Lisdexamfetamine

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Lisdexamfetamine
Lisdexamfetamine-Structural Formula V.1.svg
Lisdexamfetamine molecule ball.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
Licence data US FDA:link
  • AU: B3
  • US: C (Risk not ruled out)
Oral
Pharmacokinetic data
Bioavailability 96.4%[1]
Metabolism Hydrolysis by enzymes in red blood cells initially.
Subsequent metabolism follows Amphetamine#Pharmacokinetics.
Half-life < 1 hour (prodrug molecule), 10-13 hours (dextroamphetamine)
Excretion Renal: ~2%
Identifiers
608137-32-2 YesY[IUPHAR]
N06BA12
PubChem CID 11597698
IUPHAR ligand 7213
DrugBank DB01255 YesY
ChemSpider 9772458 YesY
UNII H645GUL8KJ YesY
ChEMBL CHEMBL1201222 YesY
Synonyms Vyvanse
Chemical data
Formula C15H25N3O
263.378 g/mol
 N (what is this?)  (verify)
30mg Vyvanse capsules

Lisdexamfetamine (contracted from L-lysine-dextroamphetamine) is a central nervous system (CNS) stimulant prodrug of the phenethylamine and amphetamine chemical classes. 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 - as a part of a treatment program that may include other measures (i.e., psychological, educational, social). The safety and the efficacy of lisdexamfetamine dimesylate in people three to five years old have not been established.[2] It was approved by the Food and Drug Administration in the United States for treatment of binge eating disorder in January 2015.[3]

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) [4] and the aggregate production quota for 2014 is 23,750 kilograms of anhydrous acid or base.[5] Lisdexamfetamine is licensed under the brand name Vyvanse in the United States and Canada, Venvanse in Brazil, and Elvanse in the United Kingdom, Denmark, Sweden, Germany, Finland, Spain and Norway (Tyvense in Ireland).[6] Lisdexamfetamine is currently in Phase II trials in Japan for ADHD and was approved by The US Food and Drug Administration (FDA) to treat binge eating disorder (BED) in adults.[7][8]

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;[9] it has similar off-label uses as those of other pharmaceutical amphetamines.[9][10] Long-term amphetamine exposure in some animal species is known to produce abnormal dopamine system development or nerve damage,[11][12] but, in humans with ADHD, pharmaceutical amphetamines appear to improve brain development and nerve growth.[13][14][15] 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.[13][14][15]

Reviews of clinical stimulant research have established the safety and effectiveness of long-term amphetamine use for ADHD.[16][17][18] Controlled trials spanning two years have demonstrated treatment effectiveness and safety.[16][18] 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.[16]

Current models of ADHD suggest that it is associated with functional impairments in some of the brain's neurotransmitter systems;[19] these functional impairments involve impaired dopamine neurotransmission in the mesocorticolimbic projection and norepinephrine neurotransmission in the locus coeruleus and prefrontal cortex.[19] Psychostimulants like methylphenidate and amphetamine are effective in treating ADHD because they increase neurotransmitter activity in these systems.[20][19][21] Approximately 80% of those who use these stimulants see improvements in ADHD symptoms.[22] 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.[23][24] The Cochrane Collaboration's review[note 1] on the treatment of adult ADHD with pharmaceutical amphetamines stated that while these drugs improve short-term symptoms, they have higher discontinuation rates than non-stimulant medications due to their adverse side effects.[25] 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.[26]

Investigational

Cochrane reviews on the use of amphetamine following a stroke or acute traumatic brain injury indicated that it may improve recovery, but further research is needed to confirm this.[27][28][29] A review of clinical trials that used lisdexamfetamine as an adjunct therapy with a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) for treatment-resistant depression indicated that this adjunct therapy is no more effective than the use of an SSRI or SNRI alone.[30] This observation is consistent with previous findings that serotonin–norepinephrine–dopamine reuptake inhibitors (SNDRIs) demonstrate no additional efficacy over SSRIs and SNRIs for the treatment of major depressive disorder.[30] Lisdexamfetamine is also being investigated for possible treatment of cognitive impairment associated with schizophrenia and excessive daytime sleepiness.[7]

