Lisdexamfetamine

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Not to be confused with Levoamphetamine.
Lisdexamfetamine
Lisdexamfetamine structure.svg
Lisdexamfetamine ball-and-stick model.png
Systematic (IUPAC) name
(2S)-2,6-diamino-N-[(2S)-1-phenylpropan-2-yl]hexanamide
Clinical data
Trade names Tyvense, Elvanse, Venvanse, Vyvanse
AHFS/Drugs.com Monograph
MedlinePlus a607047
License data
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
Dependence
liability
Physical: none
Psychological: moderate
Addiction
liability
Moderate
Routes of
administration
Oral (capsules)
Legal status
Legal status
Pharmacokinetic data
Bioavailability 96.4%[1]
Metabolism Hydrolysis by enzymes in red blood cells initially.
Subsequent metabolism follows Amphetamine#Pharmacokinetics.
Onset of action 2 hours[2][3]
Biological half-life ≤1 hour (prodrug molecule)
9–11 hours (dextroamphetamine)
Duration of action 12 hours[2][3]
Excretion Renal: ~2%
Identifiers
CAS Number 608137-32-2 YesY[IUPHAR]
ATC code N06BA12 (WHO)
PubChem CID 11597698
IUPHAR/BPS 7213
DrugBank DB01255 YesY
ChemSpider 9772458 YesY
UNII H645GUL8KJ YesY
ChEMBL CHEMBL1201222 YesY
Synonyms Vyvanse
Chemical data
Formula C15H25N3O
Molar mass 263.378 g/mol
 NYesY (what is this?)  (verify)
30mg Vyvanse capsules

Lisdexamfetamine (contracted from L-lysine-dextroamphetamine) is a central nervous system (CNS) stimulant and dextroamphetamine prodrug of the phenethylamine class and amphetamine class that is used in the treatment of attention deficit hyperactivity disorder (ADHD) and binge eating disorder.[4][5] Its chemical structure consists of dextroamphetamine coupled with the essential amino acid L-lysine. Lisdexamfetamine itself is inactive and acts as a prodrug to dextroamphetamine upon cleavage of the lysine portion of the molecule.

Lisdexamfetamine can be prescribed for the treatment of attention deficit hyperactivity disorder (ADHD) in children aged 6 and up as well as adults. The safety and the efficacy of lisdexamfetamine dimesylate in children three to five years old have not been established.[6]

Lisdexamfetamine is a Class B/Schedule II substance in the United Kingdom and a Schedule II controlled substance in the United States (DEA number 1205)[7] and the aggregate production quota for 2016 in the United States is 29,750 kilograms of anhydrous acid or base.[8] Lisdexamfetamine is currently in Phase III trials in Japan for ADHD.[9]

Uses[edit]

Medical[edit]

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

Lisdexamfetamine is used primarily as a treatment for attention deficit hyperactivity disorder (ADHD) and binge eating disorder;[4] it has similar off-label uses as those of other pharmaceutical amphetamines.[4][5] Long-term amphetamine exposure at sufficiently high doses in some animal species is known to produce abnormal dopamine system development or nerve damage,[10][11] but, in humans with ADHD, pharmaceutical amphetamines appear to improve brain development and nerve growth.[12][13][14] 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.[12][13][14]

Reviews of clinical stimulant research have established the safety and effectiveness of long-term amphetamine use for ADHD.[15][16][17] Controlled trials spanning two years have demonstrated treatment effectiveness and safety.[15][17] 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.[15]

Current models of ADHD suggest that it is associated with functional impairments in some of the brain's neurotransmitter systems;[18] these functional impairments involve impaired dopamine neurotransmission in the mesocorticolimbic projection and norepinephrine neurotransmission in the locus coeruleus and prefrontal cortex.[18] Psychostimulants like methylphenidate and amphetamine are effective in treating ADHD because they increase neurotransmitter activity in these systems.[19][18][20] Approximately 80% of those who use these stimulants see improvements in ADHD symptoms.[21] 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.[22][23] The Cochrane Collaboration's reviews[note 1] 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.[25][26] 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.[27]

Individuals over the age of 65 were not commonly tested in clinical trials of lisdexamfetamine for ADHD.[4] Lisdexamfetamine is being investigated for possible treatment of cognitive impairment associated with schizophrenia and excessive daytime sleepiness.[28]

Performance-enhancing[edit]

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

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;[29][30] 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.[19][29] A systematic review from 2014 noted that low doses of amphetamine also improve memory consolidation, in turn leading to improved recall of information.[31] Therapeutic doses of amphetamine also enhance cortical network efficiency, an effect which mediates improvements in working memory in all individuals.[19][32] Amphetamine and other ADHD stimulants also improve task saliency (motivation to perform a task) and increase arousal (wakefulness), in turn promoting goal-directed behavior.[19][33][34] 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.[19][34][35] 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.[36][37][38] However, high amphetamine doses that are above the therapeutic range can interfere with working memory and other aspects of cognitive control.[19][34]

Amphetamine is used by some athletes for its psychological and athletic performance-enhancing effects, such as increased endurance and alertness;[39][40] however, non-medical amphetamine use is prohibited at sporting events that are regulated by collegiate, national, and international anti-doping agencies.[41][42] 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.[39][43][44] Amphetamine improves endurance and reaction time primarily through reuptake inhibition and effluxion of dopamine in the central nervous system.[43][44][45] 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.[44][46][47] At therapeutic doses, the adverse effects of amphetamine do not impede athletic performance;[39][43] however, at much higher doses, amphetamine can induce effects that severely impair performance, such as rapid muscle breakdown and elevated body temperature.[48][49][43]

Available forms[edit]

Vyvanse capsules are available in doses of 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, and 70 mg of the active ingredient, lisdexamfetamine dimesylate.[50] Vyvanse capsules contain several inactive ingredients, including microcrystalline cellulose, croscarmellose sodium, and magnesium stearate.[50] The capsule shells contain gelatin and titanium dioxide, and may contain FD&C Red 3, FD&C Yellow 6, FD&C Blue 1, black iron oxide, and yellow iron oxide.[50]

Contraindications[edit]

Pharmaceutical lisdexamfetamine dimesylate is contraindicated in patients with hypersensitivity to amphetamine products or any of the formulation's inactive ingredients.[4] It is also contraindicated in patients who have used a monoamine oxidase inhibitor (MAOI) within the last 14 days.[4][51] Amphetamine products are contraindicated by the United States Food and Drug Administration (USFDA) in people with a history of drug abuse, heart disease, or severe agitation or anxiety, or in those currently experiencing arteriosclerosis, glaucoma, hyperthyroidism, or severe hypertension.[52] The USFDA advises anyone with bipolar disorder, depression, elevated blood pressure, liver or kidney problems, mania, psychosis, Raynaud's phenomenon, seizures, thyroid problems, tics, or Tourette syndrome to monitor their symptoms while taking amphetamine.[52] Amphetamine is classified in US pregnancy category C.[52] This means that detriments to the fetus have been observed in animal studies and adequate human studies have not been conducted; amphetamine may still be prescribed to pregnant women if the potential benefits outweigh the risks.[53] Amphetamine has also been shown to pass into breast milk, so the USFDA advises mothers to avoid breastfeeding when using it.[52] Due to the potential for stunted growth, the USFDA advises monitoring the height and weight of children and adolescents prescribed amphetamines.[52] Prescribing information approved by the Australian Therapeutic Goods Administration further contraindicates anorexia.[54]

