions inhibit NMDA receptors by blocking the receptor calcium channel.[102][137] One review suggested that, based upon animal testing, pathological (addiction-inducing) psychostimulant use significantly reduces the level of intracellular magnesium throughout the brain.[102] Supplemental magnesium[note 13] 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.[102]

Behavioral treatments

Cognitive behavioral therapy is currently the most effective clinical treatment for psychostimulant addictions.[110] 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.[107][108][109] Exercise leads to better treatment outcomes when used as an adjunct treatment, particularly for psychostimulant addictions.[107][109] 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.[106] This is the opposite of pathological stimulant use, which induces decreased striatal DRD2 density.[106] One review noted that exercise may also prevent the development of a drug addiction by altering ΔFosB or c-Fos immunoreactivity in the striatum or other parts of the reward system.[108]

Summary of addiction-related plasticity
Form of neuroplasticity
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
[106]
Behavioral plasticity
Escalation of intake Yes Yes Yes [106]
Psychostimulant
cross-sensitization
Yes Not applicable Yes Yes Attenuated Attenuated [106]
Psychostimulant
self-administration
[106]
Psychostimulant
conditioned place preference
[106]
Reinstatement of drug-seeking behavior [106]
Neurochemical plasticity
CREB phosphorylation
in the nucleus accumbens
[106]
Sensitized dopamine response
in the nucleus accumbens
No Yes No Yes [106]
Altered striatal dopamine signaling DRD2, ↑DRD3 DRD1, ↓DRD2, ↑DRD3 DRD1, ↓DRD2, ↑DRD3 DRD2 DRD2 [106]
Altered striatal opioid signaling No change or
μ-opioid receptors
μ-opioid receptors
κ-opioid receptors
μ-opioid receptors μ-opioid receptors No change No change [106]
Changes in striatal opioid peptides dynorphin
No change: enkephalin
dynorphin enkephalin dynorphin dynorphin [106]
Mesocorticolimbic synaptic plasticity
Number of dendrites in the nucleus accumbens [106]
Dendritic spine density in
the nucleus accumbens
[106]

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."[138] 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.[138] 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.[138] The review indicated that withdrawal symptoms are associated with the degree of dependence, suggesting that therapeutic use would result in far milder discontinuation symptoms.[138] Manufacturer prescribing information does not indicate the presence of withdrawal symptoms following discontinuation of amphetamine use after an extended period at therapeutic doses.[86][139][140]

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.[141] There is no evidence that amphetamine is directly neurotoxic in humans.[142][143] However, large doses of amphetamine may cause indirect neurotoxicity as a result of increased oxidative stress from reactive oxygen species and autoxidation of dopamine.[49][144][145]

A severe amphetamine overdose can result in a stimulant psychosis that may involve a variety of symptoms, such as paranoia and delusions.[41] A Cochrane Collaboration review on treatment for amphetamine, dextroamphetamine, and methamphetamine psychosis states that about 5–15% of users fail to recover completely.[41][146] According to the same review, there is at least one trial that shows antipsychotic medications effectively resolve the symptoms of acute amphetamine psychosis.[41] Psychosis very rarely arises from therapeutic use.[42][84]

Interactions

Many types of substances are known to interact with amphetamine, resulting in altered drug action or metabolism of amphetamine, the interacting substance, or both.[5][147] Inhibitors of the enzymes that metabolize amphetamine (e.g., CYP2D6 and FMO3) will prolong its elimination half-life, meaning that its effects will last longer.[9][147] Amphetamine also interacts with MAOIs, particularly monoamine oxidase A inhibitors, since both MAOIs and amphetamine increase plasma catecholamines (i.e., norepinephrine and dopamine);[147] therefore, concurrent use of both is dangerous.[147] 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.[147] Amphetamine may also decrease the effects of antihypertensives and antipsychotics due to its effects on blood pressure and dopamine respectively.[147] Zinc supplementation may reduce the minimum effective dose of amphetamine when it is used for the treatment of ADHD.[note 14][151]

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.[147] Acidic substances reduce the absorption of amphetamine and increase urinary excretion, and alkaline substances do the opposite.[147] 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).[147]

Pharmacology

Pharmacodynamics

For a simpler and less technical explanation of amphetamine's mechanism of action, see Adderall § Mechanism of action.
Pharmacodynamics of amphetamine in a dopamine neuron
v · t · e
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.[37] Once inside, it binds to TAAR1 or enters synaptic vesicles through VMAT2.[37][152] When amphetamine enters the synaptic vesicles through VMAT2, dopamine is released into the cytosol (yellow-orange area).[152] When amphetamine binds to TAAR1, it reduces postsynaptic neuron firing rate via potassium channels and triggers protein kinase A (PKA) and protein kinase C (PKC) signaling, resulting in DAT phosphorylation.[37][153][154] PKA-phosphorylation causes DAT to withdraw into the presynaptic neuron (internalize) and cease transport.[37] PKC-phosphorylated DAT may either operate in reverse or, like PKA-phosphorylated DAT, internalize and cease transport.[37] 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.[155][156][157]

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.[37][58] The concentrations of the main neurotransmitters involved in reward circuitry and executive functioning, dopamine and norepinephrine, increase dramatically in a dose-dependent manner by amphetamine due to its effects on monoamine transporters.[37][58][152] The reinforcing and task saliency effects of amphetamine are mostly due to enhanced dopaminergic activity in the mesolimbic pathway.[26]

Amphetamine has been identified as a potent full agonist of trace amine-associated receptor 1 (TAAR1), a Gs-coupled and Gq-coupled G protein-coupled receptor (GPCR) discovered in 2001, which is important for regulation of brain monoamines.[37][155] Activation of TAAR1 increases cAMP production via adenylyl cyclase activation and inhibits monoamine transporter function.[37][158] Monoamine autoreceptors (e.g., D2 short, presynaptic α2, and presynaptic 5-HT1A) have the opposite effect of TAAR1, and together these receptors provide a regulatory system for monoamines.[37][38] Notably, amphetamine and trace amines bind to TAAR1, but not monoamine autoreceptors.[37][38] Imaging studies indicate that monoamine reuptake inhibition by amphetamine and trace amines is site specific and depends upon the presence of TAAR1 co-localization in the associated monoamine neurons.[37] As of 2010, co-localization of TAAR1 and the dopamine transporter (DAT) has been visualized in rhesus monkeys, but co-localization of TAAR1 with the norepinephrine transporter (NET) and the serotonin transporter (SERT) has only been evidenced by messenger RNA (mRNA) expression.[37]

