Dextroamphetamine

Dextroamphetamine[note 1] is a central nervous system (CNS) stimulant and an amphetamine enantiomer[note 2] that is prescribed for the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy.[17][18] It is also used as an athletic performance and cognitive enhancer, and recreationally as an aphrodisiac and euphoriant. Dextroamphetamine was also used in the past by some countries' military forces to fight fatigue during extended combat operations.

For the racemate, see Amphetamine. For the prodrug marketed under the brand name Vyvanse, see Lisdexamfetamine.

Dextroamphetamine
INN: Dexamfetamine

Clinical data
Pronunciation	/ˌdɛkstroʊæmˈfɛtəmiːn/
Trade names	Dexedrine, DextroStat, Metamina, Attentin, Zenzedi, Procentra, Amfexa
Other names	D-Amphetamine
AHFS/Drugs.com	Monograph
MedlinePlus	a605027
License data	US FDA: Dextroamphetamine
Pregnancy category	AU: B3 US: C (Risk not ruled out)
Dependence liability	Moderate[1][2]
Addiction liability	High
Routes of administration	By mouth
ATC code	N06BA02 (WHO)
Legal status
Legal status	AU: S8 (Controlled drug) CA: Schedule I DE: Anlage III (Special prescription form required) UK: Class B US: Schedule II
Pharmacokinetic data
Bioavailability	Oral: 75–100%[3]
Protein binding	15–40%[4]
Metabolism	CYP2D6,[5] DBH,[6] FMO3[7]
Onset of action	IR dosing: 0.5–1.5 hours[8][9] XR dosing: 1.5–2 hours[10][11]
Elimination half-life	9–11 hours[5][12] pH-dependent: 7–34 hours[13]
Duration of action	IR dosing: 3–6 hours[10][14] XR dosing: 8–12 hours[2][10][14]
Excretion	Renal (45%);[15] urinary pH-dependent
Identifiers
IUPAC name (2S)-1-Phenylpropan-2-amine
CAS Number	51-64-9^Y
PubChem CID	5826
IUPHAR/BPS	2147
DrugBank	DB01576^Y
ChemSpider	5621^Y
UNII	TZ47U051FI
KEGG	D03740^Y
ChEBI	CHEBI:4469^Y
ChEMBL	ChEMBL612^Y
CompTox Dashboard (EPA)	DTXSID8022907
ECHA InfoCard	100.000.103
Chemical and physical data
Formula	C9H13N
Molar mass	135.210 g·mol^−1
3D model (JSmol)	Interactive image
Density	0.913 g/cm^3
Boiling point	201.5 °C (394.7 °F)
Solubility in water	20 mg/mL (20 °C)
SMILES C[C@@H](Cc1ccccc1)N
InChI InChI=InChI=1S/C9H13N/c1-8(10)7-9-5-3-2-4-6-9/h2-6,8H,7,10H2,1H3/t8-/m0/s1^N Key:KWTSXDURSIMDCE-QMMMGPOBSA-N^Y
^NY (what is this?)  (verify)

The amphetamine molecule exists as two enantiomers,[note 2] levoamphetamine and dextroamphetamine. Dextroamphetamine is the dextrorotatory, or 'right-handed', enantiomer and exhibits more pronounced effects on the central nervous system than levoamphetamine. 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 several distinct actions: it inhibits or reverses the transporter proteins for the monoamine neurotransmitters (namely the serotonin, norepinephrine and dopamine transporters) either via trace amine-associated receptor 1 (TAAR1) or in a TAAR1 independent fashion when there are high cytosolic concentrations of the monoamine neurotransmitters[20] and it releases these neurotransmitters from synaptic vesicles via vesicular monoamine transporter 2.[21] 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

Medical

Dexedrine IR tablets

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.[17][18] Long-term amphetamine exposure at sufficiently high doses in some animal species is known to produce abnormal dopamine system development or nerve damage,[22][23] but, in humans with ADHD, pharmaceutical amphetamines, at therapeutic dosages, appear to improve brain development and nerve growth.[24][25][26] 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.[24][25][26]

Reviews of clinical stimulant research have established the safety and effectiveness of long-term continuous amphetamine use for the treatment of ADHD.[27][28][29] Randomized controlled trials of continuous stimulant therapy for the treatment of ADHD spanning 2 years have demonstrated treatment effectiveness and safety.[27][28] Two reviews have indicated that long-term continuous stimulant therapy for ADHD is effective for reducing the core symptoms of ADHD (i.e., hyperactivity, inattention, and impulsivity), enhancing quality of life and academic achievement, and producing improvements in a large number of functional outcomes[note 3] across 9 categories of outcomes related to academics, antisocial behavior, driving, non-medicinal drug use, obesity, occupation, self-esteem, service use (i.e., academic, occupational, health, financial, and legal services), and social function.[27][29] One review highlighted a nine-month randomized controlled trial of amphetamine treatment for ADHD in children that found an average increase of 4.5 IQ points, continued increases in attention, and continued decreases in disruptive behaviors and hyperactivity.[28] Another review indicated that, based upon the longest follow-up studies conducted to date, lifetime stimulant therapy that begins during childhood is continuously effective for controlling ADHD symptoms and reduces the risk of developing a substance use disorder as an adult.[27]

Current models of ADHD suggest that it is associated with functional impairments in some of the brain's neurotransmitter systems;[30] these functional impairments involve impaired dopamine neurotransmission in the mesocorticolimbic projection and norepinephrine neurotransmission in the noradrenergic projections from the locus coeruleus to the prefrontal cortex.[30] Psychostimulants like methylphenidate and amphetamine are effective in treating ADHD because they increase neurotransmitter activity in these systems.[31][30][32] Approximately 80% of those who use these stimulants see improvements in ADHD symptoms.[33] 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.[34][35] The Cochrane reviews[note 4] on the treatment of ADHD in children, adolescents, and adults with pharmaceutical amphetamines stated that short-term studies have demonstrated that these drugs decrease the severity of symptoms, but they have higher discontinuation rates than non-stimulant medications due to their adverse side effects.[37][38] A Cochrane review on the treatment of ADHD in children with tic disorders such as Tourette syndrome indicated that stimulants in general do not make tics worse, but high doses of dextroamphetamine could exacerbate tics in some individuals.[39]

Enhancing performance

Cognitive performance

In 2015, a systematic review and a meta-analysis of high quality clinical trials found that, when used at low (therapeutic) doses, amphetamine produces modest yet unambiguous improvements in cognition, including working memory, long-term episodic memory, inhibitory control, and some aspects of attention, in normal healthy adults;[40][41] these cognition-enhancing effects of amphetamine are known to be partially mediated through the indirect activation of both dopamine receptor D₁ and adrenoceptor α₂ in the prefrontal cortex.[31][40] A systematic review from 2014 found that low doses of amphetamine also improve memory consolidation, in turn leading to improved recall of information.[42] Therapeutic doses of amphetamine also enhance cortical network efficiency, an effect which mediates improvements in working memory in all individuals.[31][43] Amphetamine and other ADHD stimulants also improve task saliency (motivation to perform a task) and increase arousal (wakefulness), in turn promoting goal-directed behavior.[31][44][45] 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.[31][45][46] Based upon studies of self-reported illicit stimulant use, 5–35% of college students use diverted ADHD stimulants, which are primarily used for enhancement of academic performance rather than as recreational drugs.[47][48][49] However, high amphetamine doses that are above the therapeutic range can interfere with working memory and other aspects of cognitive control.[31][45]