Side effects[edit]

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

Products containing lisdexamfetamine have a side effect profile comparable to those containing amphetamine.[4][48][49]

Physical

At normal therapeutic doses, the physical side effects of amphetamine vary widely by age and from person to person.[49] 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).[49][40][55] Sexual side effects in males may include erectile dysfunction, frequent erections, or prolonged erections.[49] Abdominal side effects may include abdominal pain, appetite loss, nausea, and weight loss.[49][56] 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 1] 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 2]

Psychological

Common psychological effects of therapeutic doses can include increased alertness, apprehension, concentration, decreased sense of fatigue, mood swings (elated mood followed by mildly depressed mood), increased initiative, insomnia or wakefulness, self-confidence, and sociability.[49][40] Less common side effects include anxiety, change in libido, grandiosity, irritability, repetitive or obsessive behaviors, and restlessness;[sources 3] these effects depend on the user's personality and current mental state.[40] Amphetamine psychosis (e.g., delusions and paranoia) can occur in heavy users.[48][49][64] Although very rare, this psychosis can also occur at therapeutic doses during long-term therapy.[48][49][65] According to the USFDA, "there is no systematic evidence" that stimulants produce aggressive behavior or hostility.[49]

Amphetamine has also been shown to produce a conditioned place preference in humans taking therapeutic doses,[25][66] meaning that individuals acquire a preference for spending time in places where they have previously used amphetamine.[66][67]

Overdose[edit]

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

An amphetamine overdose can lead to many different symptoms, but is rarely fatal with appropriate care.[51][68] The severity of overdose symptoms increases with dosage and decreases with drug tolerance to amphetamine.[40][51] 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.[51] Symptoms of a moderate and extremely large overdose are listed below; fatal amphetamine poisoning usually also involves convulsions and coma.[48][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 2][69]

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.[70][71] 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.[72][73][74] 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.[72][75] 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.[76][77] Sustained aerobic exercise on a regular basis also appears to be an effective treatment for amphetamine addiction;[75][76][78] 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.[76][78][79]

Overdose symptoms by system
System Minor or moderate overdose[48][40][51] Severe overdose[sources 4]
Cardiovascular
Central nervous
system
Musculoskeletal
Respiratory
  • Rapid breathing
Urinary
Other

Addiction

Addiction and dependence glossary[67][73][82][83]
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)

Addiction is a serious risk with heavy recreational amphetamine use but is unlikely to arise from typical long-term medical use at therapeutic doses.[84][85][86] Compared to other amphetamine pharmaceuticals, lisdexamfetamine may have a lower liability for abuse as a recreational drug.[87] 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.[88][89]

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.[90][91][92] The most important transcription factors[note 3] that produce these alterations are ΔFosB, cAMP response element binding protein (CREB), and nuclear factor kappa B (NF-κB).[91] 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 4] for most of the behavioral and neural adaptations that arise from addiction.[72][73][91] Once ΔFosB is sufficiently overexpressed, it induces an addictive state that becomes increasingly more severe with further increases in ΔFosB expression.[72][73] It has been implicated in addictions to alcohol, cannabinoids, cocaine, methylphenidate, nicotine, opioids, phencyclidine, propofol, and substituted amphetamines, among others.[sources 5]

ΔJunD, a transcription factor, and G9a, a histone methyltransferase enzyme, both directly oppose the induction of ΔFosB in the nucleus accumbens (i.e., they oppose increases in its expression).[73][91][96] 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).[91] ΔFosB also plays an important role in regulating behavioral responses to natural rewards, such as palatable food, sex, and exercise.[75][91][97] 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.[75][91] 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.[75][98][99] These sex addictions are associated with a dopamine dysregulation syndrome which occurs in some patients taking dopaminergic drugs.[75][97]

The effects of amphetamine on gene regulation are both dose- and route-dependent.[92] Most of the research on gene regulation and addiction is based upon animal studies with intravenous amphetamine administration at very high doses.[92] 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.[92] This suggests that medical use of amphetamine does not significantly affect gene regulation.[92]

Pharmacological treatments

Further information: Addiction § Research

As of May 2014, there is no effective pharmacotherapy for amphetamine addiction.[100][101][102] Reviews from 2015 and 2016 indicated that TAAR1-selective agonists have significant therapeutic potential as a treatment for psychostimulant addictions;[103][104] however, as of February 2016, the only compounds which are known to function as TAAR1-selective agonists are experimental drugs.[103][104] Amphetamine addiction is largely mediated through increased activation of dopamine receptors and co-localized NMDA receptors[note 5] in the nucleus accumbens;[71] magnesium ions inhibit NMDA receptors by blocking the receptor calcium channel.[71][105] One review suggested that, based upon animal testing, pathological (addiction-inducing) psychostimulant use significantly reduces the level of intracellular magnesium throughout the brain.[71] Supplemental magnesium[note 6] 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.[71]

Behavioral treatments

Cognitive behavioral therapy is currently the most effective clinical treatment for psychostimulant addictions.[79] 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.[76][77][78] Exercise leads to better treatment outcomes when used as an adjunct treatment, particularly for psychostimulant addictions.[76][78] 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.[75] This is the opposite of pathological stimulant use, which induces decreased striatal DRD2 density.[75] 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.[77]

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
[75]
Behavioral plasticity
Escalation of intake Yes Yes Yes [75]
Psychostimulant
cross-sensitization
Yes Not applicable Yes Yes Attenuated Attenuated [75]
Psychostimulant
self-administration
[75]
Psychostimulant
conditioned place preference
[75]
Reinstatement of drug-seeking behavior [75]
Neurochemical plasticity
CREB phosphorylation
in the nucleus accumbens
[75]
Sensitized dopamine response
in the nucleus accumbens
No Yes No Yes [75]
Altered striatal dopamine signaling DRD2, ↑DRD3 DRD1, ↓DRD2, ↑DRD3 DRD1, ↓DRD2, ↑DRD3 DRD2 DRD2 [75]
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 [75]
Changes in striatal opioid peptides dynorphin
No change: enkephalin
dynorphin enkephalin dynorphin dynorphin [75]
Mesocorticolimbic synaptic plasticity
Number of dendrites in the nucleus accumbens [75]
Dendritic spine density in
the nucleus accumbens
[75]

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."[106] 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.[106] 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.[106] The review indicated that withdrawal symptoms are associated with the degree of dependence, suggesting that therapeutic use would result in far milder discontinuation symptoms.[106] Manufacturer prescribing information does not indicate the presence of withdrawal symptoms following discontinuation of amphetamine use after an extended period at therapeutic doses.[107][108][109]

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.[110] There is no evidence that amphetamine is directly neurotoxic in humans.[111][112] However, large doses of amphetamine may cause indirect neurotoxicity as a result of increased oxidative stress from reactive oxygen species and autoxidation of dopamine.[10][113][114]

A severe amphetamine overdose can result in a stimulant psychosis that may involve a variety of symptoms, such as paranoia and delusions.[64] A Cochrane Collaboration review on treatment for amphetamine, dextroamphetamine, and methamphetamine psychosis states that about 5–15% of users fail to recover completely.[64][115] According to the same review, there is at least one trial that shows antipsychotic medications effectively resolve the symptoms of acute amphetamine psychosis.[64] Psychosis very rarely arises from therapeutic use.[65][52]

Interactions[edit]

  • Acidifying Agents: Drugs that acidify the urine, such as ascorbic acid, increase urinary excretion of dextroamphetamine, thus decreasing the half-life of dextroamphetamine in the body.[4][116]
  • Alkalinizing Agents: Drugs that alkalinize the urine, such as sodium bicarbonate, decrease urinary excretion of dextroamphetamine, thus increasing the half-life of dextroamphetamine in the body.[4][116]
  • Monoamine Oxidase Inhibitors: Concomitant use of MAOIs and central nervous system stimulants such as lisdexamfetamine can cause a hypertensive crisis.[4]

Pharmacology[edit]

The main section for this topic is on the page Amphetamine, in the section Pharmacology.