In addition to the neuronal monoamine transporters, amphetamine also inhibits both vesicular monoamine transporters, VMAT1 and VMAT2, as well as SLC1A1, SLC22A3, and SLC22A5.[sources 10] 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.[sources 10] Amphetamine is known to strongly induce cocaine- and amphetamine-regulated transcript (CART) gene expression,[164][165] a neuropeptide involved in feeding behavior, stress, and reward, which induces observable increases in neuronal development and survival in vitro.[165][166][167] The CART receptor has yet to be identified, but there is significant evidence that CART binds to a unique Gi/Go-coupled GPCR.[167][168] Amphetamine also inhibits monoamine oxidase at very high doses, resulting in less dopamine and phenethylamine metabolism and consequently higher concentrations of synaptic monoamines.[19][169] In humans, the only post-synaptic receptor at which amphetamine is known to bind is the 5-HT1A receptor, where it acts as an agonist with micromolar affinity.[170][171]

The full profile of amphetamine's short-term drug effects in humans is mostly derived through increased cellular communication or neurotransmission of dopamine,[37] serotonin,[37] norepinephrine,[37] epinephrine,[152] histamine,[152] CART peptides,[164][165] acetylcholine,[172][173] endogenous opioids,[174][175] adrenocorticotropic hormone,[176][177] corticosteroids,[176][177] and glutamate,[156][160] which it effects through interactions with CART, 5-HT1A, EAAT3, TAAR1, VMAT1, VMAT2, and possibly other biological targets.[sources 11]

Dextroamphetamine is a more potent agonist of TAAR1 than levoamphetamine.[178] Consequently, dextroamphetamine produces greater CNS stimulation than levoamphetamine, roughly three to four times more, but levoamphetamine has slightly stronger cardiovascular and peripheral effects.[40][178]

Dopamine

In certain brain regions, amphetamine increases the concentration of dopamine in the synaptic cleft.[37] Amphetamine can enter the presynaptic neuron either through DAT or by diffusing across the neuronal membrane directly.[37] As a consequence of DAT uptake, amphetamine produces competitive reuptake inhibition at the transporter.[37] Upon entering the presynaptic neuron, amphetamine activates TAAR1 which, through protein kinase A (PKA) and protein kinase C (PKC) signaling, causes DAT phosphorylation.[37] Phosphorylation by either protein kinase can result in DAT internalization (non-competitive reuptake inhibition), but PKC-mediated phosphorylation alone induces reverse transporter function (dopamine efflux).[37][179] Amphetamine is also known to increase intracellular calcium, an effect which is associated with DAT phosphorylation through an unidentified Ca2+/calmodulin-dependent protein kinase (CAMK)-dependent pathway, in turn producing dopamine efflux.[155][156][157] Through direct activation of G protein-coupled inwardly-rectifying potassium channels, TAAR1 reduces the firing rate of postsynaptic dopamine neurons, preventing a hyper-dopaminergic state.[153][154][180]

Amphetamine is also a substrate for the presynaptic vesicular monoamine transporter, VMAT2.[152] Following amphetamine uptake at VMAT2, the synaptic vesicle releases dopamine molecules into the cytosol in exchange.[152] Subsequently, the cytosolic dopamine molecules exit the presynaptic neuron via reverse transport at DAT.[37][152]

Norepinephrine

Similar to dopamine, amphetamine dose-dependently increases the level of synaptic norepinephrine, the direct precursor of epinephrine.[46][58] Based upon neuronal TAAR1 mRNA expression, amphetamine is thought to affect norepinephrine analogously to dopamine.[37][152][179] In other words, amphetamine induces TAAR1-mediated efflux and non-competitive reuptake inhibition at phosphorylated NET, competitive NET reuptake inhibition, and norepinephrine release from VMAT2.[37][152]

Serotonin

Amphetamine exerts analogous, yet less pronounced, effects on serotonin as on dopamine and norepinephrine.[37][58] Amphetamine affects serotonin via VMAT2 and, like norepinephrine, is thought to phosphorylate SERT via TAAR1.[37][152] Like dopamine, amphetamine has low, micromolar affinity at the human 5-HT1A receptor.[170][171]

Other neurotransmitters, peptides, and hormones

Amphetamine has no direct effect on acetylcholine neurotransmission, but several studies have noted that acetylcholine release increases after its use.[172][173] In lab animals, amphetamine increases acetylcholine levels in certain brain regions as a downstream effect.[172] In humans, a similar phenomenon occurs via the ghrelin-mediated cholinergic–dopaminergic reward link in the ventral tegmental area.[173] Acute amphetamine administration in humans also increases endogenous opioid release in several brain structures in the reward system.[174][175] Extracellular levels of glutamate, the primary excitatory neurotransmitter in the brain, have been shown to increase in the striatum following exposure to amphetamine.[156] This increase in extracellular glutamate presumably occurs via the amphetamine-induced internalization of EAAT3, a glutamate reuptake transporter, in dopamine neurons.[156][160]

Amphetamine also induces the selective release of histamine from mast cells and efflux from histaminergic neurons through VMAT2.[152] Acute amphetamine administration can also increase adrenocorticotropic hormone and corticosteroid levels in blood plasma by stimulating the hypothalamic–pituitary–adrenal axis.[35][176][177]

Pharmacokinetics

The oral bioavailability of amphetamine varies with gastrointestinal pH;[147] it is well absorbed from the gut, and bioavailability is typically over 75% for dextroamphetamine.[3] Amphetamine is a weak base with a pKa of 9.9;[5] 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.[5][147] Conversely, an acidic pH means the drug is predominantly in a water-soluble cationic (salt) form, and less is absorbed.[5] Approximately 15–40% of amphetamine circulating in the bloodstream is bound to plasma proteins.[4]