Physical performance

Amphetamine is used by some athletes for its psychological and athletic performance-enhancing effects, such as increased endurance and alertness;[50][51] however, non-medical amphetamine use is prohibited at sporting events that are regulated by collegiate, national, and international anti-doping agencies.[52][53] 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.[50][54][55] Amphetamine improves endurance and reaction time primarily through reuptake inhibition and release of dopamine in the central nervous system.[54][55][56] Amphetamine and other dopaminergic drugs also increase power output at fixed levels of perceived exertion by overriding a "safety switch", allowing the core temperature limit to increase in order to access a reserve capacity that is normally off-limits.[55][57][58] At therapeutic doses, the adverse effects of amphetamine do not impede athletic performance;[50][54] however, at much higher doses, amphetamine can induce effects that severely impair performance, such as rapid muscle breakdown and elevated body temperature.[59][54]

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. Dextroamphetamine is considered to have a high potential for misuse in a recreational manner since individuals typically report feeling euphoric, more alert, and more energetic after taking the drug.[60][61][62] Large recreational doses of dextroamphetamine may produce symptoms of dextroamphetamine overdose.[62] Recreational users sometimes open dexedrine capsules and crush the contents in order to insufflate it or subsequently dissolve it in water and inject it.[62] Injection into the bloodstream can be dangerous because insoluble fillers within the tablets can block small blood vessels.[62] Chronic overuse of dextroamphetamine can lead to severe drug dependence, resulting in withdrawal symptoms when drug use stops.[62]

Contraindications

According to the International Programme on Chemical Safety (IPCS) and the United States Food and Drug Administration (USFDA),[note 5] amphetamine is contraindicated in people with a history of drug abuse,[note 6] cardiovascular disease, severe agitation, or severe anxiety.[64][59][65] It is also contraindicated in individuals with advanced arteriosclerosis (hardening of the arteries), glaucoma (increased eye pressure), hyperthyroidism (excessive production of thyroid hormone), or moderate to severe hypertension.[64][59][65] These agencies indicate that people who have experienced allergic reactions to other stimulants or who are taking monoamine oxidase inhibitors (MAOIs) should not take amphetamine,[64][59][65] 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.[59][65] 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.[65] Amphetamine has also been shown to pass into breast milk, so the IPCS and the USFDA advise mothers to avoid breastfeeding when using it.[59][65] Due to the potential for reversible growth impairments,[note 7] the USFDA advises monitoring the height and weight of children and adolescents prescribed an amphetamine pharmaceutical.[59]

Adverse effects

Physical

Cardiovascular side effects can include hypertension or hypotension from a vasovagal response, Raynaud's phenomenon (reduced blood flow to the hands and feet), and tachycardia (increased heart rate).[59][51][68] Sexual side effects in males may include erectile dysfunction, frequent erections, or prolonged erections.[59] Gastrointestinal side effects may include abdominal pain, constipation, diarrhea, and nausea.[1][59][69] Other potential physical side effects include appetite loss, blurred vision, dry mouth, excessive grinding of the teeth, nosebleed, profuse sweating, rhinitis medicamentosa (drug-induced nasal congestion), reduced seizure threshold, tics (a type of movement disorder), and weight loss.[sources 1] Dangerous physical side effects are rare at typical pharmaceutical doses.[51]

Amphetamine stimulates the medullary respiratory centers, producing faster and deeper breaths.[51] In a normal person at therapeutic doses, this effect is usually not noticeable, but when respiration is already compromised, it may be evident.[51] Amphetamine also induces contraction in the urinary bladder sphincter, the muscle which controls urination, which can result in difficulty urinating.[51] This effect can be useful in treating bed wetting and loss of bladder control.[51] The effects of amphetamine on the gastrointestinal tract are unpredictable.[51] If intestinal activity is high, amphetamine may reduce gastrointestinal motility (the rate at which content moves through the digestive system);[51] however, amphetamine may increase motility when the smooth muscle of the tract is relaxed.[51] Amphetamine also has a slight analgesic effect and can enhance the pain relieving effects of opioids.[1][51]

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] However, amphetamine pharmaceuticals are contraindicated in individuals with cardiovascular disease.[sources 3]

Psychological

At normal therapeutic doses, the most common psychological side effects of amphetamine include increased alertness, apprehension, concentration, initiative, self-confidence and sociability, mood swings (elated mood followed by mildly depressed mood), insomnia or wakefulness, and decreased sense of fatigue.[59][51] Less common side effects include anxiety, change in libido, grandiosity, irritability, repetitive or obsessive behaviors, and restlessness;[sources 4] these effects depend on the user's personality and current mental state.[51] Amphetamine psychosis (e.g., delusions and paranoia) can occur in heavy users.[59][77][78] Although very rare, this psychosis can also occur at therapeutic doses during long-term therapy.[59][78][79] According to the USFDA, "there is no systematic evidence" that stimulants produce aggressive behavior or hostility.[59]

Amphetamine has also been shown to produce a conditioned place preference in humans taking therapeutic doses,[37][80] meaning that individuals acquire a preference for spending time in places where they have previously used amphetamine.[80][81]

Reinforcement disorders

Addiction

Addiction and dependence glossary[81][82][83][84]
addiction – a biopsychosocial disorder characterized by compulsively seeking to achieve a desired effect, such as intoxication, despite harm and adverse consequences to self and others 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 and desirable or as something to approach 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

Transcription factor glossary
gene expression – the process by which information from a gene is used in the synthesis of a functional gene product such as a protein transcription – the process of making messenger RNA (mRNA) from a DNA template by RNA polymerase transcription factor – a protein that binds to DNA and regulates gene expression by promoting or suppressing transcription transcriptional regulation – controlling the rate of gene transcription for example by helping or hindering RNA polymerase binding to DNA upregulation, activation, or promotion – increase the rate of gene transcription downregulation, repression, or suppression – decrease the rate of gene transcription coactivator – a protein that works with transcription factors to increase the rate of gene transcription corepressor – a protein that works with transcription factors to decrease the rate of gene transcription response element – a specific sequence of DNA that a transcription factor binds to

Signaling cascade in the nucleus accumbens that results in amphetamine addiction Note: colored text contains article links. Nuclear pore Nuclear membrane Plasma membrane Cav1.2 NMDAR AMPAR DRD1 DRD5 DRD2 DRD3 DRD4 Gs Gi/o AC cAMP cAMP PKA CaM CaMKII DARPP-32 PP1 PP2B CREB ΔFosB JunD c-Fos SIRT1 HDAC1 [Color legend 1] 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,[85][86] postsynaptic receptors for these neurotransmitters trigger internal signaling events through a cAMP-dependent pathway and a calcium-dependent pathway that ultimately result in increased CREB phosphorylation.[85][87][88] Phosphorylated CREB increases levels of ΔFosB, which in turn represses the c-Fos gene with the help of corepressors;[85][89][90] c-Fos repression acts as a molecular switch that enables the accumulation of ΔFosB in the neuron.[91] A highly stable (phosphorylated) form of ΔFosB, one that persists in neurons for 1–2 months, slowly accumulates following repeated high-dose exposure to stimulants through this process.[89][90] 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.[89][90]

Addiction is a serious risk with heavy recreational amphetamine use, but is unlikely to occur from long-term medical use at therapeutic doses;[27][92][93] in fact, lifetime stimulant therapy for ADHD that begins during childhood reduces the risk of developing substance use disorders as an adult.[27] 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.[94][95] Individuals who frequently self-administer high doses of amphetamine have a high risk of developing an amphetamine addiction, since chronic use at high doses gradually increase the level of accumbal ΔFosB, a "molecular switch" and "master control protein" for addiction.[82][96][97] 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.[96][98] 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.[99][100] Sustained aerobic exercise on a regular basis also appears to be an effective treatment for amphetamine addiction;[sources 5] exercise therapy improves clinical treatment outcomes and may be used as an adjunct therapy with behavioral therapies for addiction.[99][101]