Mechanism of action[edit]

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

Lisdexamfetamine is an inactive prodrug that is converted in the body to dextroamphetamine, a pharmacologically active compound which is responsible for the drug’s activity.[117] After oral ingestion, lisdexamfetamine is broken down by enzymes in red blood cells to form L-lysine, a naturally occurring essential amino acid, and dextroamphetamine.[4] The conversion of lisdexamfetamine to dextroamphetamine is not affected by gastrointestinal pH and is unlikely to be affected by alterations in normal gastrointestinal transit times.[4][118]

The optical isomers of amphetamine, i.e., dextroamphetamine and levoamphetamine, are TAAR1 agonists and vesicular monoamine transporter 2 inhibitors that can enter monoamine neurons;[119][120] this allows them to release monoamine neurotransmitters (dopamine, norepinephrine, and serotonin, among others) from their storage sites and the presynaptic neuron, as well as prevent the reuptake of these neurotransmitters from the synaptic cleft.[119][120]

Lisdexamfetamine was developed with the goal of providing a long duration of effect that is consistent throughout the day, with reduced potential for abuse. The attachment of the amino acid lysine slows down the relative amount of dextroamphetamine available to the blood stream. Because no free dextroamphetamine is present in lisdexamfetamine capsules, dextroamphetamine does not become available through mechanical manipulation, such as crushing or simple extraction. A relatively sophisticated biochemical process is needed to produce dextroamphetamine from lisdexamfetamine.[118] As opposed to Adderall, which contains roughly equal parts of racemic amphetamine and dextroamphetamine salts, lisdexamfetamine is a single-enantiomer dextroamphetamine formula.[117][121] Studies conducted show that lisdexamfetamine dimesylate may have less abuse potential than dextroamphetamine and an abuse profile similar to diethylpropion at dosages that are FDA-approved for treatment of ADHD, but still has a high abuse potential when this dosage is exceeded by over 100%.[118]

Pharmacokinetics[edit]

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

The oral bioavailability of amphetamine varies with gastrointestinal pH;[116] it is well absorbed from the gut, and bioavailability is typically over 75% for dextroamphetamine.[122] Amphetamine is a weak base with a pKa of 9.9;[123] 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.[123][116] Conversely, an acidic pH means the drug is predominantly in a water-soluble cationic (salt) form, and less is absorbed.[123] Approximately 15–40% of amphetamine circulating in the bloodstream is bound to plasma proteins.[124]

The half-life of amphetamine enantiomers differ and vary with urine pH.[123] At normal urine pH, the half-lives of dextroamphetamine and levoamphetamine are 9–11 hours and 11–14 hours, respectively.[123] An acidic diet will reduce the enantiomer half-lives to 8–11 hours; an alkaline diet will increase the range to 16–31 hours.[125][126] The biological half-life is longer and distribution volumes are larger in amphetamine dependent individuals.[126] 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.[123] Amphetamine is eliminated via the kidneys, with 30–40% of the drug being excreted unchanged at normal urinary pH.[123] When the urinary pH is basic, amphetamine is in its free base form, so less is excreted.[123] 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.[123] Amphetamine is usually eliminated within two days of the last oral dose.[125] 

The prodrug lisdexamfetamine is not as sensitive to pH as amphetamine when being absorbed in the gastrointestinal tract;[127] following absorption into the blood stream, it is converted by red blood cell-associated enzymes to dextroamphetamine via hydrolysis.[127] The elimination half-life of lisdexamfetamine is generally less than one hour.[127]

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 6] Amphetamine has a variety of excreted metabolic products, including 4-hydroxyamphetamine, 4-hydroxynorephedrine, 4-hydroxyphenylacetone, benzoic acid, hippuric acid, norephedrine, and phenylacetone.[123][125][133] Among these metabolites, the active sympathomimetics are 4‑hydroxyamphetamine,[136] 4‑hydroxynorephedrine,[137] and norephedrine.[138] The main metabolic pathways involve aromatic para-hydroxylation, aliphatic alpha- and beta-hydroxylation, N-oxidation, N-dealkylation, and deamination.[123][125] The known metabolic pathways, detectable metabolites, and metabolizing enzymes in humans include the following:

Metabolic pathways of amphetamine in humans[sources 6]
Graphic of several routes of amphetamine metabolism
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;[133] at normal urine pH, about 30–40% of amphetamine is excreted unchanged and roughly 50% is excreted as the inactive metabolites (bottom row).[123] The remaining 10–20% is excreted as the active metabolites.[123] Benzoic acid is metabolized by XM-ligase into an intermediate product, benzoyl-CoA,[134] which is then metabolized by GLYAT into hippuric acid.[135]

Chemistry[edit]

Lisdexamfetamine dimesylate is a water-soluble (792 mg/mL) powder with a white to off-white color.[50]

Comparison to other formulations[edit]

Lisdexamfetamine dimesylate is one marketed formulation delivering dextroamphetamine. The following table compares the drug to other amphetamine pharmaceuticals.

Amphetamine base in marketed amphetamine medications
drug formula molecular mass
[note 7]
amphetamine base
[note 8]
amphetamine base
in equal doses
doses with
equal base
content
[note 9]
(g/mol) (percent) (30 mg dose)
total base total dextro- levo- dextro- levo-
dextroamphetamine sulfate[140][141] (C9H13N)2•H2SO4
368.49
270.41
73.38%
73.38%
22.0 mg
30.0 mg
amphetamine sulfate[142] (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[140][141] (C9H13N)2•H2SO4
368.49
270.41
73.38%
73.38%
25% amphetamine sulfate[142] (C9H13N)2•H2SO4
368.49
270.41
73.38%
36.69%
36.69%
25% dextroamphetamine saccharate[143] (C9H13N)2•C6H10O8
480.55
270.41
56.27%
56.27%
25% amphetamine aspartate monohydrate[144] (C9H13N)•C4H7NO4•H2O
286.32
135.21
47.22%
23.61%
23.61%
lisdexamfetamine dimesylate[145] C15H25N3O•(CH4O3S)2
455.49
135.21
29.68%
29.68%
8.9 mg
74.2 mg
amphetamine base suspension[note 10][56] C9H13N
135.21
135.21
100%
76.19%
23.81%
22.9 mg
7.1 mg
22.0 mg

History, society, and culture[edit]

Lisdexamfetamine was developed by New River Pharmaceuticals, who were bought by Shire Pharmaceuticals shortly before lisdexamfetamine began being marketed. It was developed for the intention of creating a longer-lasting and less-easily abused version of dextroamphetamine, as the requirement of conversion into dextroamphetamine via enzymes in the red blood cells increases its duration of action, regardless of the route of ingestion.[146] The drug lisdexamfetamine dimesylate is the first prodrug of its kind.