Dosing and administration[edit]

Individuals over the age of 65 were not commonly tested in clinical trials of lisdexamfetamine. Therefore, there is insufficient data to determine how older individuals respond. People over the age of 65 should start on the low end of dosing schedules due to the prevalence of decreased hepatic function, decreased renal function, and comorbidities in this population.[9]

Performance-enhancing[edit]

In 2015, a systematic review and a meta-analysis of high quality clinical trials found that, when used at low (therapeutic) doses, amphetamine produces unambiguous improvements in cognition, including working memory, episodic memory, and inhibitory control, in normal healthy adults;[31][32] the cognition-enhancing effects of amphetamine are known to occur through its indirect activation of both dopamine receptor D1 and adrenoceptor A2 in the prefrontal cortex.[31] Therapeutic doses of amphetamine also enhance cortical network efficiency, an effect which mediates improvements in working memory in all individuals.[20][33] Amphetamine and other ADHD stimulants also improve task saliency (motivation to perform a task) and increase arousal (wakefulness), in turn promoting goal-directed behavior.[20][34][35] 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.[20][34][36] Based upon studies of self-reported illicit stimulant use, students primarily use stimulants such as amphetamine for performance enhancement rather than using them as recreational drugs.[37] However, high amphetamine doses that are above the therapeutic range can interfere with working memory and other aspects of cognitive control.[20][34]

Amphetamine is used by some athletes for its psychological and performance-enhancing effects, such as increased stamina and alertness;[38][39] however, its use is prohibited at sporting events regulated by collegiate, national, and international anti-doping agencies.[40][41] In healthy people at oral therapeutic doses, amphetamine has been shown to increase physical strength, acceleration, stamina, and endurance, while reducing reaction time.[38][42][43] Amphetamine improves stamina, endurance, and reaction time primarily through reuptake inhibition and effluxion of dopamine in the central nervous system.[42][43][44] At therapeutic doses, the adverse effects of amphetamine do not impede athletic performance;[38][42][43] however, at much higher doses, amphetamine can induce effects that severely impair performance, such as rapid muscle breakdown and elevated body temperature.[45][46][42]

Contraindications[edit]

Pharmaceutical lisdexamfetamine dimesylate is contraindicated in patients with hypersensitivity to amphetamine or any other ingredients that it contains.[9] It is also contraindicated in patients who have used a monoamine oxidase inhibitor (MAOI) within the last 14 days.[9][47] 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.[48] 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.[48] Amphetamine is classified in US pregnancy category C.[48] 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.[49] Amphetamine has also been shown to pass into breast milk, so the USFDA advises mothers to avoid breastfeeding when using it.[48] Due to the potential for stunted growth, the USFDA advises monitoring the height and weight of children and adolescents prescribed amphetamines.[48] Prescribing information approved by the Australian Therapeutic Goods Administration further contraindicates anorexia.[50]

Availability[edit]

Lisdexamfetamine dimesylate is a white to off-white powder that is soluble in water (792 mg/mL). Vyvanse capsules contain 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, and 70 mg of lisdexamfetamine dimesylate and the following inactive ingredients: microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. The capsule shells contain gelatin, titanium dioxide, and one or more of the following: FD&C Red #3, FD&C Yellow #6, FD&C Blue #1, Black Iron Oxide, and Yellow Iron Oxide.[51]

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.[9][45][46]

Physical

At normal therapeutic doses, the physical side effects of amphetamine vary widely by age and from person to person.[46] 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).[46][39][52] Sexual side effects in males may include erectile dysfunction, frequent erections, or prolonged erections.[46] Abdominal side effects may include stomach pain, loss of appetite, nausea, and weight loss.[46] Other potential side effects include acne, blurred vision, dry mouth, excessive grinding of the teeth, 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.[39]