Biomolecular mechanisms

Chronic use of amphetamine at excessive doses causes alterations in gene expression in the mesocorticolimbic projection, which arise through transcriptional and epigenetic mechanisms.[97][102][103] The most important transcription factors[note 8] that produce these alterations are Delta FBJ murine osteosarcoma viral oncogene homolog B (ΔFosB), cAMP response element binding protein (CREB), and nuclear factor-kappa B (NF-κB).[97] ΔFosB is the most significant biomolecular mechanism in addiction because ΔFosB overexpression (i.e., an abnormally high level of gene expression which produces a pronounced gene-related phenotype) in the D1-type medium spiny neurons in the nucleus accumbens is necessary and sufficient[note 9] for many of the neural adaptations and regulates multiple behavioral effects (e.g., reward sensitization and escalating drug self-administration) involved in addiction.[82][96][97] Once ΔFosB is sufficiently overexpressed, it induces an addictive state that becomes increasingly more severe with further increases in ΔFosB expression.[82][96] It has been implicated in addictions to alcohol, cannabinoids, cocaine, methylphenidate, nicotine, opioids, phencyclidine, propofol, and substituted amphetamines, among others.[sources 6]

ΔJunD, a transcription factor, and G9a, a histone methyltransferase enzyme, both oppose the function of ΔFosB and inhibit increases in its expression.[82][97][107] 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).[97] Similarly, accumbal G9a hyperexpression results in markedly increased histone 3 lysine residue 9 dimethylation (H3K9me2) and blocks the induction of ΔFosB-mediated neural and behavioral plasticity by chronic drug use,[sources 7] which occurs via H3K9me2-mediated repression of transcription factors for ΔFosB and H3K9me2-mediated repression of various ΔFosB transcriptional targets (e.g., CDK5).[97][107][108] ΔFosB also plays an important role in regulating behavioral responses to natural rewards, such as palatable food, sex, and exercise.[98][97][111] Since both natural rewards and addictive drugs induce the expression of ΔFosB (i.e., they cause the brain to produce more of it), chronic acquisition of these rewards can result in a similar pathological state of addiction.[98][97] Consequently, ΔFosB is the most significant factor involved in both amphetamine addiction and amphetamine-induced sexual addictions, which are compulsive sexual behaviors that result from excessive sexual activity and amphetamine use.[98][112][113] These sexual addictions are associated with a dopamine dysregulation syndrome which occurs in some patients taking dopaminergic drugs.[98][111]

The effects of amphetamine on gene regulation are both dose- and route-dependent.[103] Most of the research on gene regulation and addiction is based upon animal studies with intravenous amphetamine administration at very high doses.[103] 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.[103] This suggests that medical use of amphetamine does not significantly affect gene regulation.[103]

Pharmacological treatments

Further information: Addiction § Research

As of December 2019, there is no effective pharmacotherapy for amphetamine addiction.[114][115][116] Reviews from 2015 and 2016 indicated that TAAR1-selective agonists have significant therapeutic potential as a treatment for psychostimulant addictions;[117][118] however, as of February 2016, the only compounds which are known to function as TAAR1-selective agonists are experimental drugs.[117][118] Amphetamine addiction is largely mediated through increased activation of dopamine receptors and co-localized NMDA receptors[note 10] in the nucleus accumbens;[95] magnesium ions inhibit NMDA receptors by blocking the receptor calcium channel.[95][119] One review suggested that, based upon animal testing, pathological (addiction-inducing) psychostimulant use significantly reduces the level of intracellular magnesium throughout the brain.[95] Supplemental magnesium[note 11] 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.[95]

A systematic review and meta-analysis from 2019 assessed the efficacy of 17 different pharmacotherapies used in RCTs for amphetamine and methamphetamine addiction;[115] it found only low-strength evidence that methylphenidate might reduce amphetamine or methamphetamine self-administration.[115] There was low- to moderate-strength evidence of no benefit for most of the other medications used in RCTs, which included antidepressants (bupropion, mirtazapine, sertraline), antipsychotics (aripiprazole), anticonvulsants (topiramate, baclofen, gabapentin), naltrexone, varenicline, citicoline, ondansetron, prometa, riluzole, atomoxetine, dextroamphetamine, and modafinil.[115]

Behavioral treatments

A 2018 systematic review and network meta-analysis of 50 trials involving 12 different psychosocial interventions for amphetamine, methamphetamine, or cocaine addiction found that combination therapy with both contingency management and community reinforcement approach had the highest efficacy (i.e., abstinence rate) and acceptability (i.e., lowest dropout rate).[120] Other treatment modalities examined in the analysis included monotherapy with contingency management or community reinforcement approach, cognitive behavioral therapy, 12-step programs, non-contingent reward-based therapies, psychodynamic therapy, and other combination therapies involving these.[120]

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.[sources 5] Exercise leads to better treatment outcomes when used as an adjunct treatment, particularly for psychostimulant addictions.[99][101][121] 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.[98][121] This is the opposite of pathological stimulant use, which induces decreased striatal DRD2 density.[98] 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.[100]

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	↑	↑	↑	↑	↑	↑	[98]
Behavioral plasticity
Escalation of intake	Yes	Yes	Yes				[98]
Psychostimulant cross-sensitization	Yes	Not applicable	Yes	Yes	Attenuated	Attenuated	[98]
Psychostimulant self-administration	↑	↑	↓		↓	↓	[98]
Psychostimulant conditioned place preference	↑	↑	↓	↑	↓	↑	[98]
Reinstatement of drug-seeking behavior	↑	↑			↓	↓	[98]
Neurochemical plasticity
CREB phosphorylation in the nucleus accumbens	↓	↓	↓		↓	↓	[98]
Sensitized dopamine response in the nucleus accumbens	No	Yes	No	Yes			[98]
Altered striatal dopamine signaling	↓DRD2, ↑DRD3	↑DRD1, ↓DRD2, ↑DRD3	↑DRD1, ↓DRD2, ↑DRD3		↑DRD2	↑DRD2	[98]
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	[98]
Changes in striatal opioid peptides	↑dynorphin No change: enkephalin	↑dynorphin	↓enkephalin		↑dynorphin	↑dynorphin	[98]
Mesocorticolimbic synaptic plasticity
Number of dendrites in the nucleus accumbens	↓	↑		↑			[98]
Dendritic spine density in the nucleus accumbens	↓	↑		↑			[98]

Dependence and withdrawal

Drug tolerance develops rapidly in amphetamine abuse (i.e., recreational amphetamine use), so periods of extended abuse require increasingly larger doses of the drug in order to achieve the same effect.[122][123] According to a Cochrane review on withdrawal in individuals who compulsively use amphetamine and methamphetamine, "when chronic heavy users abruptly discontinue amphetamine use, many report a time-limited withdrawal syndrome that occurs within 24 hours of their last dose."[124] This review noted that withdrawal symptoms in chronic, high-dose users are frequent, occurring in roughly 88% of cases, and persist for 3–4 weeks with a marked "crash" phase occurring during the first week.[124] 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.[124] The review indicated that the severity of withdrawal symptoms is positively correlated with the age of the individual and the extent of their dependence.[124] Mild withdrawal symptoms from the discontinuation of amphetamine treatment at therapeutic doses can be avoided by tapering the dose.[1]

Overdose

An amphetamine overdose can lead to many different symptoms, but is rarely fatal with appropriate care.[1][65][125] The severity of overdose symptoms increases with dosage and decreases with drug tolerance to amphetamine.[51][65] 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.[65] Symptoms of a moderate and extremely large overdose are listed below; fatal amphetamine poisoning usually also involves convulsions and coma.[59][51] 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 12][126]