On 23 April 2008, Vyvanse received FDA approval for the adult population.[147] On 19 February 2009, Health Canada approved 30 mg and 50 mg capsules of lisdexamfetamine for treatment of ADHD.[148] On 8 February 2012, Vyvanse received FDA approval for maintenance treatment of adult ADHD.[149] In February 2014, Shire announced that two late-stage clinical trials had shown that Vyvanse was not an effective treatment for depression.[150] Lisdexamfetamine was granted approval in a number of European countries for the treatment of ADHD in children and adolescents over the age of 6 years, as well as adults who are continuing treatment from childhood, after a positive outcome of the regulatory procedure.[151] Shire also recently announced receipt of a positive result from a European decentralised procedure for lisdexamfetamine for adult patients with ADHD in the United Kingdom, Sweden and Denmark, expanding the indication of lisdexamfetamine to include newly diagnosed adult patients.[152]

In January 2015, lisdexamfetamine was approved by the U.S. Food and Drug Administration for treatment of binge eating disorder in adults.[28][153][154]

Brand names[edit]

Lisdexamfetamine is sold as Tyvense (IE), Elvanse (UK), Venvanse (BR), Vyvanse (CA, US).[155]

Clinical research[edit]

Some clinical trials that used lisdexamfetamine as an add-on therapy with a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) for treatment-resistant depression indicated that this is no more effective than the use of an SSRI or SNRI alone.[156] Other studies indicated that psychostimulants potentiated antidepressants, and were under-prescribed for treatment resistant depression. In those studies patients showed significant improvement in energy mood.[157]

Notes[edit]

  1. ^ Cochrane Collaboration reviews are high quality meta-analytic systematic reviews of randomized controlled trials.[24]
  2. ^ The 95% confidence interval indicates that there is a 95% probability that the true number of deaths lies between 3,425 and 4,145.
  3. ^ Transcription factors are proteins that increase or decrease the expression of specific genes.[93]
  4. ^ 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.
  5. ^ 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.[105]
  6. ^ The review indicated that magnesium L-aspartate and magnesium chloride produce significant changes in addictive behavior;[71] other forms of magnesium were not mentioned.
  7. ^ For uniformity, molecular masses were calculated using the Lenntech Molecular Weight Calculator[139] and were within 0.01g/mol of published pharmaceutical values.
  8. ^ Amphetamine base percentage = molecular massbase / molecular masstotal. Amphetamine base percentage for Adderall = sum of component percentages / 4.
  9. ^ 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.
  10. ^ 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.[56] The amphetamine base contains dextro- to levo-amphetamine in a ratio of 3.2:1,[56] which is approximately the ratio in Adderall. The product uses an ion exchange resin to achieve extended release of the amphetamine base.[56]

Reference notes[edit]

References[edit]

  1. ^ "Public Assessment Report Decentralised Procedure" (PDF). Shire Pharmaceuticals Contracts Limited. p. 14. Retrieved 23 August 2014. 
  2. ^ a b Millichap JG (2010). "Chapter 9: Medications for ADHD". In Millichap JG. Attention Deficit Hyperactivity Disorder Handbook: A Physician's Guide to ADHD (2nd ed.). New York, USA: Springer. p. 112. ISBN 9781441913968.
    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]
     
  3. ^ a b Brams M, Mao AR, Doyle RL (September 2008). "Onset of efficacy of long-acting psychostimulants in pediatric attention-deficit/hyperactivity disorder". Postgrad. Med. 120 (3): 69–88. doi:10.3810/pgm.2008.09.1909. PMID 18824827. Onset of efficacy was earliest for d-MPH-ER at 0.5 hours, followed by d, l-MPH-LA at 1 to 2 hours, MCD at 1.5 hours, d, l-MPH-OR at 1 to 2 hours, MAS-XR at 1.5 to 2 hours, MTS at 2 hours, and LDX at approximately 2 hours. ... MAS-XR, and LDX have a long duration of action at 12 hours postdose 
  4. ^ a b c d e f g h i j k l "Vyvanse Prescribing Information" (PDF). United States Food and Drug Administration. Shire US Inc. January 2015. Retrieved 24 February 2015. 
  5. ^ a b 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. 
  6. ^ "Lisdexamfetamine dimesylate (generic)." Brown University Psychopharmacology Update 19.7 (2008): 1–2. Academic Search Premier. EBSCO. Web. 12 September 2010.
  7. ^ "DEA – Department of Justice" (PDF). DEA – Department of Justice. Retrieved 1 July 2014. 
  8. ^ "DEA Office of Diversion Control" (PDF). DEA. Retrieved 1 July 2014. 
  9. ^ "Phase-III clinical trials in Attention-deficit hyperactivity disorder (In children, In adolescents) in Japan (PO)". Retrieved 20 March 2016. 
  10. ^ a b Carvalho M, Carmo H, Costa VM, Capela JP, Pontes H, Remião F, Carvalho F, Bastos Mde L (August 2012). "Toxicity of amphetamines: an update". Arch. Toxicol. 86 (8): 1167–1231. doi:10.1007/s00204-012-0815-5. PMID 22392347. 
  11. ^ Berman S, O'Neill J, Fears S, Bartzokis G, London ED (October 2008). "Abuse of amphetamines and structural abnormalities in the brain". Ann. N. Y. Acad. Sci. 1141: 195–220. doi:10.1196/annals.1441.031. PMC 2769923free to read. PMID 18991959. 
  12. ^ a b Hart H, Radua J, Nakao T, Mataix-Cols D, Rubia K (February 2013). "Meta-analysis of functional magnetic resonance imaging studies of inhibition and attention in attention-deficit/hyperactivity disorder: exploring task-specific, stimulant medication, and age effects". JAMA Psychiatry. 70 (2): 185–198. doi:10.1001/jamapsychiatry.2013.277. PMID 23247506. 
  13. ^ a b 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". J. Clin. Psychiatry. 74 (9): 902–917. doi:10.4088/JCP.12r08287. PMC 3801446free to read. PMID 24107764. 
  14. ^ a b 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 Scand. 125 (2): 114–126. doi:10.1111/j.1600-0447.2011.01786.x. PMID 22118249. 
  15. ^ a b c Millichap JG (2010). "Chapter 9: Medications for ADHD". In Millichap JG. 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. 
  16. ^ 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 4340791free to read. 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. 
  17. ^ a b 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. 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. 
  18. ^ a b c Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York, USA: McGraw-Hill Medical. pp. 154–157. ISBN 9780071481274. 
  19. ^ a b c d e f 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.
     
