Lisdexamfetamine, sold under the brand names Vyvanse and Elvanse among others, is a stimulant medication that is used to treat attention deficit hyperactivity disorder (ADHD) in children and adults and for moderate-to-severe binge eating disorder in adults.[15] Lisdexamfetamine is taken by mouth. Its effects generally begin within two hours and last for up to 14 hours.[15]
Lisdexamfetamine is used primarily as a treatment for attention deficit hyperactivity disorder (ADHD) and binge eating disorder;[7] it has similar off-label uses as those of other pharmaceutical amphetamines.[14] Individuals over the age of 65 were not commonly tested in clinical trials of lisdexamfetamine for ADHD.[7] According to a 2019 systematic review, lisdexamfetamine was the most effective treatment for adult ADHD.[24]
ADHD
Long-term amphetamine exposure at sufficiently high doses in some animal species is known to produce abnormal dopamine system development or nerve damage,[25][26] but, in humans with ADHD, long-term use of pharmaceutical amphetamines at therapeutic doses appears to improve brain development and nerve growth.[27][28][29] 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.[27][28][29]
Reviews of clinical stimulant research have established the safety and effectiveness of long-term continuous amphetamine use for the treatment of ADHD.[30][31][32]Randomized controlled trials of continuous stimulant therapy for the treatment of ADHD spanning 2 years have demonstrated treatment effectiveness and safety.[30][31] Two reviews have indicated that long-term continuous stimulant therapy for ADHD is effective for reducing the core symptoms of ADHD (i.e., hyperactivity, inattention, and impulsivity), enhancing quality of life and academic achievement, and producing improvements in a large number of functional outcomes[note 1] across 9 categories of outcomes related to academics, antisocial behavior, driving, non-medicinal drug use, obesity, occupation, self-esteem, service use (i.e., academic, occupational, health, financial, and legal services), and social function.[30][32] Additionally, a 2024 meta-analyticsystematic review reported moderate improvements in quality of life when amphetamine treatment is used for ADHD.[34] One review highlighted a nine-month randomized controlled trial of amphetamine treatment for ADHD in children that found an average increase of 4.5 IQ points, continued increases in attention, and continued decreases in disruptive behaviors and hyperactivity.[31] Another review indicated that, based upon the longest follow-up studies conducted to date, lifetime stimulant therapy that begins during childhood is continuously effective for controlling ADHD symptoms and reduces the risk of developing a substance use disorder as an adult.[30] A 2025 meta-analytic systematic review of 113 randomized controlled trials demonstrated that stimulant medications significantly improved core ADHD symptoms in adults over a three-month period, with good acceptability compared to other pharmacological and non-pharmacological treatments.[35]
Current models of ADHD suggest that it is associated with functional impairments in some of the brain's neurotransmitter systems;[36] these functional impairments involve impaired dopamine neurotransmission in the mesocorticolimbic projection and norepinephrine neurotransmission in the noradrenergic projections from the locus coeruleus to the prefrontal cortex.[36] Stimulants like methylphenidate and amphetamine are effective in treating ADHD because they increase neurotransmitter activity in these systems.[37][36][38] Approximately 80% of those who use these stimulants see improvements in ADHD symptoms.[39] 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.[40][41] The Cochrane reviews[note 2] on the treatment of ADHD in children, adolescents, and adults with pharmaceutical amphetamines stated that short-term studies have demonstrated that these drugs decrease the severity of symptoms, but they have higher discontinuation rates than non-stimulant medications due to their adverse side effects.[43][44] A Cochrane review on the treatment of ADHD in children with tic disorders such as Tourette syndrome indicated that stimulants in general do not make tics worse, but high doses of dextroamphetamine could exacerbate tics in some individuals.[45]
Binge eating disorder
Binge eating disorder (BED) is characterized by recurrent and persistent episodes of compulsive binge eating.[46] These episodes are often accompanied by marked distress and a feeling of loss of control over eating.[46] The pathophysiology of BED is not fully understood, but it is believed to involve dysfunctional dopaminergic reward circuitry along the cortico-striatal-thalamic-cortical loop.[47][48] As of July 2024, lisdexamfetamine is the only USFDA- and TGA-approved pharmacotherapy for BED.[49][50] Evidence suggests that lisdexamfetamine's treatment efficacy in BED is underpinned at least in part by a psychopathological overlap between BED and ADHD, with the latter conceptualized as a cognitive control disorder that also benefits from treatment with lisdexamfetamine.[47][48]