Overdose symptoms by system

System	Minor or moderate overdose[59][51][65]	Severe overdose[sources 8]
Cardiovascular	Abnormal heartbeat High or low blood pressure	Cardiogenic shock (heart not pumping enough blood) Cerebral hemorrhage (bleeding in the brain) Circulatory collapse (partial or complete failure of the circulatory system)
Central nervous system	Confusion Abnormally fast reflexes Severe agitation Tremor (involuntary muscle twitching)	Acute amphetamine psychosis (e.g., delusions and paranoia) Compulsive and repetitive movement Serotonin syndrome (excessive serotonergic nerve activity) Sympathomimetic toxidrome (excessive adrenergic nerve activity)
Musculoskeletal	Muscle pain	Rhabdomyolysis (rapid muscle breakdown)
Respiratory	Rapid breathing	Pulmonary edema (fluid accumulation in the lungs) Pulmonary hypertension (high blood pressure in the arteries of the lung) Respiratory alkalosis (reduced blood CO2)
Urinary	Painful urination Urinary retention (inability to urinate)	No urine production Kidney failure
Other	Elevated body temperature Mydriasis (dilated pupils)	Elevated or low blood potassium Hyperpyrexia (extremely elevated core body temperature) Metabolic acidosis (excessively acidic bodily fluids)

Toxicity

In rodents and primates, sufficiently high doses of amphetamine cause dopaminergic neurotoxicity, or damage to dopamine neurons, which is characterized by dopamine terminal degeneration and reduced transporter and receptor function.[129][130] There is no evidence that amphetamine is directly neurotoxic in humans.[131][132] However, large doses of amphetamine may indirectly cause dopaminergic neurotoxicity as a result of hyperpyrexia, the excessive formation of reactive oxygen species, and increased autoxidation of dopamine.[sources 9] Animal models of neurotoxicity from high-dose amphetamine exposure indicate that the occurrence of hyperpyrexia (i.e., core body temperature ≥ 40 °C) is necessary for the development of amphetamine-induced neurotoxicity.[130] Prolonged elevations of brain temperature above 40 °C likely promote the development of amphetamine-induced neurotoxicity in laboratory animals by facilitating the production of reactive oxygen species, disrupting cellular protein function, and transiently increasing blood–brain barrier permeability.[130]

Psychosis

See also: Stimulant psychosis

An amphetamine overdose can result in a stimulant psychosis that may involve a variety of symptoms, such as delusions and paranoia.[77][78] A Cochrane review on treatment for amphetamine, dextroamphetamine, and methamphetamine psychosis states that about 5–15% of users fail to recover completely.[77][135] 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 rarely arises from therapeutic use.[59][78][79]

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][136] 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.[7][136] Amphetamine also interacts with MAOIs, particularly monoamine oxidase A inhibitors, since both MAOIs and amphetamine increase plasma catecholamines (i.e., norepinephrine and dopamine);[136] therefore, concurrent use of both is dangerous.[136] 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.[136] Amphetamine may also decrease the effects of antihypertensives and antipsychotics due to its effects on blood pressure and dopamine respectively.[136] Zinc supplementation may reduce the minimum effective dose of amphetamine when it is used for the treatment of ADHD.[note 13][140]

Pharmacology

Pharmacodynamics

Main section: Amphetamine § Pharmacodynamics

Pharmacodynamics of amphetamine in a dopamine neuron via AADC Amphetamine enters the presynaptic neuron across the neuronal membrane or through DAT.[20] Once inside, it binds to TAAR1 or enters synaptic vesicles through VMAT2.[20][21] When amphetamine enters synaptic vesicles through VMAT2, it collapses the vesicular pH gradient, which in turn causes dopamine to be released into the cytosol (light tan-colored area) through VMAT2.[21][141] When amphetamine binds to TAAR1, it reduces the firing rate of the dopamine neuron via potassium channels and activates protein kinase A (PKA) and protein kinase C (PKC), which subsequently phosphorylate DAT.[20][142][143] PKA-phosphorylation causes DAT to withdraw into the presynaptic neuron (internalize) and cease transport.[20] PKC-phosphorylated DAT may either operate in reverse or, like PKA-phosphorylated DAT, internalize and cease transport.[20] 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.[144][145]

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.[146][147] 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).[20][146][148] Amphetamine enantiomers are also substrates for a specific neuronal synaptic vesicle uptake transporter called VMAT2.[21] When amphetamine is taken up by VMAT2, the vesicle releases (effluxes) dopamine, norepinephrine, and serotonin, among other monoamines, into the cytosol in exchange.[21]

Dextroamphetamine (the dextrorotary enantiomer) and levoamphetamine (the levorotary enantiomer) have identical pharmacodynamics, but their binding affinities to their biomolecular targets vary.[147][149] Dextroamphetamine is a more potent agonist of TAAR1 than levoamphetamine.[147] Consequently, dextroamphetamine produces roughly three to four times more central nervous system (CNS) stimulation than levoamphetamine;[147][149] however, levoamphetamine has slightly greater cardiovascular and peripheral effects.[149]

Related endogenous compounds

Further information on related compounds: Trace amine

Amphetamine has a very similar structure and function to the endogenous trace amines, which are naturally occurring neuromodulator molecules produced in the human body and brain.[20][150][151] 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).[20][150][152] 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.[150][152] In turn, N-methylphenethylamine is metabolized from phenethylamine by phenylethanolamine N-methyltransferase, the same enzyme that metabolizes norepinephrine into epinephrine.[150][152] Like amphetamine, both phenethylamine and N-methylphenethylamine regulate monoamine neurotransmission via TAAR1;[20][151][152] unlike amphetamine, both of these substances are broken down by monoamine oxidase B, and therefore have a shorter half-life than amphetamine.[150][152]

Pharmacokinetics

The oral bioavailability of amphetamine varies with gastrointestinal pH;[59] it is well absorbed from the gut, and bioavailability is typically over 75% for dextroamphetamine.[153] Amphetamine is a weak base with a pK_a 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][59] 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] Following absorption, amphetamine readily distributes into most tissues in the body, with high concentrations occurring in cerebrospinal fluid and brain tissue.[13]

The half-lives 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] Highly acidic urine will reduce the enantiomer half-lives to 7 hours;[13] highly alkaline urine will increase the half-lives up to 34 hours.[13] 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] Following oral administration, amphetamine appears in urine within 3 hours.[13] Roughly 90% of ingested amphetamine is eliminated 3 days after the last oral dose.[13]

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 10] Amphetamine has a variety of excreted metabolic products, including 4-hydroxyamphetamine, 4-hydroxynorephedrine, 4-hydroxyphenylacetone, benzoic acid, hippuric acid, norephedrine, and phenylacetone.[5][154] Among these metabolites, the active sympathomimetics are 4-hydroxyamphetamine,[155] 4-hydroxynorephedrine,[156] and norephedrine.[157] The main metabolic pathways involve aromatic para-hydroxylation, aliphatic alpha- and beta-hydroxylation, N-oxidation, N-dealkylation, and deamination.[5][158] The known metabolic pathways, detectable metabolites, and metabolizing enzymes in humans include the following:

Metabolic pathways of amphetamine in humans[sources 10] 4-Hydroxyphenylacetone Phenylacetone Benzoic acid Hippuric acid Amphetamine Norephedrine 4-Hydroxyamphetamine 4-Hydroxynorephedrine Para- Hydroxylation Para- Hydroxylation Para- Hydroxylation CYP2D6 CYP2D6 unidentified Beta- Hydroxylation Beta- Hydroxylation DBH DBH [note 14] Oxidative Deamination FMO3 Oxidation unidentified Glycine Conjugation XM-ligase GLYAT The primary active metabolites of amphetamine are 4-hydroxyamphetamine and norephedrine;[154] 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, which is then metabolized by GLYAT into hippuric acid.[163]

History, society, and culture

Racemic amphetamine was first synthesized under the chemical name "phenylisopropylamine" in Berlin, 1887 by the Romanian chemist Lazar Edeleanu. 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 15] 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.[167] In the United States, Dexedrine was approved to treat narcolepsy, attention disorders, and obesity. In Canada indications once included epilepsy and parkinsonism.[168] 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").[169] Preparations containing dextroamphetamine were also used in World War II as a treatment against fatigue.[170]

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.[171] 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).[172] It became popular on the mod scene in England in the early 1960s, and carried through to the Northern Soul scene in the north of England to the end of the 1970s.