  20. ^ Bidwell LC, McClernon FJ, Kollins SH (August 2011). "Cognitive enhancers for the treatment of ADHD". Pharmacol. Biochem. Behav. 99 (2): 262–274. doi:10.1016/j.pbb.2011.05.002. PMC 3353150free to read. PMID 21596055. 
  21. ^ 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". Psychol. Res. Behav. Manag. 6: 87–99. doi:10.2147/PRBM.S49114. PMC 3785407free to read. 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. 
  22. ^ Millichap JG (2010). "Chapter 9: Medications for ADHD". In Millichap JG. Attention Deficit Hyperactivity Disorder Handbook: A Physician's Guide to ADHD (2nd ed.). New York, USA: Springer. pp. 111–113. ISBN 9781441913968. 
  23. ^ "Stimulants for Attention Deficit Hyperactivity Disorder". WebMD. Healthwise. 12 April 2010. Retrieved 12 November 2013. 
  24. ^ Scholten RJ, Clarke M, Hetherington J (August 2005). "The Cochrane Collaboration". Eur. J. Clin. Nutr. 59 Suppl 1: S147–S149; discussion S195–S196. doi:10.1038/sj.ejcn.1602188. PMID 16052183. 
  25. ^ a b Castells X, Ramos-Quiroga JA, Bosch R, Nogueira M, Casas M (June 2011). Castells X, ed. "Amphetamines for Attention Deficit Hyperactivity Disorder (ADHD) in adults". Cochrane Database Syst. Rev. (6): CD007813. doi:10.1002/14651858.CD007813.pub2. PMID 21678370. 
  26. ^ 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 Syst. Rev. 2: CD009996. doi:10.1002/14651858.CD009996.pub2. PMID 26844979. 
  27. ^ Pringsheim T, Steeves T (April 2011). Pringsheim T, ed. "Pharmacological treatment for Attention Deficit Hyperactivity Disorder (ADHD) in children with comorbid tic disorders". Cochrane Database Syst. Rev. (4): CD007990. doi:10.1002/14651858.CD007990.pub2. PMID 21491404. 
  28. ^ a b http://www.shire.com/shireplc/en/rd/pipeline
  29. ^ a b Spencer RC, Devilbiss DM, Berridge CW (June 2015). "The Cognition-Enhancing Effects of Psychostimulants Involve Direct Action in the Prefrontal Cortex". Biol. Psychiatry. 77 (11): 940–950. doi:10.1016/j.biopsych.2014.09.013. 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). This information has potentially important clinical implications as well as relevance for public health policy regarding the widespread clinical use of psychostimulants and for the development of novel pharmacologic treatments for attention-deficit/hyperactivity disorder and other conditions associated with PFC dysregulation. ... 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. 
  30. ^ Ilieva IP, Hook CJ, Farah MJ (January 2015). "Prescription Stimulants' Effects on Healthy Inhibitory Control, Working Memory, and Episodic Memory: A Meta-analysis". J. Cogn. Neurosci.: 1–21. 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. 
  31. ^ 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 4471173free to read. PMID 24749160. Amphetamine has been shown to improve consolidation of information (0.02 ≥ P ≤ 0.05), leading to improved recall. 
  32. ^ Devous MD, Trivedi MH, Rush AJ (April 2001). "Regional cerebral blood flow response to oral amphetamine challenge in healthy volunteers". J. Nucl. Med. 42 (4): 535–542. PMID 11337538. 
  33. ^ Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 10: Neural and Neuroendocrine Control of the Internal Milieu". In Sydor A, Brown RY. 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. 
  34. ^ a b c Wood S, Sage JR, Shuman T, Anagnostaras SG (January 2014). "Psychostimulants and cognition: a continuum of behavioral and cognitive activation". Pharmacol. Rev. 66 (1): 193–221. doi:10.1124/pr.112.007054. PMID 24344115. 
  35. ^ Twohey M (26 March 2006). "Pills become an addictive study aid". JS Online. Archived from the original on 15 August 2007. Retrieved 2 December 2007. 
  36. ^ 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 1794223free to read. PMID 16999660. 
  37. ^ 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". Psychol. Res. Behav. Manag. 7: 223–249. doi:10.2147/PRBM.S47013. PMC 4164338free to read. 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. 
  38. ^ Clemow DB, Walker DJ (September 2014). "The potential for misuse and abuse of medications in ADHD: a review". Postgrad. Med. 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. 
  39. ^ a b c Liddle DG, Connor DJ (June 2013). "Nutritional supplements and ergogenic AIDS". Prim. Care. 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
     
  40. ^ a b c d e f g h i j k l m n o p q r s Westfall DP, Westfall TC (2010). "Miscellaneous Sympathomimetic Agonists". In Brunton LL, Chabner BA, Knollmann BC. Goodman & Gilman's Pharmacological Basis of Therapeutics (12th ed.). New York, USA: McGraw-Hill. ISBN 9780071624428. 
  41. ^ Bracken NM (January 2012). "National Study of Substance Use Trends Among NCAA College Student-Athletes" (PDF). NCAA Publications. National Collegiate Athletic Association. Retrieved 8 October 2013. 
  42. ^ Docherty JR (June 2008). "Pharmacology of stimulants prohibited by the World Anti-Doping Agency (WADA)". Br. J. Pharmacol. 154 (3): 606–622. doi:10.1038/bjp.2008.124. PMC 2439527free to read. PMID 18500382. 
  43. ^ 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). 
  44. ^ 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. 
  45. ^ 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. 
  46. ^ 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) 
  47. ^ 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 
  48. ^ a b c d e f g "Adderall XR Prescribing Information" (PDF). United States Food and Drug Administration. Shire US Inc. December 2013. p. 11. Retrieved 30 December 2013. 
  49. ^ a b c d e f g h i j k l "Adderall XR Prescribing Information" (PDF). United States Food and Drug Administration. Shire US Inc. December 2013. pp. 4–8. Retrieved 30 December 2013. 
  50. ^ a b c d "Vyvanse Prescribing Information" (PDF). Shire Inc. Retrieved 1 July 2014. 
  51. ^ a b c d e Heedes G; Ailakis J. "Amphetamine (PIM 934)". INCHEM. International Programme on Chemical Safety. Retrieved 24 June 2014. 
  52. ^ a b c d e f "Adderall XR Prescribing Information" (PDF). United States Food and Drug Administration. Shire US Inc. December 2013. pp. 4–6. Retrieved 30 December 2013. 
  53. ^ "FDA Pregnancy Categories" (PDF). United States Food and Drug Administration. 21 October 2004. Retrieved 31 October 2013. 
  54. ^ "Dexamphetamine tablets". Therapeutic Goods Administration. Retrieved 12 April 2014. 
  55. ^ a b Vitiello B (April 2008). "Understanding the risk of using medications for attention deficit hyperactivity disorder with respect to physical growth and cardiovascular function". Child Adolesc. Psychiatr. Clin. N. Am. 17 (2): 459–474. doi:10.1016/j.chc.2007.11.010. PMC 2408826free to read. PMID 18295156. 
  56. ^ a b c d e f "Dyanavel XR Prescribing Information" (PDF). Tris Pharmaceuticals. October 2015. pp. 1–16. Retrieved 23 November 2015. DYANAVEL XR contains d-amphetamine and l-amphetamine in a ratio of 3.2 to 1 ... The most common (≥2% in the DYANAVEL XR group and greater than placebo) adverse reactions reported in the Phase 3 controlled study conducted in 108 patients with ADHD (aged 6–12 years) were: epistaxis, allergic rhinitis and upper abdominal pain. ...
    DOSAGE FORMS AND STRENGTHS
    Extended-release oral suspension contains 2.5 mg amphetamine base per mL.
     