Amphetamine stimulates the medullary respiratory centers, producing faster and deeper breaths.[39] In a normal person at therapeutic doses, this effect is usually not noticeable, but when respiration is already compromised, it may be evident.[39] Amphetamine also induces contraction in the urinary bladder sphincter, the muscle which controls urination, which can result in difficulty urinating. This effect can be useful in treating bed wetting and loss of bladder control.[39] The effects of amphetamine on the gastrointestinal tract are unpredictable.[39] If intestinal activity is high, amphetamine may reduce gastrointestinal motility (the rate at which content moves through the digestive system);[39] however, amphetamine may increase motility when the smooth muscle of the tract is relaxed.[39] Amphetamine also has a slight analgesic effect and can enhance the pain relieving effects of opioids.[39]

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.[46][39] 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.[39] Amphetamine psychosis (e.g., delusions and paranoia) can occur in heavy users.[45][46][53] Although very rare, this psychosis can also occur at therapeutic doses during long-term therapy.[45][46][54] According to the USFDA, "there is no systematic evidence" that stimulants produce aggressive behavior or hostility.[46]

Amphetamine has also been shown to produce a conditioned place preference in humans taking therapeutic doses,[25][55] meaning that individuals acquire a preference for spending time in places where they have previously used amphetamine.[55][56]

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.[47][57] The severity of overdose symptoms increases with dosage and decreases with drug tolerance to amphetamine.[39][47] 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.[47] Symptoms of a moderate and extremely large overdose are listed below; fatal amphetamine poisoning usually also involves convulsions and coma.[45][39] 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][58]

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.[59][60] 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.[61][62][63] Once nucleus accumbens ΔFosB is sufficiently overexpressed, it begins to increase the severity of addictive behavior (i.e., compulsive drug-seeking).[61][64] 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.[65] Sustained aerobic exercise on a regular basis also appears to be an effective treatment for amphetamine addiction;[64][65][66] 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.[65][66][67]

Overdose symptoms by system
System Minor or moderate overdose[45][39][47] Severe overdose[sources 4]
Cardiovascular
Central nervous
system
Musculoskeletal
Respiratory
  • Rapid breathing
Urinary
Other

Addiction

Addiction glossary[56][62][68]
addiction – a state characterized by compulsive engagement in rewarding stimuli despite adverse consequences
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
addictive drug – a drug that is both rewarding and reinforcing
addictive behavior – a behavior that is both rewarding and reinforcing
sensitization – an amplified response to a stimulus resulting from repeated exposure to it
drug tolerance – the diminishing effect of a drug resulting from repeated administration at a given dose
drug sensitization or reverse tolerance – the escalating effect of a drug resulting from repeated administration at a given dose
dependence – an adaptive state associated with a withdrawal syndrome upon cessation of repeated exposure to a stimulus (e.g., drug intake)
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)
(edit | history)

Addiction is a serious risk with heavy recreational amphetamine use but is unlikely to arise from typical medical use at therapeutic doses.[69][70][39] 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.[71][72]

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.[73][74][75] The most important transcription factors[note 3] that produce these alterations are ΔFosB, cAMP response element binding protein (CREB), and nuclear factor kappa B (NFκB).[74] 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.[61][62][74] Once ΔFosB is sufficiently overexpressed, it induces an addictive state that becomes increasingly more severe with further increases in ΔFosB expression.[61][62] It has been implicated in addictions to alcohol, cannabinoids, cocaine, nicotine, opioids, phencyclidine, and substituted amphetamines, among others.[64][74][76]

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).[62][74][77] 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).[74] ΔFosB also plays an important role in regulating behavioral responses to natural rewards, such as palatable food, sex, and exercise.[64][74][78] 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.[64][74] 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.[64][79] These sex addictions are associated with a dopamine dysregulation syndrome which occurs in some patients taking dopaminergic drugs.[64][78][79]

The effects of amphetamine on gene regulation are both dose- and route-dependent.[75] Most of the research on gene regulation and addiction is based upon animal studies with intravenous amphetamine administration at very high doses.[75] 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.[75] This suggests that medical use of amphetamine does not significantly affect gene regulation.[75]