The half-life of amphetamine enantiomers differ and vary with urine pH.[5] At normal urine pH, the half-lives of dextroamphetamine and levoamphetamine are 9–11 hours and 11–14 hours, respectively.[5] An acidic diet will reduce the enantiomer half-lives to 8–11 hours; an alkaline diet will increase the range to 16–31 hours.[11][17] The biological half-life is longer and distribution volumes are larger in amphetamine dependent individuals.[17] 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.[5] Amphetamine is eliminated via the kidneys, with 30–40% of the drug being excreted unchanged at normal urinary pH.[5] When the urinary pH is basic, amphetamine is in its free base form, so less is excreted.[5] 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.[5] Amphetamine is usually eliminated within two days of the last oral dose.[11] 

The prodrug lisdexamfetamine is not as sensitive to pH as amphetamine when being absorbed in the gastrointestinal tract;[181] following absorption into the blood stream, it is converted by red blood cell-associated enzymes to dextroamphetamine via hydrolysis.[181] The elimination half-life of lisdexamfetamine is generally less than one hour.[181]

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.[sources 12] Amphetamine has a variety of excreted metabolic products, including 4-hydroxyamphetamine, 4-hydroxynorephedrine, 4-hydroxyphenylacetone, benzoic acid, hippuric acid, norephedrine, and phenylacetone.[5][11][12] Among these metabolites, the active sympathomimetics are 4‑hydroxyamphetamine,[184] 4‑hydroxynorephedrine,[185] and norephedrine.[186] The main metabolic pathways involve aromatic para-hydroxylation, aliphatic alpha- and beta-hydroxylation, N-oxidation, N-dealkylation, and deamination.[5][11] The known metabolic pathways, detectable metabolites, and metabolizing enzymes in humans include the following:

Metabolic pathways of amphetamine in humans[sources 12]
Graphic of several routes of amphetamine metabolism
Amphetamine
Para-
Hydroxylation
Para-
Hydroxylation
Para-
Hydroxylation
unidentified
Beta-
Hydroxylation
Beta-
Hydroxylation
Oxidative
Deamination
Oxidation
unidentified
Glycine
Conjugation
The image above contains clickable links
The primary active metabolites of amphetamine are 4-hydroxyamphetamine and norephedrine;[12] at normal urine pH, about 30–40% of amphetamine is excreted unchanged and roughly 50% is excreted as the inactive metabolites (bottom row).[5] The remaining 10–20% is excreted as the active metabolites.[5] Benzoic acid is metabolized by XM-ligase into an intermediate product, benzoyl-CoA,[182] which is then metabolized by GLYAT into hippuric acid.[183]

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.[37][46] 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).[37][46][187] 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.[46][187] In turn, N‑methylphenethylamine is metabolized from phenethylamine by phenylethanolamine N-methyltransferase, the same enzyme that metabolizes norepinephrine into epinephrine.[46][187] Like amphetamine, both phenethylamine and N‑methylphenethylamine regulate monoamine neurotransmission via TAAR1;[37][187] unlike amphetamine, both of these substances are broken down by monoamine oxidase B, and therefore have a shorter half-life than amphetamine.[46][187]

Chemistry

Racemic amphetamine
The image above contains clickable links
The skeletal structures of L-amph and D-amph
An image of amphetamine free base
A vial of the colorless amphetamine free base
An image of phenyl-2-nitropropene and amphetamine hydrochloride
Amphetamine hydrochloride (left bowl)
Phenyl-2-nitropropene (right cups)

Amphetamine is a methyl homolog of the mammalian neurotransmitter phenethylamine with the chemical formula C9H13N. The carbon atom adjacent to the primary amine is a stereogenic center, and amphetamine is composed of a racemic 1:1 mixture of two enantiomeric mirror images.[23] This racemic mixture can be separated into its optical isomers:[note 15] levoamphetamine and dextroamphetamine.[23] Physically, at room temperature, the pure free base of amphetamine is a mobile, colorless, and volatile liquid with a characteristically strong amine odor, and acrid, burning taste.[22] Frequently prepared solid salts of amphetamine include amphetamine aspartate,[28] hydrochloride,[188] phosphate,[189] saccharate,[28] and sulfate,[28] the last of which is the most common amphetamine salt.[47] Amphetamine is also the parent compound of its own structural class, which includes a number of psychoactive derivatives.[6][23] In organic chemistry, amphetamine is an excellent chiral ligand for the stereoselective synthesis of 1,1'-bi-2-naphthol.[190]

Substituted derivatives

For a more comprehensive list, see Substituted amphetamine.

The substituted derivatives of amphetamine, or "substituted amphetamines", are a broad range of chemicals that contain amphetamine as a "backbone";[6][48][191] specifically, this chemical class includes derivative compounds that are formed by replacing one or more hydrogen atoms in the amphetamine core structure with substituents.[6][48][192] The class includes amphetamine itself, stimulants like methamphetamine, serotonergic empathogens like MDMA, and decongestants like ephedrine, among other subgroups.[6][48][191]

Synthesis

For more details on illicit amphetamine synthesis, see History and culture of substituted amphetamines § Illegal synthesis.

Since the first preparation was reported in 1887,[193] numerous synthetic routes to amphetamine have been developed.[194][195] The most common route of both legal and illicit amphetamine synthesis employs a non-metal reduction known as the Leuckart reaction (method 1).[47][196] In the first step, a reaction between phenylacetone and formamide, either using additional formic acid or formamide itself as a reducing agent, yields N-formylamphetamine. This intermediate is then hydrolyzed using hydrochloric acid, and subsequently basified, extracted with organic solvent, concentrated, and distilled to yield the free base. The free base is then dissolved in an organic solvent, sulfuric acid added, and amphetamine precipitates out as the sulfate salt.[196][197]

A number of chiral resolutions have been developed to separate the two enantiomers of amphetamine.[194] For example, racemic amphetamine can be treated with d-tartaric acid to form a diastereoisomeric salt which is fractionally crystallized to yield dextroamphetamine.[198] Chiral resolution remains the most economical method for obtaining optically pure amphetamine on a large scale.[199] In addition, several enantioselective syntheses of amphetamine have been developed. In one example, optically pure (R)-1-phenyl-ethanamine is condensed with phenylacetone to yield a chiral Schiff base. In the key step, this intermediate is reduced by catalytic hydrogenation with a transfer of chirality to the carbon atom alpha to the amino group. Cleavage of the benzylic amine bond by hydrogenation yields optically pure dextroamphetamine.[199]