  57. ^ Ramey JT, Bailen E, Lockey RF (2006). "Rhinitis medicamentosa" (PDF). J. Investig. Allergol. Clin. Immunol. 16 (3): 148–155. PMID 16784007. Retrieved 29 April 2015. Table 2. Decongestants Causing Rhinitis Medicamentosa
    – Nasal decongestants:
      – Sympathomimetic:
       • Amphetamine
     
  58. ^ "FDA Drug Safety Communication: Safety Review Update of Medications used to treat Attention-Deficit/Hyperactivity Disorder (ADHD) in children and young adults". United States Food and Drug Administration. 20 December 2011. Retrieved 4 November 2013. 
  59. ^ 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. 
  60. ^ "FDA Drug Safety Communication: Safety Review Update of Medications used to treat Attention-Deficit/Hyperactivity Disorder (ADHD) in adults". United States Food and Drug Administration. 15 December 2011. Retrieved 4 November 2013. 
  61. ^ Habel LA, Cooper WO, Sox CM, Chan KA, Fireman BH, Arbogast PG, Cheetham TC, Quinn VP, Dublin S, Boudreau DM, Andrade SE, Pawloski PA, Raebel MA, Smith DH, Achacoso N, Uratsu C, Go AS, Sidney S, Nguyen-Huynh MN, Ray WA, Selby JV (December 2011). "ADHD medications and risk of serious cardiovascular events in young and middle-aged adults". JAMA. 306 (24): 2673–2683. doi:10.1001/jama.2011.1830. PMC 3350308free to read. PMID 22161946. 
  62. ^ Montgomery KA (June 2008). "Sexual desire disorders". Psychiatry (Edgmont). 5 (6): 50–55. PMC 2695750free to read. PMID 19727285. 
  63. ^ O'Connor PG (February 2012). "Amphetamines". Merck Manual for Health Care Professionals. Merck. Retrieved 8 May 2012. 
  64. ^ a b c d 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.
     
  65. ^ a b Greydanus D. "Stimulant Misuse: Strategies to Manage a Growing Problem" (PDF). American College Health Association (Review Article). ACHA Professional Development Program. p. 20. Archived from the original (PDF) on 3 November 2013. Retrieved 2 November 2013. 
  66. ^ a b Childs E, de Wit H (May 2009). "Amphetamine-induced place preference in humans". Biol. Psychiatry. 65 (10): 900–904. doi:10.1016/j.biopsych.2008.11.016. PMC 2693956free to read. 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. 
  67. ^ 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. 
  68. ^ a b Spiller HA, Hays HL, Aleguas A (June 2013). "Overdose of drugs for attention-deficit hyperactivity disorder: clinical presentation, mechanisms of toxicity, and management". CNS Drugs. 27 (7): 531–543. doi:10.1007/s40263-013-0084-8. PMID 23757186. Amphetamine, dextroamphetamine, and methylphenidate act as substrates for the cellular monoamine transporter, especially the dopamine transporter (DAT) and less so the norepinephrine (NET) and serotonin transporter. The mechanism of toxicity is primarily related to excessive extracellular dopamine, norepinephrine, and serotonin. 
  69. ^ Collaborators (2015). "Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013" (PDF). Lancet. 385 (9963): 117–171. doi:10.1016/S0140-6736(14)61682-2. PMC 4340604free to read. PMID 25530442. Retrieved 3 March 2015. Amphetamine use disorders ... 3,788 (3,425–4,145) 
  70. ^ Kanehisa Laboratories (10 October 2014). "Amphetamine – Homo sapiens (human)". KEGG Pathway. Retrieved 31 October 2014. 
  71. ^ a b c d e f Nechifor M (March 2008). "Magnesium in drug dependences". Magnes. Res. 21 (1): 5–15. PMID 18557129. 
  72. ^ a b c d e Ruffle JK (November 2014). "Molecular neurobiology of addiction: what's all the (Δ)FosB about?". Am. J. Drug 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. 
  73. ^ a b c d e Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues Clin. Neurosci. 15 (4): 431–443. PMC 3898681free to read. PMID 24459410. 
  74. ^ 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. 
  75. ^ 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). 
  76. ^ 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. 
  77. ^ 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. 
  78. ^ a b c d Linke SE, Ussher M (January 2015). "Exercise-based treatments for substance use disorders: evidence, theory, and practicality". Am. J. Drug Alcohol Abuse. 41 (1): 7–15. doi:10.3109/00952990.2014.976708. 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. 
  79. ^ 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, USA: McGraw-Hill Medical. p. 386. ISBN 9780071481274. Currently, cognitive–behavioral therapies are the most successful treatment available for preventing the relapse of psychostimulant use. 
  80. ^ Greene SL, Kerr F, Braitberg G (October 2008). "Review article: amphetamines and related drugs of abuse". Emerg. Med. Australas. 20 (5): 391–402. doi:10.1111/j.1742-6723.2008.01114.x. PMID 18973636. 
  81. ^ Albertson TE (2011). "Amphetamines". In Olson KR, Anderson IB, Benowitz NL, Blanc PD, Kearney TE, Kim-Katz SY, Wu AH. Poisoning & Drug Overdose (6th ed.). New York: McGraw-Hill Medical. pp. 77–79. ISBN 9780071668330. 
  82. ^ "Glossary of Terms". Mount Sinai School of Medicine. Department of Neuroscience. Retrieved 9 February 2015. 
  83. ^ Volkow ND, Koob GF, McLellan AT (January 2016). "Neurobiologic Advances from the Brain Disease Model of Addiction". N. Engl. J. Med. 374 (4): 363–371. doi:10.1056/NEJMra1511480. PMID 26816013. 
  84. ^ 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.
     