Pharmacological treatments

As of May 2014, there is no effective pharmacotherapy for amphetamine addiction.[80][81][82] Amphetamine addiction is largely mediated through increased activation of dopamine receptors and co-localized NMDA receptors[note 5] in the nucleus accumbens;[60] magnesium ions inhibit NMDA receptors by blocking the receptor calcium channel.[60][83] One review suggested that, based upon animal testing, pathological (addiction-inducing) amphetamine use significantly reduces the level of intracellular magnesium throughout the brain.[60] Supplemental magnesium[note 6] and fluoxetine treatment have been shown to reduce amphetamine self-administration (doses given to oneself) in humans, but neither is an effective monotherapy for amphetamine addiction.[60][84]

Behavioral treatments

Cognitive behavioral therapy is currently the most effective clinical treatment for psychostimulant addiction.[67] 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.[64][65][66] Exercise leads to better treatment outcomes when used as an adjunct treatment, particularly for psychostimulant addictions.[65][66] 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.[64] This is the opposite of pathological stimulant use, which induces decreased striatal DRD2 density.[64]

Summary of addiction-related plasticity
Form of neural or behavioral plasticity Type of reinforcer Sources
Opiates Psycho­stimulants High fat or sugar food Sexual reward Physical exercise
(aerobic)
Environmental
enrichment
ΔFosB expression in
nucleus accumbens D1-type MSNs
[64]
Behavioral plasticity
Escalation of intake Yes Yes Yes [64]
Psychostimulant
cross-sensitization
Yes Not applicable Yes Yes Attenuated Attenuated [64]
Psychostimulant
self-administration
[64]
Psychostimulant
conditioned place preference
[64]
Reinstatement of drug-seeking behavior [64]
Neurochemical plasticity
CREB phosphorylation
in the nucleus accumbens
[64]
Sensitized dopamine response
in the nucleus accumbens
No Yes No Yes [64]
Altered striatal dopamine signaling DRD2, ↑DRD3 DRD1, ↓DRD2, ↑DRD3 DRD1, ↓DRD2, ↑DRD3 DRD2 DRD2 [64]
Altered striatal opioid signaling μ-opioid receptors μ-opioid receptors
κ-opioid receptors
μ-opioid receptors μ-opioid receptors No change No change [64]
Changes in striatal opioid peptides dynorphin dynorphin enkephalin dynorphin dynorphin [64]
Mesocorticolimbic synaptic plasticity
Number of dendrites in the nucleus accumbens [64]
Dendritic spine density in
the nucleus accumbens
No change [64]

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."[85] 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.[85] 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.[85] The review indicated that withdrawal symptoms are associated with the degree of dependence, suggesting that therapeutic use would result in far milder discontinuation symptoms.[85] Manufacturer prescribing information does not indicate the presence of withdrawal symptoms following discontinuation of amphetamine use after an extended period at therapeutic doses.[86][87][88]

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.[89] There is no evidence that amphetamine is directly neurotoxic in humans.[90][91] However, large doses of amphetamine may cause indirect neurotoxicity as a result of increased oxidative stress from reactive oxygen species and autoxidation of dopamine.[11][92][93]

A severe amphetamine overdose can result in a stimulant psychosis that may involve a variety of symptoms, such as paranoia and delusions.[53] A Cochrane Collaboration review on treatment for amphetamine, dextroamphetamine, and methamphetamine psychosis states that about 5–15% of users fail to recover completely.[53][94] According to the same review, there is at least one trial that shows antipsychotic medications effectively resolve the symptoms of acute amphetamine psychosis.[53] Psychosis very rarely arises from therapeutic use.[54][48]

Interactions[edit]

  • Acidifying Agents: Drugs that acidify the urine, such as ascorbic acid, increase urinary excretion of amphetamines thus decreasing the half-life time of lisdexamfetamine in the body.[9]
  • Alkalinizing Agents: Drugs that alkalinize the urine, such as sodium bicarbonate, decrease urinary excretion of amphetamines thus increasing the half-life time of lisdexamfetamine in the body.[9]