A large number of alternative synthetic routes to amphetamine have been developed based on classic organic reactions.[194][195] One example is the Friedel–Crafts alkylation of chlorobenzene by allyl chloride to yield beta chloropropylbenzene which is then reacted with ammonia to produce racemic amphetamine (method 2).[200] 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.[201][202] A third route starts with ethyl 3-oxobutanoate which through a double alkylation with methyl iodide followed by benzyl chloride can be converted into 2-methyl-3-phenyl-propanoic acid. This synthetic intermediate can be transformed into amphetamine using either a Hofmann or Curtius rearrangement (method 4).[203]

A significant number of amphetamine syntheses feature a reduction of a nitro, imine, oxime or other nitrogen-containing functional groups.[195] In one such example, a Knoevenagel condensation of benzaldehyde with nitroethane yields phenyl-2-nitropropene. The double bond and nitro group of this intermediate is reduced using either catalytic hydrogenation or by treatment with lithium aluminium hydride (method 5).[196][204] 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).[196]

Amphetamine synthetic routes
Diagram of amphetamine synthesis by the Leuckart reaction
Method 1: Synthesis by the Leuckart reaction
 
Diagram of a chiral resolution of racemic amphetamine and a stereoselective synthesis
Top: Chiral resolution of amphetamine
Bottom: Stereoselective synthesis of amphetamine
Diagram of amphetamine synthesis by Friedel–Crafts alkylation
Method 2: Synthesis by Friedel–Crafts alkylation
Diagram of amphetamine via Ritter synthesis
Method 3: Ritter synthesis
Diagram of amphetamine synthesis via Hofmann and Curtius rearrangements
Method 4: Synthesis via Hofmann and Curtius rearrangements
Diagram of amphetamine synthesis by Knoevenagel condensation
Method 5: Synthesis by Knoevenagel condensation
Diagram of amphetamine synthesis from phenylacetone and ammonia
Method 6: Synthesis using phenylacetone and ammonia

Detection in body fluids

Amphetamine is frequently measured in urine or blood as part of a drug test for sports, employment, poisoning diagnostics, and forensics.[sources 13] Techniques such as immunoassay, which is the most common form of amphetamine test, may cross-react with a number of sympathomimetic drugs.[208] Chromatographic methods specific for amphetamine are employed to prevent false positive results.[209] 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,[note 16] or illicitly obtained substituted amphetamines.[209][212][213] Several prescription drugs produce amphetamine as a metabolite, including benzphetamine, clobenzorex, famprofazone, fenproporex, lisdexamfetamine, mesocarb, methamphetamine, prenylamine, and selegiline, among others.[2][214][215] These compounds may produce positive results for amphetamine on drug tests.[214][215] Amphetamine is generally only detectable by a standard drug test for approximately 24 hours, although a high dose may be detectable for two to four days.[208]

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.[212] Gas chromatography–mass spectrometry (GC–MS) of amphetamine and methamphetamine with the derivatizing agent (S)-(−)-trifluoroacetylprolyl chloride allows for the detection of methamphetamine in urine.[209] 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.[209] 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.[209]

History, society, and culture

Global estimates of illegal drug users in 2014
(in millions of users)[216]
Substance Best
estimate
Low
estimate
High
estimate
Amphetamine-
type stimulants
35.65 15.34 55.90
Cannabis 182.50 127.54 233.65
Cocaine 18.26 14.88 22.08
Ecstasy 19.40 9.89 29.01
Opiates 17.44 13.74 21.59
Opioids 33.12 28.57 38.52

Amphetamine was first synthesized in 1887 in Germany by Romanian chemist Lazăr Edeleanu who named it phenylisopropylamine;[193][217][218] its stimulant effects remained unknown until 1927, when it was independently resynthesized by Gordon Alles and reported to have sympathomimetic properties.[218] Amphetamine had no pharmacological use until 1934, when Smith, Kline and French began selling it as an inhaler under the trade name Benzedrine as a decongestant.[29] Benzedrine sulfate was introduced three years later and found a wide variety of medical applications, including narcolepsy.[29][219] During World War II, amphetamine and methamphetamine were used extensively by both the Allied and Axis forces for their stimulant and performance-enhancing effects.[193][220][221] As the addictive properties of the drug became known, governments began to place strict controls on the sale of amphetamine.[193] For example, during the early 1970s in the United States, amphetamine became a schedule II controlled substance under the Controlled Substances Act.[222] In spite of strict government controls, amphetamine has been used legally or illicitly by people from a variety of backgrounds, including authors,[223] musicians,[224] mathematicians,[225] and athletes.[27]

Amphetamine is still illegally synthesized today in clandestine labs and sold on the black market, primarily in European countries.[226] Among European Union (EU) member states, 1.2 million young adults used illicit amphetamine or methamphetamine in 2013.[227] During 2012, approximately 5.9 metric tons of illicit amphetamine were seized within EU member states;[227] the "street price" of illicit amphetamine within the EU ranged from 6–38 per gram during the same period.[227] Outside Europe, the illicit market for amphetamine is much smaller than the market for methamphetamine and MDMA.[226]

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.[30] Consequently, it is heavily regulated in most countries.[228][229] Some countries, such as South Korea and Japan, have banned substituted amphetamines even for medical use.[230][231] In other nations, such as Canada (schedule I drug),[232] the Netherlands (List I drug),[233] the United States (schedule II drug),[28] Australia (schedule 8),[234] Thailand (category 1 narcotic),[235] and United Kingdom (class B drug),[236] amphetamine is in a restrictive national drug schedule that allows for its use as a medical treatment.[226][31]