In October 2010, GlaxoSmithKline sold the rights for Dexedrine Spansule to Amedra Pharmaceuticals (a subsidiary of CorePharma).[173]

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".[174][175][176][177] 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.[175]

Formulations

Dextroamphetamine pharmaceuticals and prodrugs[note 16]

Brand name	United States Adopted Name	(D:L) ratio	Dosage form	Marketing start date	US consumer price data	Sources
Adderall	–	3:1 (salts)	tablet	1996	GoodRx	[18][186]
Adderall XR	–	3:1 (salts)	capsule	2001	GoodRx	[18][186]
Mydayis	–	3:1 (salts)	capsule	2017	GoodRx	[187]
Adzenys XR-ODT	amphetamine	3:1 (base)	ODT	2016	GoodRx	[188][189]
Dyanavel XR	amphetamine	3.2:1 (base)	suspension	2015	GoodRx	[69][190]
Evekeo	amphetamine sulfate	1:1 (salts)	tablet	2012	GoodRx	[64] [191]
Dexedrine	dextroamphetamine sulfate	1:0 (salts)	capsule	1976	GoodRx	[18][186]
Zenzedi	dextroamphetamine sulfate	1:0 (salts)	tablet	2013	GoodRx	[186]
Vyvanse	lisdexamfetamine dimesylate	1:0 (prodrug)	capsule	2007	GoodRx	[18][192]
			tablet

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.[193] 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.[194] The conversion rate between dextroamphetamine sulfate to amphetamine free base is .728.[195]

In Australia, dexamphetamine is available in bottles of 100 instant release 5 mg tablets as a generic drug.[196] or slow release dextroamphetamine preparations may be compounded by individual chemists.[197] In the United Kingdom, it is available in 5 mg instant release sulfate tablets under the generic name dexamfetamine sulfate as well as 10 mg and 20 mg strength tablets under the brand name Amfexa. It is also available in generic dexamfetamine sulfate 5 mg/ml oral sugar-free syrup.[198] The brand name Dexedrine was available in the United Kingdom prior to UCB Pharma disinvesting the product to another pharmaceutical company (Auden Mckenzie).[199]

Lisdexamfetamine

Main article: Lisdexamfetamine

Dextroamphetamine is the active metabolite of the prodrug lisdexamfetamine (L-lysine-dextroamphetamine), available by the brand name Vyvanse (Elvanse in the European market) (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.[200][201] 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 chewable tablets, and in seven strengths; 10 mg, 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%.[202][203][204]

Adderall

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%.[205] 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 17]

Amphetamine base in marketed amphetamine medications

drug		formula	molecular mass [note 18]		amphetamine base [note 19]			amphetamine base in equal doses		doses with equal base content [note 20]
			(g/mol)		(percent)			(30 mg dose)
			total	base	total	dextro-	levo-	dextro-	levo-
dextroamphetamine sulfate[207][208]		(C9H13N)2•H2SO4	368.49	270.41	73.38%	73.38%	—	22.0 mg	—	30.0 mg
amphetamine sulfate[209]		(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[207][208]	(C9H13N)2•H2SO4	368.49	270.41	73.38%	73.38%	—
25%	amphetamine sulfate[209]	(C9H13N)2•H2SO4	368.49	270.41	73.38%	36.69%	36.69%
25%	dextroamphetamine saccharate[210]	(C9H13N)2•C6H10O8	480.55	270.41	56.27%	56.27%	—
25%	amphetamine aspartate monohydrate[211]	(C9H13N)•C4H7NO4•H2O	286.32	135.21	47.22%	23.61%	23.61%
lisdexamfetamine dimesylate[192]		C15H25N3O•(CH4O3S)2	455.49	135.21	29.68%	29.68%	—	8.9 mg	—	74.2 mg
amphetamine base suspension[note 21][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: (2S)-1-phenylpropan-2-amine (IUPAC name), dexamfetamine (INN),[16] dexamphetamine, (S)-amphetamine, (+)-amphetamine, and D-amphetamine.
2. Enantiomers are molecules that are mirror images of one another; they are structurally identical, but of the opposite orientation.[19]
3. The ADHD-related outcome domains with the greatest proportion of significantly improved outcomes from long-term continuous stimulant therapy include academics (≈55% of academic outcomes improved), driving (100% of driving outcomes improved), non-medical drug use (47% of addiction-related outcomes improved), obesity (≈65% of obesity-related outcomes improved), self-esteem (50% of self-esteem outcomes improved), and social function (67% of social function outcomes improved).[29]
   
   The largest effect sizes for outcome improvements from long-term stimulant therapy occur in the domains involving academics (e.g., grade point average, achievement test scores, length of education, and education level), self-esteem (e.g., self-esteem questionnaire assessments, number of suicide attempts, and suicide rates), and social function (e.g., peer nomination scores, social skills, and quality of peer, family, and romantic relationships).[29]
   
   Long-term combination therapy for ADHD (i.e., treatment with both a stimulant and behavioral therapy) produces even larger effect sizes for outcome improvements and improves a larger proportion of outcomes across each domain compared to long-term stimulant therapy alone.[29]
4. Cochrane reviews are high quality meta-analytic systematic reviews of randomized controlled trials.[36]
5. 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.[63]
6. 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.[18]
7. 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.[27][28][68] The average reduction in final adult height from 3 years of continuous stimulant therapy is 2 cm.[68]
8. Transcription factors are proteins that increase or decrease the expression of specific genes.[104]
9. 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.
10. 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.[119]
11. The review indicated that magnesium L-aspartate and magnesium chloride produce significant changes in addictive behavior;[95] other forms of magnesium were not mentioned.
12. The 95% confidence interval indicates that there is a 95% probability that the true number of deaths lies between 3,425 and 4,145.
13. 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.[137][138][139] The human serotonin transporter and norepinephrine transporter do not contain zinc binding sites.[139]
14. 4-Hydroxyamphetamine has been shown to be metabolized into 4-hydroxynorephedrine by dopamine beta-hydroxylase (DBH) in vitro and it is presumed to be metabolized similarly in vivo.[159][162] Evidence from studies that measured the effect of serum DBH concentrations on 4-hydroxyamphetamine metabolism in humans suggests that a different enzyme may mediate the conversion of 4-hydroxyamphetamine to 4-hydroxynorephedrine;[162][164] however, other evidence from animal studies suggests that this reaction is catalyzed by DBH in synaptic vesicles within noradrenergic neurons in the brain.[165][166]
15. Free-base form amphetamine is a volatile oil, hence the efficacy of the inhalers.
16. 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;[178][179] Dexedrine listed here represents the extended release "Spansule" capsule which was approved in 1976.[180][181] Amphetamine sulfate tablets, now sold as Evekeo (brand), were originally sold as Benzedrine (brand) sulfate in 1935[182][183] and discontinued sometime after 1982.[184][185]
17. 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.
18. For uniformity, molecular masses were calculated using the Lenntech Molecular Weight Calculator[206] and were within 0.01g/mol of published pharmaceutical values.
19. Amphetamine base percentage = molecular mass_base / molecular mass_total. Amphetamine base percentage for Adderall = sum of component percentages / 4.
20. dose = (1 / amphetamine base percentage) × scaling factor = (molecular mass_total / molecular mass_base) × scaling factor. The values in this column were scaled to a 30 mg dose of dextroamphetamine sulfate. 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.
21. 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]