Pharmacology[edit]

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

Mechanism of action[edit]

Pharmacodynamics of amphetamine enantiomers in a dopamine neuron
v · t · e
A pharmacodynamic model of amphetamine and TAAR1
via AADC
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 dopamine receptor 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, a known effect of TAAR1 activation, which is associated with DAT phosphorylation through a CAMK-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.[95] 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.[9] 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.[9][96]

The optical isomers of amphetamine, i.e., dextroamphetamine and levoamphetamine, are TAAR1 agonists and vesicular monoamine transporter 2 inhibitors that can enter monoamine neurons;[97][98] 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.[97][98]

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.[96] As opposed to Adderall, which contains roughly equal parts of racemic amphetamine and dextroamphetamic salts, lisdexamfetamine is a single-enantiomer dextroamphetamine formula.[95][99] 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%.[96]

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.[100] The drug lisdexamfetamine dimesylate is the first prodrug of its kind.

On April 23, 2008, Vyvanse received FDA approval for the adult population.[101] In a randomized, double-blind, four-week phase III trial in adult patients with ADHD, dosages of 30, 50 or 70 mg/day of oral lisdexamfetamine caused a significantly greater improvement in ADHD-Rating Scale total score than placebo.[102] On February 19, 2009, Health Canada approved 30 mg and 50 mg capsules of lisdexamfetamine for treatment of ADHD.[103] On February 8, 2012, Vyvanse received FDA approval for maintenance treatment of adult ADHD.[104] In February 2014, Shire announced that two late-stage clinical trials had shown that Vyvanse was not an effective treatment for depression.[105] 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.[106] 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.[107]

Brand names[edit]

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

Notes[edit]

  1. ^ Cochrane Collaboration reviews are high quality meta-analytic systematic reviews of randomized controlled trials.[108]
  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.[109]
  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.[83]
  6. ^ The review indicated that magnesium L-aspartate and magnesium chloride produce significant changes in addictive behavior;[60] other forms of magnesium were not mentioned.

Reference notes[edit]

References[edit]