  85. ^ 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". Curr. Med. Res. Opin. 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. 
  86. ^ Stolerman IP (2010). Stolerman IP, ed. Encyclopedia of Psychopharmacology. Berlin, Germany; London, England: Springer. p. 78. ISBN 9783540686989. 
  87. ^ Coghill DR, Caballero B, Sorooshian S, Civil R (June 2014). "A systematic review of the safety of lisdexamfetamine dimesylate". CNS Drugs. 28 (6): 497–511. doi:10.1007/s40263-014-0166-2. PMC 4057639free to read. PMID 24788672. The prodrug formulation of LDX may also lead to reduced abuse potential of LDX compared with immediate-release d-AMP. 
  88. ^ "Amphetamines: Drug Use and Abuse". Merck Manual Home Edition. Merck. February 2003. Archived from the original on 17 February 2007. Retrieved 28 February 2007. 
  89. ^ Perez-Mana C, Castells X, Torrens M, Capella D, Farre M (September 2013). Pérez-Mañá C, ed. "Efficacy of psychostimulant drugs for amphetamine abuse or dependence". Cochrane Database Syst. Rev. 9: CD009695. doi:10.1002/14651858.CD009695.pub2. PMID 23996457. 
  90. ^ Hyman SE, Malenka RC, Nestler EJ (July 2006). "Neural mechanisms of addiction: the role of reward-related learning and memory". Annu. Rev. Neurosci. 29: 565–598. doi:10.1146/annurev.neuro.29.051605.113009. PMID 16776597. 
  91. ^ a b c d e f g h 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. 
  92. ^ a b c d e Steiner H, Van Waes V (January 2013). "Addiction-related gene regulation: risks of exposure to cognitive enhancers vs. other psychostimulants". Prog. Neurobiol. 100: 60–80. doi:10.1016/j.pneurobio.2012.10.001. PMC 3525776free to read. PMID 23085425. 
  93. ^ Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 4: Signal Transduction in the Brain". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York, USA: McGraw-Hill Medical. p. 94. ISBN 9780071481274. 
  94. ^ Kanehisa Laboratories (29 October 2014). "Alcoholism – Homo sapiens (human)". KEGG Pathway. Retrieved 31 October 2014. 
  95. ^ Kim Y, Teylan MA, Baron M, Sands A, Nairn AC, Greengard P (February 2009). "Methylphenidate-induced dendritic spine formation and DeltaFosB expression in nucleus accumbens". Proc. Natl. Acad. Sci. U.S.A. 106 (8): 2915–2920. doi:10.1073/pnas.0813179106. PMC 2650365free to read. PMID 19202072. 
  96. ^ Nestler EJ (January 2014). "Epigenetic mechanisms of drug addiction". Neuropharmacology. 76 Pt B: 259–268. doi:10.1016/j.neuropharm.2013.04.004. PMC 3766384free to read. PMID 23643695. 
  97. ^ a b Blum K, Werner T, Carnes S, Carnes P, Bowirrat A, Giordano J, Oscar-Berman M, Gold M (March 2012). "Sex, drugs, and rock 'n' roll: hypothesizing common mesolimbic activation as a function of reward gene polymorphisms". J. Psychoactive Drugs. 44 (1): 38–55. doi:10.1080/02791072.2012.662112. PMC 4040958free to read. PMID 22641964. 
  98. ^ Pitchers KK, Vialou V, Nestler EJ, Laviolette SR, Lehman MN, Coolen LM (February 2013). "Natural and drug rewards act on common neural plasticity mechanisms with ΔFosB as a key mediator". J. Neurosci. 33 (8): 3434–3442. doi:10.1523/JNEUROSCI.4881-12.2013. PMC 3865508free to read. PMID 23426671. 
  99. ^ Beloate LN, Weems PW, Casey GR, Webb IC, Coolen LM (February 2016). "Nucleus accumbens NMDA receptor activation regulates amphetamine cross-sensitization and deltaFosB expression following sexual experience in male rats". Neuropharmacology. 101: 154–164. doi:10.1016/j.neuropharm.2015.09.023. PMID 26391065. 
  100. ^ Stoops WW, Rush CR (May 2014). "Combination pharmacotherapies for stimulant use disorder: a review of clinical findings and recommendations for future research". Expert Rev Clin Pharmacol. 7 (3): 363–374. doi:10.1586/17512433.2014.909283. PMID 24716825. Despite concerted efforts to identify a pharmacotherapy for managing stimulant use disorders, no widely effective medications have been approved. 
  101. ^ Perez-Mana C, Castells X, Torrens M, Capella D, Farre M (September 2013). "Efficacy of psychostimulant drugs for amphetamine abuse or dependence". Cochrane Database Syst. Rev. 9: CD009695. doi:10.1002/14651858.CD009695.pub2. PMID 23996457. To date, no pharmacological treatment has been approved for [addiction], and psychotherapy remains the mainstay of treatment. ... Results of this review do not support the use of psychostimulant medications at the tested doses as a replacement therapy 
  102. ^ Forray A, Sofuoglu M (February 2014). "Future pharmacological treatments for substance use disorders". Br. J. Clin. Pharmacol. 77 (2): 382–400. doi:10.1111/j.1365-2125.2012.04474.x. PMC 4014020free to read. PMID 23039267. 
  103. ^ a b 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. 
  104. ^ a b Jing L, Li JX (August 2015). "Trace amine-associated receptor 1: A promising target for the treatment of psychostimulant addiction". Eur. J. Pharmacol. 761: 345–352. doi:10.1016/j.ejphar.2015.06.019. PMID 26092759. Taken together,the data reviewed here strongly support that TAAR1 is implicated in the functional regulation of monoaminergic systems, especially dopaminergic system, and that TAAR1 serves as a homeostatic “brake” system that is involved in the modulation of dopaminergic activity. Existing data provided robust preclinical evidence supporting the development of TAAR1 agonists as potential treatment for psychostimulant abuse and addiction. ... Given that TAAR1 is primarily located in the intracellular compartments and existing TAAR1 agonists are proposed to get access to the receptors by translocation to the cell interior (Miller, 2011), future drug design and development efforts may need to take strategies of drug delivery into consideration (Rajendran et al., 2010). 
  105. ^ a b Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 5: Excitatory and Inhibitory Amino Acids". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York, USA: McGraw-Hill Medical. pp. 124–125. ISBN 9780071481274. 
  106. ^ a b c d Shoptaw SJ, Kao U, Heinzerling K, Ling W (April 2009). Shoptaw SJ, ed. "Treatment for amphetamine withdrawal". Cochrane Database Syst. Rev. (2): CD003021. doi:10.1002/14651858.CD003021.pub2. PMID 19370579. 
  107. ^ "Dexedrine Prescribing Information" (PDF). United States Food and Drug Administration. Amedra Pharmaceuticals LLC. October 2013. Retrieved 4 November 2013. 
  108. ^ "Adderall IR Prescribing Information" (PDF). United States Food and Drug Administration. Teva Pharmaceuticals USA, Inc. October 2015. Retrieved 18 May 2016. 
  109. ^ "Adderall XR Prescribing Information" (PDF). United States Food and Drug Administration. Shire US Inc. December 2013. Retrieved 30 December 2013. 
  110. ^ Advokat C (July 2007). "Update on amphetamine neurotoxicity and its relevance to the treatment of ADHD". J. Atten. Disord. 11 (1): 8–16. doi:10.1177/1087054706295605. PMID 17606768. 
  111. ^ "Amphetamine". Hazardous Substances Data Bank. United States National Library of Medicine – Toxicology Data Network. Retrieved 26 February 2014. Direct toxic damage to vessels seems unlikely because of the dilution that occurs before the drug reaches the cerebral circulation. 
  112. ^ 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, USA: McGraw-Hill Medical. p. 370. ISBN 9780071481274. Unlike cocaine and amphetamine, methamphetamine is directly toxic to midbrain dopamine neurons. 
  113. ^ Sulzer D, Zecca L (February 2000). "Intraneuronal dopamine-quinone synthesis: a review". Neurotox. Res. 1 (3): 181–195. doi:10.1007/BF03033289. PMID 12835101. 