This diagram illustrates how TAAR1 activation induces incretin-like effects through the release of gastrointestinal hormones and influences food intake, blood glucose levels, and insulin release.[51] TAAR1 expression in the periphery is indicated with "x".[51]
Lisdexamfetamine's therapeutic effects for BED primarily involve direct action in the central nervous system after conversion to its pharmacologically active metabolite, dextroamphetamine.[50] Centrally, dextroamphetamine increases neurotransmitter activity of dopamine and norepinephrine in prefrontal cortical regions that regulate cognitive control of behavior.[47][50] Similar to its therapeutic effect in ADHD, dextroamphetamine enhances cognitive control and may reduce impulsivity in patients with BED by enhancing the cognitive processes responsible for overriding prepotent feeding responses that precede binge eating episodes.[47][52][53] In addition, dextroamphetamine's actions outside of the central nervous system may also contribute to its treatment effects in BED. Peripherally, dextroamphetamine triggers lipolysis through noradrenergic signaling in adipose fat cells, leading to the release of triglycerides into blood plasma to be utilized as a fuel substrate.[48][54] Dextroamphetamine also activates TAAR1 in peripheral organs along the gastrointestinal tract that are involved in the regulation of food intake and body weight.[51] Together, these actions confer an anorexigenic effect that promotes satiety in response to feeding and may decrease binge eating as a secondary effect.[53][51]
Medical reviews of randomized controlled trials have demonstrated that lisdexamfetamine, at doses between 50–70 mg, is safe and effective for the treatment of moderate-to-severe BED in adults.[sources 1] These reviews suggest that lisdexamfetamine is persistently effective at treating BED and is associated with significant reductions in the number of binge eating days and binge eating episodes per week.[sources 1] Furthermore, a meta-analytic systematic review highlighted an open-label, 12-month extension safety and tolerability study that reported lisdexamfetamine remained effective at reducing the number of binge eating days for the duration of the study.[53] In addition, both a review and a meta-analytic systematic review found lisdexamfetamine to be superior to placebo in several secondary outcome measures, including persistent binge eating cessation, reduction of obsessive-compulsive related binge eating symptoms, reduction of body-weight, and reduction of triglycerides.[48][53] Lisdexamfetamine, like all pharmaceutical amphetamines, has direct appetite suppressant effects that may be therapeutically useful in both BED and its comorbidities.[49][53] Based on reviews of neuroimaging studies involving BED-diagnosed participants, therapeautic neuroplasticity in dopaminergic and noradrenergic pathways from long-term use of lisdexamfetamine may be implicated in lasting improvements in the regulation of eating behaviors that are observed even after the drug is discontinued.[49][50][53]
Amphetamine’s therapeutic mode of action in narcolepsy primarily involves increasing monoamine neurotransmitter activity in the ARAS.[58][61][62] This includes noradrenergic neurons in the locus coeruleus, dopaminergic neurons in the ventral tegmental area, histaminergic neurons in the tuberomammillary nucleus, and serotonergic neurons in the dorsal raphe nucleus.[60][62] Dextroamphetamine, the more dopaminergic enantiomer of amphetamine, is particularly effective at promoting wakefulness because dopamine release has the greatest influence on cortical activation and cognitive arousal, relative to other monoamines.[58] In contrast, levoamphetamine may have a greater effect on cataplexy, a symptom more sensitive to the effects of norepinephrine and serotonin.[58] Noradrenergic and serotonergic nuclei in the ARAS are involved in the regulation of the REM sleep cycle and function as "REM-off" cells, with amphetamine's effect on norepinephrine and serotonin contributing to the suppression of REM sleep and a possible reduction of cataplexy at high doses.[58][57][60]
The American Academy of Sleep Medicine (AASM) 2021 clinical practice guideline conditionally recommends dextroamphetamine for the treatment of both type 1 and type 2 narcolepsy.[63] Treatment with pharmaceutical amphetamines is generally less preferred relative to other stimulants (e.g., modafinil) and is considered a third-line treatment option.[64][65][66] Medical reviews indicate that amphetamine is safe and effective for the treatment of narcolepsy.[58][64][63] Amphetamine appears to be most effective at improving symptoms associated with hypersomnolence, with three reviews finding clinically significant reductions in daytime sleepiness in patients with narcolepsy.[58][64][63] Additionally, these reviews suggest that amphetamine may dose-dependently improve cataplexy symptoms.[58][64][63] However, the quality of evidence for these findings is low and is consequently reflected in the AASM's conditional recommendation for dextroamphetamine as a treatment option for narcolepsy.[63]