  1. ^ "Public Assessment Report Decentralised Procedure Elvanse 30 mg, 50 mg and 70 mg capsules, hard Lisdexamfetamine dimesylate" (PDF). http://www.mhra.gov.uk/home/groups/par/documents/websiteresources/con261790.pdf#page=33. Shire Pharmaceuticals Contracts Limited. Retrieved 23 August 2014. 
  2. ^ "Lisdexamfetamine dimesylate (generic)." Brown University Psychopharmacology Update 19.7 (2008): 1-2. Academic Search Premier. EBSCO. Web. 12 September 2010.
  3. ^ http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm432543.htm
  4. ^ "DEA - Department of Justice" (PDF). http://www.justice.gov/dea/pr/multimedia-library/publications/drug_of_abuse.pdf#page=38. DEA - Department of Justice. Retrieved 1 July 2014. 
  5. ^ "DEA Office of Diversion Control" (PDF). http://www.deadiversion.usdoj.gov/quotas/quota_history.pdf. DEA. Retrieved 1 July 2014. 
  6. ^ http://www.shire.com/shireplc/en/investors/investorsnews/irshirenews?id=684
  7. ^ a b http://www.shire.com/shireplc/en/rd/pipeline
  8. ^ Cassels, Caroline. "FDA Okays Vyvanse for Binge Eating Disorder". medscape.com. Retrieved 30 January 2015. 
  9. ^ a b c d e f g h i j k "Vyvanse Drug Insert" (PDF). United States Food and Drug Administration. Shire US Inc. January 2015. Retrieved 24 February 2015. 
  10. ^ 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 3666194. PMID 23539642. 
  11. ^ 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. 
  12. ^ 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 2769923. PMID 18991959. 
  13. ^ 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. 
  14. ^ 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 3801446. PMID 24107764. 
  15. ^ 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. 
  16. ^ a b c Millichap JG (2010). "Chapter 3: 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. 
  17. ^ Arnold LE, Hodgkins P, Caci H, Kahle J, Young S (February 2015). "Effect of treatment modality on long-term outcomes in attention-deficit/hyperactivity disorder: a systematic review". PLoS ONE 10 (2): e0116407. doi:10.1371/journal.pone.0116407. PMC 4340791. PMID 25714373. The highest proportion of improved outcomes was reported with combination treatment (83% of outcomes). Among significantly improved outcomes, the largest effect sizes were found for combination treatment. The greatest improvements were associated with academic, self-esteem, or social function outcomes. 
  18. ^ 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. 
  19. ^ 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. 
  20. ^ a b c d e 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. p. 318. ISBN 9780071481274. 
  21. ^ 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 3353150. PMID 21596055. 
  22. ^ 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 3785407. PMID 24082796. Only one paper53 examining outcomes beyond 36 months met the review criteria. ... There is high level evidence suggesting that pharmacological treatment can have a major beneficial effect on the core symptoms of ADHD (hyperactivity, inattention, and impulsivity) in approximately 80% of cases compared with placebo controls, in the short term. 
  23. ^ Millichap JG (2010). "Chapter 3: 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. 
  24. ^ "Stimulants for Attention Deficit Hyperactivity Disorder". WebMD. Healthwise. 12 April 2010. Retrieved 12 November 2013. 
  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. ^ 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. 
  27. ^ Martinsson L, Hårdemark H, Eksborg S (January 2007). Martinsson L, ed. "Amphetamines for improving recovery after stroke". Cochrane Database Syst. Rev. (1): CD002090. doi:10.1002/14651858.CD002090.pub2. PMID 17253474. 
  28. ^ Forsyth RJ, Jayamoni B, Paine TC (October 2006). Forsyth RJ, ed. "Monoaminergic agonists for acute traumatic brain injury". Cochrane Database Syst. Rev. (4): CD003984. doi:10.1002/14651858.CD003984.pub2. PMID 17054192. 
  29. ^ Harbeck-Seu A, Brunk I, Platz T, Vajkoczy P, Endres M, Spies C (April 2011). "A speedy recovery: amphetamines and other therapeutics that might impact the recovery from brain injury". Curr. Opin. Anaesthesiol. 24 (2): 144–153. doi:10.1097/ACO.0b013e328344587f. PMID 21386667. 
  30. ^ a b 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. 
  31. ^ 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. 
  32. ^ 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. 
  33. ^ 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. 
  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. ^ 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. 
  36. ^ 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. 
  37. ^ Teter CJ, McCabe SE, LaGrange K, Cranford JA, Boyd CJ (October 2006). "Illicit use of specific prescription stimulants among college students: prevalence, motives, and routes of administration". Pharmacotherapy 26 (10): 1501–1510. doi:10.1592/phco.26.10.1501. PMC 1794223. PMID 16999660. 
  38. ^ 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
     
  39. ^ 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. 
  40. ^ 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. 
  41. ^ 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 2439527. PMID 18500382. 
  42. ^ 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. 
  43. ^ 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. 
  44. ^ 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 3813949. PMID 24198770. Manipulations of dopaminergic signaling profoundly influence interval timing, leading to the hypothesis that dopamine influences internal pacemaker, or “clock,” activity. For instance, amphetamine, which increases concentrations of dopamine at the synaptic cleft advances the start of responding during interval timing, whereas antagonists of D2 type dopamine receptors typically slow timing;... Depletion of dopamine in healthy volunteers impairs timing, while amphetamine releases synaptic dopamine and speeds up timing. 
  45. ^ a b c d e f g "Adderall XR Prescribing Information" (PDF). United States Food and Drug Administration. December 2013. p. 11. Retrieved 30 December 2013. 
  46. ^ a b c d e f g h i j k l "Adderall XR Prescribing Information" (PDF). United States Food and Drug Administration. December 2013. pp. 4–8. Retrieved 30 December 2013. 
  47. ^ a b c d e Heedes G; Ailakis J. "Amphetamine (PIM 934)". INCHEM. International Programme on Chemical Safety. Retrieved 24 June 2014. 
  48. ^ a b c d e f "Adderall XR Prescribing Information" (PDF). United States Food and Drug Administration. December 2013. pp. 4–6. Retrieved 30 December 2013. 
  49. ^ "FDA Pregnancy Categories" (PDF). United States Food and Drug Administration. 21 October 2004. Retrieved 31 October 2013. 
  50. ^ "Dexamphetamine tablets". Therapeutic Goods Administration. Retrieved 12 April 2014. 
  51. ^ "Shire-full prescribing information" (PDF). http://pi.shirecontent.com/PI/PDFs/Vyvanse_USA_ENG.pdf. Shire Inc. Retrieved 1 July 2014. 
  52. ^ 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 2408826. PMID 18295156. 
  53. ^ 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.
     