  114. ^ Miyazaki I, Asanuma M (June 2008). "Dopaminergic neuron-specific oxidative stress caused by dopamine itself". Acta Med. Okayama. 62 (3): 141–150. PMID 18596830. 
  115. ^ Hofmann FG (1983). A Handbook on Drug and Alcohol Abuse: The Biomedical Aspects (2nd ed.). New York, USA: Oxford University Press. p. 329. ISBN 9780195030570. 
  116. ^ a b c d "Adderall XR Prescribing Information" (PDF). United States Food and Drug Administration. Shire US Inc. December 2013. pp. 8–10. Retrieved 30 December 2013. 
  117. ^ a b "Identification". Lisdexamfetamine. DrugBank. University of Alberta. 16 September 2013. Retrieved 13 June 2014. 
  118. ^ a b c Jasinski DR, Krishnan S (June 2009). "Abuse liability and safety of oral lisdexamfetamine dimesylate in individuals with a history of stimulant abuse". J. Psychopharmacol. (Oxford). 23 (4): 419–427. doi:10.1177/0269881109103113. PMID 19329547. 
  119. ^ a b Miller GM (January 2011). "The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity". J. Neurochem. 116 (2): 164–176. doi:10.1111/j.1471-4159.2010.07109.x. PMC 3005101free to read. PMID 21073468. 
  120. ^ a b Eiden LE, Weihe E (January 2011). "VMAT2: a dynamic regulator of brain monoaminergic neuronal function interacting with drugs of abuse". Ann. N. Y. Acad. Sci. 1216: 86–98. Bibcode:2011NYASA1216...86E. doi:10.1111/j.1749-6632.2010.05906.x. PMC 4183197free to read. PMID 21272013. VMAT2 is the CNS vesicular transporter for not only the biogenic amines DA, NE, EPI, 5-HT, and HIS, but likely also for the trace amines TYR, PEA, and thyronamine (THYR) ... [Trace aminergic] neurons in mammalian CNS would be identifiable as neurons expressing VMAT2 for storage, and the biosynthetic enzyme aromatic amino acid decarboxylase (AADC). 
  121. ^ "Adderall XR Prescribing Information" (PDF). United States Food and Drug Administration. pp. 1–18. Retrieved 7 October 2013. 
  122. ^ "Pharmacology". Dextroamphetamine. DrugBank. University of Alberta. 8 February 2013. Retrieved 5 November 2013. 
  123. ^ a b c d e f g h i j k l m n "Adderall XR Prescribing Information" (PDF). United States Food and Drug Administration. Shire US Inc. December 2013. pp. 12–13. Retrieved 30 December 2013. 
  124. ^ "Pharmacology". Amphetamine. DrugBank. University of Alberta. 8 February 2013. Retrieved 5 November 2013. 
  125. ^ a b c d "Pharmacology and Biochemistry". Amphetamine. Pubchem Compound. United States National Library of Medicine – National Center for Biotechnology Information. Retrieved 12 October 2013. 
  126. ^ a b "Metabolism/Pharmacokinetics". AMPHETAMINE. United States National Library of Medicine – Toxicology Data Network. Hazardous Substances Data Bank. Retrieved 5 January 2014. Plasma protein binding, rate of absorption, & volumes of distribution of amphetamine isomers are similar. ... The biological half-life of amphetamine is greater in drug dependent individuals than in control subjects, & distribution volumes are increased, indicating that greater affinity of tissues for the drug may contribute to development of amphetamine tolerance. ... Concentrations of (14)C-amphetamine declined less rapidly in the plasma of human subjects maintained on an alkaline diet (urinary pH > 7.5) than those on an acid diet (urinary pH < 6). Plasma half-lives of amphetamine ranged between 16-31 hr & 8-11 hr, respectively, & the excretion of (14)C in 24 hr urine was 45 & 70%. 
  127. ^ a b c "Vyvanse Prescribing Information" (PDF). United States Food and Drug Administration. Shire US Inc. January 2015. pp. 12–16. Retrieved 24 February 2015. 
  128. ^ 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. 
  129. ^ 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. 
  130. ^ 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. 
  131. ^ Krueger SK, Williams DE (June 2005). "Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism". Pharmacol. Ther. 106 (3): 357–387. doi:10.1016/j.pharmthera.2005.01.001. PMC 1828602free to read. PMID 15922018. 
    Table 5: N-containing drugs and xenobiotics oxygenated by FMO
  132. ^ 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. 
  133. ^ a b c Santagati NA, Ferrara G, Marrazzo A, Ronsisvalle G (September 2002). "Simultaneous determination of amphetamine and one of its metabolites by HPLC with electrochemical detection". J. Pharm. Biomed. Anal. 30 (2): 247–255. doi:10.1016/S0731-7085(02)00330-8. PMID 12191709. 
  134. ^ a b "Substrate/Product". butyrate-CoA ligase. BRENDA. Technische Universität Braunschweig. Retrieved 7 May 2014. 
  135. ^ a b "Substrate/Product". glycine N-acyltransferase. BRENDA. Technische Universität Braunschweig. Retrieved 7 May 2014. 
  136. ^ "Compound Summary". p-Hydroxyamphetamine. PubChem Compound. United States National Library of Medicine – National Center for Biotechnology Information. Retrieved 15 October 2013. 
  137. ^ "Compound Summary". p-Hydroxynorephedrine. PubChem Compound. United States National Library of Medicine – National Center for Biotechnology Information. Retrieved 15 October 2013. 
  138. ^ "Compound Summary". Phenylpropanolamine. PubChem Compound. United States National Library of Medicine – National Center for Biotechnology Information. Retrieved 15 October 2013. 
  139. ^ "Molecular Weight Calculator". Lenntech. Retrieved 19 August 2015. 
  140. ^ a b "Dextroamphetamine Sulfate USP". Mallinckrodt Pharmaceuticals. March 2014. Retrieved 19 August 2015. 
  141. ^ a b "D-amphetamine sulfate". Tocris. 2015. Retrieved 19 August 2015. 
  142. ^ a b "Amphetamine Sulfate USP". Mallinckrodt Pharmaceuticals. March 2014. Retrieved 19 August 2015. 
  143. ^ "Dextroamphetamine Saccharate". Mallinckrodt Pharmaceuticals. March 2014. Retrieved 19 August 2015. 
  144. ^ "Amphetamine Aspartate". Mallinckrodt Pharmaceuticals. March 2014. Retrieved 19 August 2015. 
  145. ^ "Vyvanse Prescribing Information" (PDF). United States Food and Drug Administration. Shire US Inc. January 2015. pp. 12–16. Retrieved 24 February 2015. 
  146. ^ Lisdexamfetamine Dimesylate: A Prodrug Stimulant for the Treatment of ADHD in Children and Adults
  147. ^ FDA Adult Approval of Vyvanse – FDA Label and Approval History
  148. ^ Health Canada Notice of Compliance – Vyvanse. 19 February 2009, retrieved on 9 March 2009.
  149. ^ [1]. 8 February 2012, retrieved on 9 February 2012.
  150. ^ Hirschler, Ben (7 February 2014). "UPDATE 2-Shire scraps Vyvanse for depression after failed trials". Reuters. Retrieved 13 February 2014. 
  151. ^ http://www.shire.com/shireplc/en/investors/irshirenews?id=684
  152. ^ http://www.shire.com/shireplc/en/investors/investorsnews/irshirenews?id=1055
  153. ^ http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm432543.htm
  154. ^ Cassels, Caroline. "FDA Okays Vyvanse for Binge Eating Disorder". medscape.com. Retrieved 30 January 2015. 
  155. ^ http://www.shire.com/shireplc/en/investors/investorsnews/irshirenews?id=684
  156. ^ Dale E, Bang-Andersen B, Sánchez C (May 2015). "Emerging mechanisms and treatments for depression beyond SSRIs and SNRIs". Biochem. Pharmacol. 95 (2): 81–97. doi:10.1016/j.bcp.2015.03.011. PMID 25813654. 
  157. ^ "Psychostimulants in the therapy of treatment-resistant depression Review of the literature and findings from a retrospective study in 65 depressed patients". Dialogues Clin Neurosci. 1999. PMID 3181580.