In 2015, a systematic review and a meta-analysis of high quality clinical trials found that, when used at low (therapeutic) doses, amphetamine produces modest yet unambiguous improvements in cognition, including working memory, long-term episodic memory, inhibitory control, and some aspects of attention, in normal healthy adults;[67][68] these cognition-enhancing effects of amphetamine are known to be partially mediated through the indirect activation of both dopamine D1 receptor and α2-adrenergic receptor in the prefrontal cortex.[37][67] A systematic review from 2014 found that low doses of amphetamine also improve memory consolidation, in turn leading to improved recall of information.[69] Therapeutic doses of amphetamine also enhance cortical network efficiency, an effect which mediates improvements in working memory in all individuals.[37][70] Amphetamine and other ADHD stimulants also improve task saliency (motivation to perform a task) and increase arousal (wakefulness), in turn promoting goal-directed behavior.[37][71][72] 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.[37][72][73] Based upon studies of self-reported illicit stimulant use, 5–35% of college students use diverted ADHD stimulants, which are primarily used for enhancement of academic performance rather than as recreational drugs.[74][75][76] However, high amphetamine doses that are above the therapeutic range can interfere with working memory and other aspects of cognitive control.[37][72]
Physical performance
Amphetamine is used by some athletes for its psychological and athletic performance-enhancing effects, such as increased endurance and alertness;[77][78] however, non-medical amphetamine use is prohibited at sporting events that are regulated by collegiate, national, and international anti-doping agencies.[79][80] 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.[77][81][82] Amphetamine improves endurance and reaction time primarily through reuptake inhibition and release of dopamine in the central nervous system.[81][82][83] Amphetamine and other dopaminergic drugs also increase power output at fixed levels of perceived exertion by overriding a "safety switch", allowing the core temperature limit to increase in order to access a reserve capacity that is normally off-limits.[82][84][85] At therapeutic doses, the adverse effects of amphetamine do not impede athletic performance;[77][81] however, at much higher doses, amphetamine can induce effects that severely impair performance, such as rapid muscle breakdown and elevated body temperature.[86][81]
Available forms
Lisdexamfetamine is available as the dimesylatesalt in the form of both oralcapsules and chewable tablets.[7] A dose of 50 mg of lisdexamfetamine dimesylate is approximately equimolar to a 20 mg dose of dextroamphetamine sulfate or to 15 mg dextroamphetamine free-base in terms of the amount of dextroamphetamine contained.[13][87][88] Lisdexamfetamine capsules can be swallowed intact, or they can be opened and mixed into water, yogurt, or applesauce and consumed in that manner.[7][89]
Acidifying agents: Drugs or foods that acidify the urine, such as ascorbic acid, increase urinary excretion of dextroamphetamine, thus decreasing the half-life and effectiveness of dextroamphetamine in the body.[7][91]
Alkalinizing agents: Drugs or foods that alkalinize the urine, such as sodium bicarbonate, decrease urinary excretion of dextroamphetamine, thus increasing the half-life and effectiveness of dextroamphetamine in the body.[7][91]
Monoamine oxidase inhibitors: Concomitant use of MAOIs and central nervous system stimulants such as lisdexamfetamine can cause a hypertensive crisis.[7]
Amphetamine enters the presynaptic neuron across the neuronal membrane or through DAT.[95] Once inside, it binds to TAAR1 or enters synaptic vesicles through VMAT2.[95][96] When amphetamine enters synaptic vesicles through VMAT2, it collapses the vesicular pH gradient, which in turn causes dopamine to be released into the cytosol (light tan-colored area) through VMAT2.[96][97] When amphetamine binds to TAAR1, it reduces the firing rate of the dopamine neuron via G protein-coupled inwardly rectifying potassium channels (GIRKs) and activates protein kinase A (PKA) and protein kinase C (PKC), which subsequently phosphorylate DAT.[95][98][99]PKA phosphorylation causes DAT to withdraw into the presynaptic neuron (internalize) and cease transport.[95]PKC-phosphorylated DAT may either operate in reverse or, like PKA-phosphorylated DAT, internalize and cease transport.[95] 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.[100][101]
Lisdexamfetamine is an inactive prodrug that is converted in the body to dextroamphetamine, a pharmacologically active compound that is responsible for the drug's activity.[102] 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.[7] The half-life of this conversion is roughly 1 hour. 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.[7][103] Studies show a linear relationship between peak plasma concentration of dextroamphetamine and lisdexamfetamine dose up to lisdexamfetamine doses of 250mg.[104]