Pharmaceutical products

Several currently prescribed amphetamine formulations contain both enantiomers, including Adderall, Dyanavel XR, and Evekeo, the last of which is racemic amphetamine sulfate.[2][35][90] Amphetamine is also prescribed in enantiopure and prodrug form as dextroamphetamine and lisdexamfetamine respectively.[36][237] Lisdexamfetamine is structurally different from amphetamine, and is inactive until it metabolizes into dextroamphetamine.[237] The free base of racemic amphetamine was previously available as Benzedrine, Psychedrine, and Sympatedrine.[2] Levoamphetamine was previously available as Cydril.[2] Many current amphetamine pharmaceuticals are salts due to the comparatively high volatility of the free base.[2][36][47] However, oral suspension and orally disintegrating tablet (ODT) dosage forms composed of the free base were introduced in 2015 and 2016.[90][238][239] 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 [2][36]
Adderall XR 3:1 (salts) capsule 2001 [2][36]
Adzenys XR amphetamine 3:1 (base) ODT 2016 [239][240]
Dyanavel XR amphetamine 3.2:1 (base) suspension 2015 [90][238]
Evekeo amphetamine sulfate 1:1 (salts) tablet 2012 [35][241]
Dexedrine dextroamphetamine sulfate 1:0 (salts) capsule 1976 [2][36]
ProCentra dextroamphetamine sulfate 1:0 (salts) liquid 2010 [36]
Zenzedi dextroamphetamine sulfate 1:0 (salts) tablet 2013 [36]
Vyvanse lisdexamfetamine dimesylate 1:0 (prodrug) capsule 2007 [2][237]
 
An image of the lisdexamfetamine compound
The skeletal structure of lisdexamfetamine
Amphetamine base in marketed amphetamine medications
drug formula molecular mass
[note 17]
amphetamine base
[note 18]
amphetamine base
in equal doses
doses with
equal base
content
[note 19]
(g/mol) (percent) (30 mg dose)
total base total dextro- levo- dextro- levo-
dextroamphetamine sulfate[243][244] (C9H13N)2•H2SO4
368.49
270.41
73.38%
73.38%
22.0 mg
30.0 mg
amphetamine sulfate[245] (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[243][244] (C9H13N)2•H2SO4
368.49
270.41
73.38%
73.38%
25% amphetamine sulfate[245] (C9H13N)2•H2SO4
368.49
270.41
73.38%
36.69%
36.69%
25% dextroamphetamine saccharate[246] (C9H13N)2•C6H10O8
480.55
270.41
56.27%
56.27%
25% amphetamine aspartate monohydrate[247] (C9H13N)•C4H7NO4•H2O
286.32
135.21
47.22%
23.61%
23.61%
lisdexamfetamine dimesylate[181] C15H25N3O•(CH4O3S)2
455.49
135.21
29.68%
29.68%
8.9 mg
74.2 mg
amphetamine base suspension[note 20][90] 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: 1-phenylpropan-2-amine (IUPAC name), α-methylbenzeneethanamine, α-methylphenethylamine, amfetamine (International Nonproprietary Name [INN]), β-phenylisopropylamine, desoxynorephedrine, and speed.[19][23][24]
  2. ^ Enantiomers are molecules that are mirror images of one another; they are structurally identical, but of the opposite orientation.[25]
    Levoamphetamine and dextroamphetamine are also known as L-amph or levamfetamine (INN) and D-amph or dexamfetamine (INN) respectively.[19]
  3. ^ "Adderall" is a brand name as opposed to a nonproprietary name; because the latter ("dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine sulfate, and amphetamine aspartate"[36]) is excessively long, this article exclusively refers to this amphetamine mixture by the brand name.
  4. ^ The term "amphetamines" also refers to a chemical class, but, unlike the class of substituted amphetamines,[6] the "amphetamines" class does not have a standardized definition in academic literature.[20] One of the more restrictive definitions of this class includes only the racemate and enantiomers of amphetamine and methamphetamine.[20] The most general definition of the class encompasses a broad range of pharmacologically and structurally related compounds.[20]
    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.
  5. ^ Cochrane Collaboration reviews are high quality meta-analytic systematic reviews of randomized controlled trials.[62]
  6. ^ 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.[83]
  7. ^ 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.[2]
  8. ^ 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.[54][56][89] The average reduction in final adult height from continuous stimulant therapy over a 3 year period is 2 cm.[89]
  9. ^ The 95% confidence interval indicates that there is a 95% probability that the true number of deaths lies between 3,425 and 4,145.
  10. ^ Transcription factors are proteins that increase or decrease the expression of specific genes.[126]
  11. ^ 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.
  12. ^ 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.[137]
  13. ^ The review indicated that magnesium L-aspartate and magnesium chloride produce significant changes in addictive behavior;[102] other forms of magnesium were not mentioned.
  14. ^ The human dopamine transporter contains a high affinity extracellular zinc binding site which, upon zinc binding, inhibits dopamine reuptake and amplifies amphetamine-induced dopamine efflux in vitro.[148][149][150] The human serotonin transporter and norepinephrine transporter do not contain zinc binding sites.[150]
  15. ^ Enantiomers are molecules that are mirror images of one another; they are structurally identical, but of the opposite orientation.[25]
  16. ^ The active ingredient in some OTC inhalers in the United States is listed as levmetamfetamine, the INN and USAN of levomethamphetamine.[210][211]
  17. ^ For uniformity, molecular masses were calculated using the Lenntech Molecular Weight Calculator[242] and were within 0.01g/mol of published pharmaceutical values.
  18. ^ Amphetamine base percentage = molecular massbase / molecular masstotal. Amphetamine base percentage for Adderall = sum of component percentages / 4.
  19. ^ 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.
  20. ^ 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.[90] The product uses an ion exchange resin to achieve extended release of the amphetamine base.[90]
Image legend