Image legend

1.   Ion channel
     G proteins & linked receptors
     (Text color) Transcription factors

Reference notes

1. [1][59][51][68][69][70]
2. [71][72][73][74]
3. [59][65][71][73]
4. [75][59][51][76]
5. [98][99][100][101][121]
6. [96][98][97][105][106]
7. [97][108][109][110]
8. [127][59][51][125][128]
9. [22][130][133][134]
10. [5][159][160][7][161][154][162][163]

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    Dexedrine spansules [Peak:7–8 h] [Duration:12 h] ...
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    Vyvanse [Peak:3–4 h] [Duration:12 h]
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25. Spencer TJ, Brown A, Seidman LJ, Valera EM, Makris N, Lomedico A, Faraone SV, Biederman J (September 2013). "Effect of psychostimulants on brain structure and function in ADHD: a qualitative literature review of magnetic resonance imaging-based neuroimaging studies". The Journal of Clinical Psychiatry. 74 (9): 902–917. doi:10.4088/JCP.12r08287. PMC 3801446. PMID 24107764.
26. Frodl T, Skokauskas N (February 2012). "Meta-analysis of structural MRI studies in children and adults with attention deficit hyperactivity disorder indicates treatment effects". Acta Psychiatrica Scandinavica. 125 (2): 114–126. doi:10.1111/j.1600-0447.2011.01786.x. PMID 22118249. Basal ganglia regions like the right globus pallidus, the right putamen, and the nucleus caudatus are structurally affected in children with ADHD. These changes and alterations in limbic regions like ACC and amygdala are more pronounced in non-treated populations and seem to diminish over time from child to adulthood. Treatment seems to have positive effects on brain structure.
27. Huang YS, Tsai MH (July 2011). "Long-term outcomes with medications for attention-deficit hyperactivity disorder: current status of knowledge". CNS Drugs. 25 (7): 539–554. doi:10.2165/11589380-000000000-00000. PMID 21699268. Several other studies,^[97-101] including a meta-analytic review^[98] and a retrospective study,^[97] suggested that stimulant therapy in childhood is associated with a reduced risk of subsequent substance use, cigarette smoking and alcohol use disorders. ... Recent studies have demonstrated that stimulants, along with the non-stimulants atomoxetine and extended-release guanfacine, are continuously effective for more than 2-year treatment periods with few and tolerable adverse effects. The effectiveness of long-term therapy includes not only the core symptoms of ADHD, but also improved quality of life and academic achievements. The most concerning short-term adverse effects of stimulants, such as elevated blood pressure and heart rate, waned in long-term follow-up studies. ... The current data do not support the potential impact of stimulants on the worsening or development of tics or substance abuse into adulthood. In the longest follow-up study (of more than 10 years), lifetime stimulant treatment for ADHD was effective and protective against the development of adverse psychiatric disorders.
28. Millichap JG (2010). "Chapter 9: Medications for ADHD". In Millichap JG (ed.). Attention Deficit Hyperactivity Disorder Handbook: A Physician's Guide to ADHD (2nd ed.). New York, USA: Springer. pp. 121–123, 125–127. ISBN 9781441913968. Ongoing research has provided answers to many of the parents' concerns, and has confirmed the effectiveness and safety of the long-term use of medication.
29. Arnold LE, Hodgkins P, Caci H, Kahle J, Young S (February 2015). "Effect of treatment modality on long-term outcomes in attention-deficit/hyperactivity disorder: a systematic review". PLOS ONE. 10 (2): e0116407. doi:10.1371/journal.pone.0116407. PMC 4340791. PMID 25714373. The highest proportion of improved outcomes was reported with combination treatment (83% of outcomes). Among significantly improved outcomes, the largest effect sizes were found for combination treatment. The greatest improvements were associated with academic, self-esteem, or social function outcomes.
    Figure 3: Treatment benefit by treatment type and outcome group
30. Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York, USA: McGraw-Hill Medical. pp. 154–157. ISBN 9780071481274.
31. Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 13: Higher Cognitive Function and Behavioral Control". In Sydor A, Brown RY (eds.). 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.
32. Bidwell LC, McClernon FJ, Kollins SH (August 2011). "Cognitive enhancers for the treatment of ADHD". Pharmacology Biochemistry and Behavior. 99 (2): 262–274. doi:10.1016/j.pbb.2011.05.002. PMC 3353150. PMID 21596055.
33. Parker J, Wales G, Chalhoub N, Harpin V (September 2013). "The long-term outcomes of interventions for the management of attention-deficit hyperactivity disorder in children and adolescents: a systematic review of randomized controlled trials". Psychology Research and Behavior Management. 6: 87–99. doi:10.2147/PRBM.S49114. PMC 3785407. PMID 24082796. Only one paper⁵³ examining outcomes beyond 36 months met the review criteria. ... There is high level evidence suggesting that pharmacological treatment can have a major beneficial effect on the core symptoms of ADHD (hyperactivity, inattention, and impulsivity) in approximately 80% of cases compared with placebo controls, in the short term.
34. Millichap JG (2010). "Chapter 9: Medications for ADHD". In Millichap JG (ed.). Attention Deficit Hyperactivity Disorder Handbook: A Physician's Guide to ADHD (2nd ed.). New York, USA: Springer. pp. 111–113. ISBN 9781441913968.
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38. Punja S, Shamseer L, Hartling L, Urichuk L, Vandermeer B, Nikles J, Vohra S (February 2016). "Amphetamines for attention deficit hyperactivity disorder (ADHD) in children and adolescents". Cochrane Database of Systematic Reviews. 2: CD009996. doi:10.1002/14651858.CD009996.pub2. PMID 26844979.
39. Osland ST, Steeves TD, Pringsheim T (June 2018). "Pharmacological treatment for attention deficit hyperactivity disorder (ADHD) in children with comorbid tic disorders". Cochrane Database of Systematic Reviews. 6: CD007990. doi:10.1002/14651858.CD007990.pub3. PMC 6513283. PMID 29944175.
40. Spencer RC, Devilbiss DM, Berridge CW (June 2015). "The Cognition-Enhancing Effects of Psychostimulants Involve Direct Action in the Prefrontal Cortex". Biological Psychiatry. 77 (11): 940–950. doi:10.1016/j.biopsych.2014.09.013. PMC 4377121. PMID 25499957. The procognitive actions of psychostimulants are only associated with low doses. Surprisingly, despite nearly 80 years of clinical use, the neurobiology of the procognitive actions of psychostimulants has only recently been systematically investigated. Findings from this research unambiguously demonstrate that the cognition-enhancing effects of psychostimulants involve the preferential elevation of catecholamines in the PFC and the subsequent activation of norepinephrine α2 and dopamine D1 receptors. ... This differential modulation of PFC-dependent processes across dose appears to be associated with the differential involvement of noradrenergic α2 versus α1 receptors. Collectively, this evidence indicates that at low, clinically relevant doses, psychostimulants are devoid of the behavioral and neurochemical actions that define this class of drugs and instead act largely as cognitive enhancers (improving PFC-dependent function). ... In particular, in both animals and humans, lower doses maximally improve performance in tests of working memory and response inhibition, whereas maximal suppression of overt behavior and facilitation of attentional processes occurs at higher doses.
41. Ilieva IP, Hook CJ, Farah MJ (June 2015). "Prescription Stimulants' Effects on Healthy Inhibitory Control, Working Memory, and Episodic Memory: A Meta-analysis". Journal of Cognitive Neuroscience. 27 (6): 1069–1089. doi:10.1162/jocn_a_00776. PMID 25591060. Specifically, in a set of experiments limited to high-quality designs, we found significant enhancement of several cognitive abilities. ... The results of this meta-analysis ... do confirm the reality of cognitive enhancing effects for normal healthy adults in general, while also indicating that these effects are modest in size.