Lisdexamfetamine was developed to provide a long-duration 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 in the bloodstream. 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.[103] As opposed to Adderall, which contains amphetamine salts in a 3:1 dextro:levo ratio, lisdexamfetamine is a single-enantiomer dextroamphetamine formula.[102][91] 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%.[103]
Pharmacokinetics
Dextroamphetamine concentrations after oral administration of a single equimolar dose of dextroamphetamine sulfate immediate-release (IR) (40 mg; equivalent to 30 mg dextroamphetamine free-base) and lisdexamfetamine dimesylate (100 mg) in healthy adults.[87][105]Cmax, t1/2, and AUC∞ were all similar between the two drugs, while tlag (1.5 hours vs. 0.8 hours) and tmax (4.6 hours vs. 3.3 hours) were longer for lisdexamfetamine than with dextroamphetamine.[87]
The oral bioavailability of amphetamine varies with gastrointestinal pH;[86] it is well absorbed from the gut, and bioavailability is typically 90%.[106] Amphetamine is a weak base with a pKa of 9.9;[107] 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.[107][86] Conversely, an acidic pH means the drug is predominantly in a water-soluble cationic (salt) form, and less is absorbed.[107] Approximately 20% of amphetamine circulating in the bloodstream is bound to plasma proteins.[10] Following absorption, amphetamine readily distributes into most tissues in the body, with high concentrations occurring in cerebrospinal fluid and brain tissue.[108]
The half-lives of amphetamine enantiomers differ and vary with urine pH.[107] At normal urine pH, the half-lives of dextroamphetamine and levoamphetamine are 9–11 hours and 11–14 hours, respectively.[107] Highly acidic urine will reduce the enantiomer half-lives to 7 hours;[108] highly alkaline urine will increase the half-lives up to 34 hours.[108] 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.[107] Amphetamine is eliminated via the kidneys, with 30–40% of the drug being excreted unchanged at normal urinary pH.[107] When the urinary pH is basic, amphetamine is in its free base form, so less is excreted.[107] 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.[107] Following oral administration, amphetamine appears in urine within 3 hours.[108] Roughly 90% of ingested amphetamine is eliminated 3 days after the last oral dose.[108]
Lisdexamfetamine is a prodrug of dextroamphetamine.[13][109] It is not as sensitive to pH as amphetamine when being absorbed in the gastrointestinal tract.[109] Following absorption into the blood stream, lisdexamfetamine is completely converted by red blood cells to dextroamphetamine and the amino acidL-lysine by hydrolysis via undetermined aminopeptidaseenzymes.[109][13][87] This is the rate-limiting step in the bioactivation of lisdexamfetamine.[13] The elimination half-life of lisdexamfetamine is generally less than 1 hour.[109][13] Due to the necessary conversion of lisdexamfetamine into dextroamphetamine, levels of dextroamphetamine with lisdexamfetamine peak about one hour later than with an equivalent dose of immediate-release dextroamphetamine.[13][87] Presumably due to its rate-limited activation by red blood cells, intravenous administration of lisdexamfetamine shows greatly delayed time to peak and reduced peak levels compared to intravenous administration of an equivalent dose of dextroamphetamine.[13] The pharmacokinetics of lisdexamfetamine are similar regardless of whether it is administered orally, intranasally, or intravenously.[13][87] Hence, in contrast to dextroamphetamine, parenteral use does not enhance the subjective effects of lisdexamfetamine.[13][87] Because of its behavior as a prodrug and its pharmacokinetic differences, lisdexamfetamine has a longer duration of therapeutic effect than immediate-release dextroamphetamine and shows reduced misuse potential.[13][87]
The primary active metabolites of amphetamine are 4-hydroxyamphetamine and norephedrine;[110] at normal urine pH, about 30–40% of amphetamine is excreted unchanged and roughly 50% is excreted as the inactive metabolites (bottom row).[107] The remaining 10–20% is excreted as the active metabolites.[107] Benzoic acid is metabolized by XM-ligase into an intermediate product, benzoyl-CoA, which is then metabolized by GLYAT into hippuric acid.[120]
Aminefunctional groups are vulnerable to oxidation in air and so pharmaceuticals containing them are usually formulated as salts where this moiety has been protonated. This increases stability, water solubility, and, by converting a molecular compound to an ionic compound, increases the melting point and thereby ensures a solid product.[125] In the case of lisdexamfetamine, this is achieved by reacting with two equivalents of methanesulfonic acid to produce the dimesylate salt, a water-soluble (792 mg mL−1) powder with a white to off-white color.[7]
Lisdexamfetamine dimesylate is one marketed formulation delivering dextroamphetamine. The following table compares the drug to other amphetamine pharmaceuticals.