Reference notes

References

  1. ^ Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and Addictive Disorders". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. p. 367. ISBN 9780071481274. While physical dependence and withdrawal occur with some drugs of abuse (opiates, ethanol), these phenomena are not useful in the diagnosis of addiction because they do not occur with other drugs of abuse (cocaine, amphetamine) and can occur with many drugs that are not abused (propranolol, clonidine). 
  2. ^ a b c d e f g h i j k l m n Heal DJ, Smith SL, Gosden J, Nutt DJ (June 2013). "Amphetamine, past and present – a pharmacological and clinical perspective". J. Psychopharmacol. 27 (6): 479–496. doi:10.1177/0269881113482532. PMC 3666194free to read. PMID 23539642. The intravenous use of d-amphetamine and other stimulants still pose major safety risks to the individuals indulging in this practice. Some of this intravenous abuse is derived from the diversion of ampoules of d-amphetamine, which are still occasionally prescribed in the UK for the control of severe narcolepsy and other disorders of excessive sedation. ... For these reasons, observations of dependence and abuse of prescription d-amphetamine are rare in clinical practice, and this stimulant can even be prescribed to people with a history of drug abuse provided certain controls, such as daily pick-ups of prescriptions, are put in place (Jasinski and Krishnan, 2009b). 
  3. ^ a b "Pharmacology". Dextroamphetamine. DrugBank. University of Alberta. 8 February 2013. Retrieved 5 November 2013. 
  4. ^ a b "Pharmacology". Amphetamine. DrugBank. University of Alberta. 8 February 2013. Retrieved 5 November 2013. 
  5. ^ a b c d e f g h i j k l m n o p q r s t "Adderall XR Prescribing Information" (PDF). United States Food and Drug Administration. Shire US Inc. December 2013. pp. 12–13. Retrieved 30 December 2013. 
  6. ^ a b c d e f g h Glennon RA (2013). "Phenylisopropylamine stimulants: amphetamine-related agents". In Lemke TL, Williams DA, Roche VF, Zito W. Foye's principles of medicinal chemistry (7th ed.). Philadelphia, USA: Wolters Kluwer Health/Lippincott Williams & Wilkins. pp. 646–648. ISBN 9781609133450. Retrieved 11 September 2015. The simplest unsubstituted phenylisopropylamine, 1-phenyl-2-aminopropane, or amphetamine, serves as a common structural template for hallucinogens and psychostimulants. Amphetamine produces central stimulant, anorectic, and sympathomimetic actions, and it is the prototype member of this class (39). ... The phase 1 metabolism of amphetamine analogs is catalyzed by two systems: cytochrome P450 and flavin monooxygenase. ... Amphetamine can also undergo aromatic hydroxylation to p-hydroxyamphetamine. ... Subsequent oxidation at the benzylic position by DA β-hydroxylase affords p-hydroxynorephedrine. Alternatively, direct oxidation of amphetamine by DA β-hydroxylase can afford norephedrine. 
  7. ^ a b Taylor KB (January 1974). "Dopamine-beta-hydroxylase. Stereochemical course of the reaction" (PDF). J. Biol. Chem. 249 (2): 454–458. PMID 4809526. Retrieved 6 November 2014. Dopamine-β-hydroxylase catalyzed the removal of the pro-R hydrogen atom and the production of 1-norephedrine, (2S,1R)-2-amino-1-hydroxyl-1-phenylpropane, from d-amphetamine. 
  8. ^ a b Horwitz D, Alexander RW, Lovenberg W, Keiser HR (May 1973). "Human serum dopamine-β-hydroxylase. Relationship to hypertension and sympathetic activity". Circ. Res. 32 (5): 594–599. doi:10.1161/01.RES.32.5.594. PMID 4713201. Subjects with exceptionally low levels of serum dopamine-β-hydroxylase activity showed normal cardiovascular function and normal β-hydroxylation of an administered synthetic substrate, hydroxyamphetamine. 
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    Table 5: N-containing drugs and xenobiotics oxygenated by FMO
  10. ^ a b Cashman JR, Xiong YN, Xu L, Janowsky A (March 1999). "N-oxygenation of amphetamine and methamphetamine by the human flavin-containing monooxygenase (form 3): role in bioactivation and detoxication". J. Pharmacol. Exp. Ther. 288 (3): 1251–1260. PMID 10027866. 
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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]
    Vyvanse [Peak:3–4 h] [Duration:12 h]
     
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  20. ^ a b c d e Yoshida T (1997). "Chapter 1: Use and Misuse of Amphetamines: An International Overview". In Klee H. Amphetamine Misuse: International Perspectives on Current Trends. Amsterdam, Netherlands: Harwood Academic Publishers. p. 2. ISBN 9789057020810. Retrieved 1 December 2014. Amphetamine, in the singular form, properly applies to the racemate of 2-amino-1-phenylpropane. ... In its broadest context, however, the term [amphetamines] can even embrace a large number of structurally and pharmacologically related substances. 
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  25. ^ a b "Enantiomer". IUPAC Goldbook. International Union of Pure and Applied Chemistry. doi:10.1351/goldbook.E02069. Archived from the original on 17 March 2013. Retrieved 14 March 2014. One of a pair of molecular entities which are mirror images of each other and non-superposable. 
  26. ^ a b c d e f g h i j Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 13: Higher Cognitive Function and Behavioral Control". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York, USA: McGraw-Hill Medical. pp. 318, 321. ISBN 9780071481274. Therapeutic (relatively low) doses of psychostimulants, such as methylphenidate and amphetamine, improve performance on working memory tasks both in normal subjects and those with ADHD. ... stimulants act not only on working memory function, but also on general levels of arousal and, within the nucleus accumbens, improve the saliency of tasks. Thus, stimulants improve performance on effortful but tedious tasks ... through indirect stimulation of dopamine and norepinephrine receptors. ...
    Beyond these general permissive effects, dopamine (acting via D1 receptors) and norepinephrine (acting at several receptors) can, at optimal levels, enhance working memory and aspects of attention. Drugs used for this purpose include, as stated above, methylphenidate, amphetamines, atomoxetine, and desipramine.
     
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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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  31. ^ a b Wilens TE, Adler LA, Adams J, Sgambati S, Rotrosen J, Sawtelle R, Utzinger L, Fusillo S (January 2008). "Misuse and diversion of stimulants prescribed for ADHD: a systematic review of the literature". J. Am. Acad. Child Adolesc. Psychiatry. 47 (1): 21–31. doi:10.1097/chi.0b013e31815a56f1. PMID 18174822. Stimulant misuse appears to occur both for performance enhancement and their euphorogenic effects, the latter being related to the intrinsic properties of the stimulants (e.g., IR versus ER profile) ...

    Although useful in the treatment of ADHD, stimulants are controlled II substances with a history of preclinical and human studies showing potential abuse liability.
     