42. Bagot KS, Kaminer Y (April 2014). "Efficacy of stimulants for cognitive enhancement in non-attention deficit hyperactivity disorder youth: a systematic review". Addiction. 109 (4): 547–557. doi:10.1111/add.12460. PMC 4471173. PMID 24749160. Amphetamine has been shown to improve consolidation of information (0.02 ≥ P ≤ 0.05), leading to improved recall.
43. Devous MD, Trivedi MH, Rush AJ (April 2001). "Regional cerebral blood flow response to oral amphetamine challenge in healthy volunteers". Journal of Nuclear Medicine. 42 (4): 535–542. PMID 11337538.
44. Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 10: Neural and Neuroendocrine Control of the Internal Milieu". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York, USA: McGraw-Hill Medical. p. 266. ISBN 9780071481274. Dopamine acts in the nucleus accumbens to attach motivational significance to stimuli associated with reward.
45. Wood S, Sage JR, Shuman T, Anagnostaras SG (January 2014). "Psychostimulants and cognition: a continuum of behavioral and cognitive activation". Pharmacological Reviews. 66 (1): 193–221. doi:10.1124/pr.112.007054. PMC 3880463. PMID 24344115.
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47. Teter CJ, McCabe SE, LaGrange K, Cranford JA, Boyd CJ (October 2006). "Illicit use of specific prescription stimulants among college students: prevalence, motives, and routes of administration". Pharmacotherapy. 26 (10): 1501–1510. doi:10.1592/phco.26.10.1501. PMC 1794223. PMID 16999660.
48. Weyandt LL, Oster DR, Marraccini ME, Gudmundsdottir BG, Munro BA, Zavras BM, Kuhar B (September 2014). "Pharmacological interventions for adolescents and adults with ADHD: stimulant and nonstimulant medications and misuse of prescription stimulants". Psychology Research and Behavior Management. 7: 223–249. doi:10.2147/PRBM.S47013. PMC 4164338. PMID 25228824. misuse of prescription stimulants has become a serious problem on college campuses across the US and has been recently documented in other countries as well. ... Indeed, large numbers of students claim to have engaged in the nonmedical use of prescription stimulants, which is reflected in lifetime prevalence rates of prescription stimulant misuse ranging from 5% to nearly 34% of students.
49. Clemow DB, Walker DJ (September 2014). "The potential for misuse and abuse of medications in ADHD: a review". Postgraduate Medicine. 126 (5): 64–81. doi:10.3810/pgm.2014.09.2801. PMID 25295651. Overall, the data suggest that ADHD medication misuse and diversion are common health care problems for stimulant medications, with the prevalence believed to be approximately 5% to 10% of high school students and 5% to 35% of college students, depending on the study.
50. Liddle DG, Connor DJ (June 2013). "Nutritional supplements and ergogenic AIDS". Primary Care: Clinics in Office Practice. 40 (2): 487–505. doi:10.1016/j.pop.2013.02.009. PMID 23668655. Amphetamines and caffeine are stimulants that increase alertness, improve focus, decrease reaction time, and delay fatigue, allowing for an increased intensity and duration of training ...
    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
51. Westfall DP, Westfall TC (2010). "Miscellaneous Sympathomimetic Agonists". In Brunton LL, Chabner BA, Knollmann BC (eds.). Goodman & Gilman's Pharmacological Basis of Therapeutics (12th ed.). New York, USA: McGraw-Hill. ISBN 9780071624428.
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54. Parr JW (July 2011). "Attention-deficit hyperactivity disorder and the athlete: new advances and understanding". Clinics in Sports Medicine. 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.
55. Roelands B, de Koning J, Foster C, Hettinga F, Meeusen R (May 2013). "Neurophysiological determinants of theoretical concepts and mechanisms involved in pacing". Sports Medicine. 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.
56. Parker KL, Lamichhane D, Caetano MS, Narayanan NS (October 2013). "Executive dysfunction in Parkinson's disease and timing deficits". Frontiers in Integrative Neuroscience. 7: 75. doi:10.3389/fnint.2013.00075. PMC 3813949. 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.
57. 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?". Frontiers in Physiology. 6: 79. doi:10.3389/fphys.2015.00079. PMC 4362407. 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)
58. Roelands B, De Pauw K, Meeusen R (June 2015). "Neurophysiological effects of exercise in the heat". Scandinavian Journal of Medicine & Science in Sports. 25 (Suppl 1): 65–78. doi:10.1111/sms.12350. PMID 25943657. 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.
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78. Bramness JG, Gundersen ØH, Guterstam J, Rognli EB, Konstenius M, Løberg EM, Medhus S, Tanum L, Franck J (December 2012). "Amphetamine-induced psychosis—a separate diagnostic entity or primary psychosis triggered in the vulnerable?". BMC Psychiatry. 12: 221. doi:10.1186/1471-244X-12-221. PMC 3554477. PMID 23216941. In these studies, amphetamine was given in consecutively higher doses until psychosis was precipitated, often after 100–300 mg of amphetamine ... Secondly, psychosis has been viewed as an adverse event, although rare, in children with ADHD who have been treated with amphetamine
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80. Childs E, de Wit H (May 2009). "Amphetamine-induced place preference in humans". Biological Psychiatry. 65 (10): 900–904. doi:10.1016/j.biopsych.2008.11.016. PMC 2693956. PMID 19111278. This study demonstrates that humans, like nonhumans, prefer a place associated with amphetamine administration. These findings support the idea that subjective responses to a drug contribute to its ability to establish place conditioning.
81. Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and Addictive Disorders". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 364–375. ISBN 9780071481274.
82. Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues in Clinical Neuroscience. 15 (4): 431–443. PMC 3898681. PMID 24459410. Despite the importance of numerous psychosocial factors, at its core, drug addiction involves a biological process: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. ... A large body of literature has demonstrated that such ΔFosB induction in D1-type [nucleus accumbens] neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement ... Another ΔFosB target is cFos: as ΔFosB accumulates with repeated drug exposure it represses c-Fos and contributes to the molecular switch whereby ΔFosB is selectively induced in the chronic drug-treated state.⁴¹. ... Moreover, there is increasing evidence that, despite a range of genetic risks for addiction across the population, exposure to sufficiently high doses of a drug for long periods of time can transform someone who has relatively lower genetic loading into an addict.
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    Addiction: A term used to indicate the most severe, chronic stage of substance-use disorder, in which there is a substantial loss of self-control, as indicated by compulsive drug taking despite the desire to stop taking the drug. In the DSM-5, the term addiction is synonymous with the classification of severe substance-use disorder.
85. Renthal W, Nestler EJ (September 2009). "Chromatin regulation in drug addiction and depression". Dialogues in Clinical Neuroscience. 11 (3): 257–268. PMC 2834246. PMID 19877494. [Psychostimulants] increase cAMP levels in striatum, which activates protein kinase A (PKA) and leads to phosphorylation of its targets. This includes the cAMP response element binding protein (CREB), the phosphorylation of which induces its association with the histone acetyltransferase, CREB binding protein (CBP) to acetylate histones and facilitate gene activation. This is known to occur on many genes including fosB and c-fos in response to psychostimulant exposure. ΔFosB is also upregulated by chronic psychostimulant treatments, and is known to activate certain genes (eg, cdk5) and repress others (eg, c-fos) where it recruits HDAC1 as a corepressor. ... Chronic exposure to psychostimulants increases glutamatergic [signaling] from the prefrontal cortex to the NAc. Glutamatergic signaling elevates Ca2+ levels in NAc postsynaptic elements where it activates CaMK (calcium/calmodulin protein kinases) signaling, which, in addition to phosphorylating CREB, also phosphorylates HDAC5.