  54. ^ 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. Retrieved 2 November 2013. 
  55. ^ 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 2693956. PMID 19111278. This study demonstrates that humans, like nonhumans, prefer a place associated with amphetamine administration. These findings support the idea that subjective responses to a drug contribute to its ability to establish place conditioning. 
  56. ^ 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. 
  57. ^ 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. 
  58. ^ 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 4340604. PMID 25530442. Retrieved 3 March 2015. Amphetamine use disorders ... 3,788 (3,425–4,145) 
  59. ^ Kanehisa Laboratories (10 October 2014). "Amphetamine – Homo sapiens (human)". KEGG Pathway. Retrieved 31 October 2014. 
  60. ^ a b c d e f Nechifor M (March 2008). "Magnesium in drug dependences". Magnes. Res. 21 (1): 5–15. PMID 18557129. 
  61. ^ a b c d 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. 
  62. ^ a b c d e Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues Clin. Neurosci. 15 (4): 431–443. PMC 3898681. PMID 24459410. 
  63. ^ Robison AJ, Nestler EJ (November 2011). "Transcriptional and epigenetic mechanisms of addiction". Nat. Rev. Neurosci. 12 (11): 623–637. doi:10.1038/nrn3111. PMC 3272277. PMID 21989194. ΔFosB serves as one of the master control proteins governing this structural plasticity. 
  64. ^ a b c d e f g h i j k l m n o p q r s t u v w Olsen CM (December 2011). "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology 61 (7): 1109–1122. doi:10.1016/j.neuropharm.2011.03.010. PMC 3139704. PMID 21459101. 
  65. ^ 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 3788047. PMID 23806439. . 
  66. ^ 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. 
  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, 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. 
  68. ^ "Glossary of Terms". Mount Sinai School of Medicine. Department of Neuroscience. Retrieved 9 February 2015. 
  69. ^ 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. 
  70. ^ Stolerman IP (2010). Stolerman IP, ed. Encyclopedia of Psychopharmacology. Berlin, Germany; London, England: Springer. p. 78. ISBN 9783540686989. 
  71. ^ "Amphetamines: Drug Use and Abuse". Merck Manual Home Edition. Merck. February 2003. Archived from the original on 17 February 2007. Retrieved 28 February 2007. 
  72. ^ 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. 
  73. ^ 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. 
  74. ^ 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 3272277. PMID 21989194. 
  75. ^ 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 3525776. PMID 23085425. 
  76. ^ Kanehisa Laboratories (29 October 2014). "Alcoholism – Homo sapiens (human)". KEGG Pathway. Retrieved 31 October 2014. 
  77. ^ Nestler EJ (January 2014). "Epigenetic mechanisms of drug addiction". Neuropharmacology. 76 Pt B: 259–268. doi:10.1016/j.neuropharm.2013.04.004. PMC 3766384. PMID 23643695. 
  78. ^ 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 4040958. PMID 22641964. 
  79. ^ a b 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 3865508. PMID 23426671. 
  80. ^ 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. 
  81. ^ 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 
  82. ^ 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 4014020. PMID 23039267. 
  83. ^ 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. 
  84. ^ Srisurapanont M, Jarusuraisin N, Kittirattanapaiboon P (October 2001). Srisurapanont M, ed. "Treatment for amphetamine dependence and abuse". Cochrane Database Syst. Rev. (4): CD003022. doi:10.1002/14651858.CD003022. PMID 11687171. Although there are a variety of amphetamines and amphetamine derivatives, the word "amphetamines" in this review stands for amphetamine, dextroamphetamine and methamphetamine only. 