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  38. ^ a b c d e Grandy DK, Miller GM, Li JX (February 2016). ""TAARgeting Addiction"-The Alamo Bears Witness to Another Revolution: An Overview of the Plenary Symposium of the 2015 Behavior, Biology and Chemistry Conference". Drug Alcohol Depend. 159: 9–16. doi:10.1016/j.drugalcdep.2015.11.014. PMID 26644139. When considered together with the rapidly growing literature in the field a compelling case emerges in support of developing TAAR1-selective agonists as medications for preventing relapse to psychostimulant abuse. 
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  41. ^ a b c d e Shoptaw SJ, Kao U, Ling W (January 2009). Shoptaw SJ, Ali R, ed. "Treatment for amphetamine psychosis". Cochrane Database Syst. Rev. (1): CD003026. doi:10.1002/14651858.CD003026.pub3. PMID 19160215. A minority of individuals who use amphetamines develop full-blown psychosis requiring care at emergency departments or psychiatric hospitals. In such cases, symptoms of amphetamine psychosis commonly include paranoid and persecutory delusions as well as auditory and visual hallucinations in the presence of extreme agitation. More common (about 18%) is for frequent amphetamine users to report psychotic symptoms that are sub-clinical and that do not require high-intensity intervention ...
    About 5–15% of the users who develop an amphetamine psychosis fail to recover completely (Hofmann 1983) ...
    Findings from one trial indicate use of antipsychotic medications effectively resolves symptoms of acute amphetamine psychosis.
     
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  43. ^ a b Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and Addictive Disorders". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. p. 368. ISBN 9780071481274. INITIAL ACTIONS OF DRUGS OF ABUSE AND NATURAL REINFORCERS
    Psychostimulants
    Cocaine, amphetamines, and methamphetamine are the major psychostimulants of abuse. The related drug methylphenidate is also abused, although it is far less potent. These drugs elicit similar initial subjective effects; differences generally reflect the route of administration and other pharmacokinetic factors. Such agents also have important therapeutic uses; cocaine, for example, is used as a local anesthetic (Chapter 2), and amphetamines and methylphenidate are used in low doses to treat attention deficit hyperactivity disorder and in higher doses to treat narcolepsy (Chapter 12). Despite their clinical uses, these drugs are strongly reinforcing, and their long-term use at high doses is linked with potential addiction, especially when they are rapidly administered or when high-potency forms are given.
     
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  48. ^ a b c d Hagel JM, Krizevski R, Marsolais F, Lewinsohn E, Facchini PJ (2012). "Biosynthesis of amphetamine analogs in plants". Trends Plant Sci. 17 (7): 404–412. doi:10.1016/j.tplants.2012.03.004. PMID 22502775. Substituted amphetamines, which are also called phenylpropylamino alkaloids, are a diverse group of nitrogen-containing compounds that feature a phenethylamine backbone with a methyl group at the α-position relative to the nitrogen (Figure 1). Countless variation in functional group substitutions has yielded a collection of synthetic drugs with diverse pharmacological properties as stimulants, empathogens and hallucinogens [3]. ... Beyond (1R,2S)-ephedrine and (1S,2S)-pseudoephedrine, myriad other substituted amphetamines have important pharmaceutical applications. The stereochemistry at the α-carbon is often a key determinant of pharmacological activity, with (S)-enantiomers being more potent. For example, (S)-amphetamine, commonly known as d-amphetamine or dextroamphetamine, displays five times greater psychostimulant activity compared with its (R)-isomer [78]. Most such molecules are produced exclusively through chemical syntheses and many are prescribed widely in modern medicine. For example, (S)-amphetamine (Figure 4b), a key ingredient in Adderall® and Dexedrine®, is used to treat attention deficit hyperactivity disorder (ADHD) [79]. ...
    [Figure 4](b) Examples of synthetic, pharmaceutically important substituted amphetamines.
     
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  78. ^ a b c d Parr JW (July 2011). "Attention-deficit hyperactivity disorder and the athlete: new advances and understanding". Clin. Sports Med. 30 (3): 591–610. doi:10.1016/j.csm.2011.03.007. PMID 21658550. In 1980, Chandler and Blair47 showed significant increases in knee extension strength, acceleration, anaerobic capacity, time to exhaustion during exercise, pre-exercise and maximum heart rates, and time to exhaustion during maximal oxygen consumption (VO2 max) testing after administration of 15 mg of dextroamphetamine versus placebo. Most of the information to answer this question has been obtained in the past decade through studies of fatigue rather than an attempt to systematically investigate the effect of ADHD drugs on exercise. ... In 2008, Roelands and colleagues53 studied the effect of reboxetine, a pure NE reuptake inhibitor, similar to atomoxetine, in 9 healthy, well-trained cyclists. They too exercised in both temperate and warm environments. They showed decreased power output and exercise performance at both 18 and 30 degrees centigrade. Their conclusion was that DA reuptake inhibition was the cause of the increased exercise performance seen with drugs that affect both DA and NE (MPH, amphetamine, and bupropion). 
  79. ^ a b c Roelands B, de Koning J, Foster C, Hettinga F, Meeusen R (May 2013). "Neurophysiological determinants of theoretical concepts and mechanisms involved in pacing". Sports Med. 43 (5): 301–311. doi:10.1007/s40279-013-0030-4. PMID 23456493. In high-ambient temperatures, dopaminergic manipulations clearly improve performance. The distribution of the power output reveals that after dopamine reuptake inhibition, subjects are able to maintain a higher power output compared with placebo. ... Dopaminergic drugs appear to override a safety switch and allow athletes to use a reserve capacity that is ‘off-limits’ in a normal (placebo) situation. 
  80. ^ Parker KL, Lamichhane D, Caetano MS, Narayanan NS (October 2013). "Executive dysfunction in Parkinson's disease and timing deficits". Front. Integr. Neurosci. 7: 75. doi:10.3389/fnint.2013.00075. PMC 3813949free to read. PMID 24198770. Manipulations of dopaminergic signaling profoundly influence interval timing, leading to the hypothesis that dopamine influences internal pacemaker, or “clock,” activity. For instance, amphetamine, which increases concentrations of dopamine at the synaptic cleft advances the start of responding during interval timing, whereas antagonists of D2 type dopamine receptors typically slow timing;... Depletion of dopamine in healthy volunteers impairs timing, while amphetamine releases synaptic dopamine and speeds up timing. 
  81. ^ Rattray B, Argus C, Martin K, Northey J, Driller M (March 2015). "Is it time to turn our attention toward central mechanisms for post-exertional recovery strategies and performance?". Front. Physiol. 6: 79. doi:10.3389/fphys.2015.00079. PMC 4362407free to read. PMID 25852568. Aside from accounting for the reduced performance of mentally fatigued participants, this model rationalizes the reduced RPE and hence improved cycling time trial performance of athletes using a glucose mouthwash (Chambers et al., 2009) and the greater power output during a RPE matched cycling time trial following amphetamine ingestion (Swart, 2009). ... Dopamine stimulating drugs are known to enhance aspects of exercise performance (Roelands et al., 2008) 
  82. ^ Roelands B, De Pauw K, Meeusen R (June 2015). "Neurophysiological effects of exercise in the heat". Scand. J. Med. Sci. Sports. 25 Suppl 1: 65–78. doi:10.1111/sms.12350. PMID 25943657. Retrieved 10 March 2016. Physical fatigue has classically been attributed to peripheral factors within the muscle (Fitts, 1996), the depletion of muscle glycogen (Bergstrom & Hultman, 1967) or increased cardiovascular, metabolic, and thermoregulatory strain (Abbiss & Laursen, 2005; Meeusen et al., 2006b). In recent decennia however, it became clear that the central nervous system plays an important role in the onset of fatigue during prolonged exercise (Klass et al., 2008), certainly when ambient temperature is increased ... 5-HT, DA, and NA have all been implicated in the control of thermoregulation and are thought to mediate thermoregulatory responses, certainly since their neurons innervate the hypothalamus (Roelands & Meeusen, 2010). ... This indicates that subjects did not feel they were producing more power and consequently more heat. The authors concluded that the “safety switch” or the mechanisms existing in the body to prevent harmful effects are overridden by the drug administration (Roelands et al., 2008b). Taken together, these data indicate strong ergogenic effects of an increased DA concentration in the brain, without any change in the perception of effort. ... The combined effects of DA and NA on performance in the heat were studied by our research group on a number of occasions. ... the administration of bupropion (DA/NA reuptake inhibitor) significantly improved performance. Coinciding with this ergogenic effect, the authors observed core temperatures that were much higher compared with the placebo situation. Interestingly, this occurred without any change in the subjective feelings of thermal sensation or perceived exertion. Similar to the methylphenidate study (Roelands et al., 2008b), bupropion may dampen or override inhibitory signals arising from the central nervous system to cease exercise because of hyperthermia, and enable an individual to continue maintaining a high power output 
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    DOSAGE FORMS AND STRENGTHS
    Extended-release oral suspension contains 2.5 mg amphetamine base per mL.
     