    Figure 2: Psychostimulant-induced signaling events
86. Broussard JI (January 2012). "Co-transmission of dopamine and glutamate". The Journal of General Physiology. 139 (1): 93–96. doi:10.1085/jgp.201110659. PMC 3250102. PMID 22200950. Coincident and convergent input often induces plasticity on a postsynaptic neuron. The NAc integrates processed information about the environment from basolateral amygdala, hippocampus, and prefrontal cortex (PFC), as well as projections from midbrain dopamine neurons. Previous studies have demonstrated how dopamine modulates this integrative process. For example, high frequency stimulation potentiates hippocampal inputs to the NAc while simultaneously depressing PFC synapses (Goto and Grace, 2005). The converse was also shown to be true; stimulation at PFC potentiates PFC–NAc synapses but depresses hippocampal–NAc synapses. In light of the new functional evidence of midbrain dopamine/glutamate co-transmission (references above), new experiments of NAc function will have to test whether midbrain glutamatergic inputs bias or filter either limbic or cortical inputs to guide goal-directed behavior.
87. Kanehisa Laboratories (10 October 2014). "Amphetamine – Homo sapiens (human)". KEGG Pathway. Retrieved 31 October 2014. Most addictive drugs increase extracellular concentrations of dopamine (DA) in nucleus accumbens (NAc) and medial prefrontal cortex (mPFC), projection areas of mesocorticolimbic DA neurons and key components of the "brain reward circuit". Amphetamine achieves this elevation in extracellular levels of DA by promoting efflux from synaptic terminals. ... Chronic exposure to amphetamine induces a unique transcription factor delta FosB, which plays an essential role in long-term adaptive changes in the brain.
88. Cadet JL, Brannock C, Jayanthi S, Krasnova IN (2015). "Transcriptional and epigenetic substrates of methamphetamine addiction and withdrawal: evidence from a long-access self-administration model in the rat". Molecular Neurobiology. 51 (2): 696–717. doi:10.1007/s12035-014-8776-8. PMC 4359351. PMID 24939695. Figure 1
89. Robison AJ, Nestler EJ (November 2011). "Transcriptional and epigenetic mechanisms of addiction". Nature Reviews Neuroscience. 12 (11): 623–637. doi:10.1038/nrn3111. PMC 3272277. PMID 21989194. ΔFosB serves as one of the master control proteins governing this structural plasticity. ... ΔFosB also represses G9a expression, leading to reduced repressive histone methylation at the cdk5 gene. The net result is gene activation and increased CDK5 expression. ... In contrast, ΔFosB binds to the c-fos gene and recruits several co-repressors, including HDAC1 (histone deacetylase 1) and SIRT 1 (sirtuin 1). ... The net result is c-fos gene repression.
    Figure 4: Epigenetic basis of drug regulation of gene expression
90. Nestler EJ (December 2012). "Transcriptional mechanisms of drug addiction". Clinical Psychopharmacology and Neuroscience. 10 (3): 136–143. doi:10.9758/cpn.2012.10.3.136. PMC 3569166. PMID 23430970. The 35-37 kD ΔFosB isoforms accumulate with chronic drug exposure due to their extraordinarily long half-lives. ... As a result of its stability, the ΔFosB protein persists in neurons for at least several weeks after cessation of drug exposure. ... ΔFosB overexpression in nucleus accumbens induces NFκB ... In contrast, the ability of ΔFosB to repress the c-Fos gene occurs in concert with the recruitment of a histone deacetylase and presumably several other repressive proteins such as a repressive histone methyltransferase
91. Nestler EJ (October 2008). "Transcriptional mechanisms of addiction: Role of ΔFosB". Philosophical Transactions of the Royal Society B: Biological Sciences. 363 (1507): 3245–3255. doi:10.1098/rstb.2008.0067. PMC 2607320. PMID 18640924. Recent evidence has shown that ΔFosB also represses the c-fos gene that helps create the molecular switch—from the induction of several short-lived Fos family proteins after acute drug exposure to the predominant accumulation of ΔFosB after chronic drug exposure
92. Malenka RC, Nestler EJ, Hyman SE, Holtzman DM (2015). "Chapter 16: Reinforcement and Addictive Disorders". Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (3rd ed.). New York: McGraw-Hill Medical. ISBN 9780071827706. 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.
93. Kollins SH (May 2008). "A qualitative review of issues arising in the use of psycho-stimulant medications in patients with ADHD and co-morbid substance use disorders". Current Medical Research and Opinion. 24 (5): 1345–1357. doi:10.1185/030079908X280707. PMID 18384709. When oral formulations of psychostimulants are used at recommended doses and frequencies, they are unlikely to yield effects consistent with abuse potential in patients with ADHD.
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96. Ruffle JK (November 2014). "Molecular neurobiology of addiction: what's all the (Δ)FosB about?". The American Journal of Drug and Alcohol Abuse. 40 (6): 428–437. doi:10.3109/00952990.2014.933840. PMID 25083822. ΔFosB is an essential transcription factor implicated in the molecular and behavioral pathways of addiction following repeated drug exposure.
97. Robison AJ, Nestler EJ (November 2011). "Transcriptional and epigenetic mechanisms of addiction". Nature Reviews Neuroscience. 12 (11): 623–637. doi:10.1038/nrn3111. PMC 3272277. PMID 21989194. ΔFosB has been linked directly to several addiction-related behaviors ... Importantly, genetic or viral overexpression of ΔJunD, a dominant negative mutant of JunD which antagonizes ΔFosB- and other AP-1-mediated transcriptional activity, in the NAc or OFC blocks these key effects of drug exposure^14,22–24. This indicates that ΔFosB is both necessary and sufficient for many of the changes wrought in the brain by chronic drug exposure. ΔFosB is also induced in D1-type NAc MSNs by chronic consumption of several natural rewards, including sucrose, high fat food, sex, wheel running, where it promotes that consumption^14,26–30. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states. ... ΔFosB serves as one of the master control proteins governing this structural plasticity.
98. 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 3139704. 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).
99. 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". Neuroscience & Biobehavioral Reviews. 37 (8): 1622–1644. doi:10.1016/j.neubiorev.2013.06.011. PMC 3788047. 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.
100. 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". Frontiers in Neuroendocrinology. 40: 24–41. doi:10.1016/j.yfrne.2015.07.001. PMC 4712120. 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. ... The postulate that exercise serves as an ideal intervention for drug addiction has been widely recognized and used in human and animal rehabilitation.
101. Linke SE, Ussher M (January 2015). "Exercise-based treatments for substance use disorders: evidence, theory, and practicality". The American Journal of Drug and Alcohol Abuse. 41 (1): 7–15. doi:10.3109/00952990.2014.976708. PMC 4831948. PMID 25397661. The limited research conducted suggests that exercise may be an effective adjunctive treatment for SUDs. In contrast to the scarce intervention trials to date, a relative abundance of literature on the theoretical and practical reasons supporting the investigation of this topic has been published. ... numerous theoretical and practical reasons support exercise-based treatments for SUDs, including psychological, behavioral, neurobiological, nearly universal safety profile, and overall positive health effects.
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External links

• Dextroamphetamine consumer information from Drugs.com
• Poison Information Monograph (PIM 178: Dexamphetamine Sulphate)