  85. ^ 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. 
  86. ^ "Adderall IR Prescribing Information" (PDF). United States Food and Drug Administration. Barr Laboratories, Inc. March 2007. Retrieved 4 November 2013. 
  87. ^ "Dexedrine Medication Guide" (PDF). United States Food and Drug Administration. Amedra Pharmaceuticals LLC. May 2013. Retrieved 4 November 2013. 
  88. ^ "Adderall XR Prescribing Information" (PDF). United States Food and Drug Administration. Shire US Inc. December 2013. Retrieved 30 December 2013. 
  89. ^ 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. 
  90. ^ "Amphetamine". Hazardous Substances Data Bank. National Library of Medicine. Retrieved 26 February 2014. Direct toxic damage to vessels seems unlikely because of the dilution that occurs before the drug reaches the cerebral circulation. 
  91. ^ 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. 
  92. ^ Sulzer D, Zecca L (February 2000). "Intraneuronal dopamine-quinone synthesis: a review". Neurotox. Res. 1 (3): 181–195. doi:10.1007/BF03033289. PMID 12835101. 
  93. ^ Miyazaki I, Asanuma M (June 2008). "Dopaminergic neuron-specific oxidative stress caused by dopamine itself". Acta Med. Okayama 62 (3): 141–150. PMID 18596830. 
  94. ^ 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. 
  95. ^ a b "Lisdexamfetamine". DrugBank. University of Alberta. 16 September 2013. Retrieved 13 June 2014.  |chapter= ignored (help)
  96. ^ 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. 
  97. ^ 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 3005101. PMID 21073468. 
  98. ^ 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 4183197. 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). 
  99. ^ "Adderall XR Prescribing Information" (PDF). United States Food and Drug Administration. pp. 1–18. Retrieved 7 October 2013. 
  100. ^ Lisdexamfetamine Dimesylate: A Prodrug Stimulant for the Treatment of ADHD in Children and Adults
  101. ^ FDA Adult Approval of Vyvanse - FDA Label and Approval History
  102. ^ Weber J, Siddiqui, MA. [1].CNSDrugs 2009; 23(5): 419-425. doi:10.2165/00023210-200923050-00005.
  103. ^ Health Canada Notice of Compliance - Vyvanse. February 19, 2009, retrieved on March 9, 2009.
  104. ^ [2]. February 8, 2012, retrieved on February 9, 2012.
  105. ^ Hirschler, Ben (7 February 2014). "UPDATE 2-Shire scraps Vyvanse for depression after failed trials". Reuters. Retrieved 13 February 2014. 
  106. ^ http://www.shire.com/shireplc/en/investors/irshirenews?id=684
  107. ^ http://www.shire.com/shireplc/en/investors/investorsnews/irshirenews?id=1055
  108. ^ 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. 
  109. ^ 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. 
  110. ^ 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
     
  111. ^ "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. 
  112. ^ 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. 
  113. ^ "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. 
  114. ^ 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 3350308. PMID 22161946. 
  115. ^ Montgomery KA (June 2008). "Sexual desire disorders". Psychiatry (Edgmont) 5 (6): 50–55. PMC 2695750. PMID 19727285. 
  116. ^ O'Connor PG (February 2012). "Amphetamines". Merck Manual for Health Care Professionals. Merck. Retrieved 8 May 2012. 
  117. ^ 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. 
  118. ^ Albertson TE (2011). "Amphetamines". In Olson KR, Anderson IB, Benowitz NL, Blanc PD, Kearney TE, Kim-Katz SY, Wu AHB. Poisoning & Drug Overdose (6th ed.). New York: McGraw-Hill Medical. pp. 77–79. ISBN 9780071668330.