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  93. ^ Cooper WO, Habel LA, Sox CM, Chan KA, Arbogast PG, Cheetham TC, Murray KT, Quinn VP, Stein CM, Callahan ST, Fireman BH, Fish FA, Kirshner HS, O'Duffy A, Connell FA, Ray WA (November 2011). "ADHD drugs and serious cardiovascular events in children and young adults". N. Engl. J. Med. 365 (20): 1896–1904. doi:10.1056/NEJMoa1110212. PMID 22043968. 
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  98. ^ a b Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and Addictive Disorders". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 364–375. ISBN 9780071481274. 
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  105. ^ Robison AJ, Nestler EJ (November 2011). "Transcriptional and epigenetic mechanisms of addiction". Nat. Rev. Neurosci. 12 (11): 623–637. doi:10.1038/nrn3111. PMC 3272277free to read. PMID 21989194. ΔFosB serves as one of the master control proteins governing this structural plasticity. 
  106. ^ a b c d e f g h i j k l m n o p q r s t u v Olsen CM (December 2011). "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology. 61 (7): 1109–1122. doi:10.1016/j.neuropharm.2011.03.010. PMC 3139704free to read. PMID 21459101. Similar to environmental enrichment, studies have found that exercise reduces self-administration and relapse to drugs of abuse (Cosgrove et al., 2002; Zlebnik et al., 2010). There is also some evidence that these preclinical findings translate to human populations, as exercise reduces withdrawal symptoms and relapse in abstinent smokers (Daniel et al., 2006; Prochaska et al., 2008), and one drug recovery program has seen success in participants that train for and compete in a marathon as part of the program (Butler, 2005). ... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some patients taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al., 2006; Aiken, 2007; Lader, 2008). 
  107. ^ a b c d e Lynch WJ, Peterson AB, Sanchez V, Abel J, Smith MA (September 2013). "Exercise as a novel treatment for drug addiction: a neurobiological and stage-dependent hypothesis". Neurosci. Biobehav. Rev. 37 (8): 1622–1644. doi:10.1016/j.neubiorev.2013.06.011. PMC 3788047free to read. PMID 23806439. These findings suggest that exercise may “magnitude”-dependently prevent the development of an addicted phenotype possibly by blocking/reversing behavioral and neuroadaptive changes that develop during and following extended access to the drug. ... Exercise has been proposed as a treatment for drug addiction that may reduce drug craving and risk of relapse. Although few clinical studies have investigated the efficacy of exercise for preventing relapse, the few studies that have been conducted generally report a reduction in drug craving and better treatment outcomes ... Taken together, these data suggest that the potential benefits of exercise during relapse, particularly for relapse to psychostimulants, may be mediated via chromatin remodeling and possibly lead to greater treatment outcomes. 
  108. ^ a b c Zhou Y, Zhao M, Zhou C, Li R (July 2015). "Sex differences in drug addiction and response to exercise intervention: From human to animal studies". Front. Neuroendocrinol. doi:10.1016/j.yfrne.2015.07.001. PMID 26182835. Collectively, these findings demonstrate that exercise may serve as a substitute or competition for drug abuse by changing ΔFosB or cFos immunoreactivity in the reward system to protect against later or previous drug use. ... As briefly reviewed above, a large number of human and rodent studies clearly show that there are sex differences in drug addiction and exercise. The sex differences are also found in the effectiveness of exercise on drug addiction prevention and treatment, as well as underlying neurobiological mechanisms. The postulate that exercise serves as an ideal intervention for drug addiction has been widely recognized and used in human and animal rehabilitation. ... In particular, more studies on the neurobiological mechanism of exercise and its roles in preventing and treating drug addiction are needed. 
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