Amphetamine base in marketed amphetamine medications
Lisdexamfetamine was developed by New River Pharmaceuticals, who were bought by Takeda Pharmaceuticals through its acquisition of Shire Pharmaceuticals, shortly before it began being marketed. It was developed to create a longer-lasting and less-easily abused version of dextroamphetamine, as the requirement of conversion into dextroamphetamine via enzymes in the red blood cells delays its onset of action, regardless of the route of administration.[133]
In February 2007, the US Food and Drug Administration (FDA) approved lisdexamfetamine for the treatment of ADHD.[134] In August 2009, Health Canada approved the marketing of lisdexamfetamine for prescription use.[135]
In January 2015, lisdexamfetamine was approved by the FDA for the treatment of binge eating disorder in adults.[136]
The FDA gave tentative approval to generic formulations of lisdexamfetamine in 2015.[137] The expiration date for patent protection of lisdexamfetamine in the US was 24 February 2023.[137] The Canadian patent expired 20 years from the filing date of 1 June 2004.[138]
Production quotas for 2016 in the United States were 29,750 kg.[139]
Society and culture
Name
Elvanse Adult capsules 50mg and 70mg laid on the packaging (German)
As of November 2020, lisdexamfetamine is sold under the following brand names: Aduvanz, Elvanse, Juneve, Samexid, Tyvense, Venvanse, and Vyvanse.[141]
Research
Depression
Amphetamine was used to treat depression starting in the 1930s and has been described as the first antidepressant.[142] In clinical studies in the 1970s and 1980s, psychostimulants, including amphetamine and methylphenidate, were found to transiently improve mood in a majority of people with depression and to increase psychomotor activation in almost all individuals.[143]
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.[144] 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, and psychomotor activity.[145] Clinical guidelines advise caution in the use of stimulants for depression and advise them only as second- or third-line adjunctive agents.[146]
In February 2014, Shire announced that two late-stage clinical trials had found that Vyvanse was not an effective treatment for depression, and development for this indication was discontinued.[147][148] A 2018 meta-analysis of randomized controlled trials of lisdexamfetamine for antidepressant augmentation in people with major depressive disorder—the first to be conducted—found that lisdexamfetamine was not significantly better than placebo in improving Montgomery–Åsberg Depression Rating Scale scores, response rates, or remission rates.[149] However, there was indication of a small effect in improving depressive symptoms that approached trend-level significance.[149] Lisdexamfetamine was well-tolerated in the meta-analysis.[149] The quantity of evidence was limited, with only four trials included.[149] In a subsequent 2022 network meta-analysis, lisdexamfetamine was significantly effective as an antidepressant augmentation for treatment-resistant depression.[146]
Although lisdexamfetamine has shown limited effectiveness in the treatment of depression in clinical trials, a phase IIclinical study found that the addition of lisdexamfetamine to an antidepressant improved executive dysfunction in people with mild major depressive disorder but persisting executive dysfunction.[150][151]
Explanatory notes
^The ADHD-related outcome domains with the greatest proportion of significantly improved outcomes from long-term continuous stimulant therapy include academics (≈55% of academic outcomes improved), driving (100% of driving outcomes improved), non-medical drug use (47% of addiction-related outcomes improved), obesity (≈65% of obesity-related outcomes improved), self-esteem (50% of self-esteem outcomes improved), and social function (67% of social function outcomes improved).[32]
The largest effect sizes for outcome improvements from long-term stimulant therapy occur in the domains involving academics (e.g., grade point average, achievement test scores, length of education, and education level), self-esteem (e.g., self-esteem questionnaire assessments, number of suicide attempts, and suicide rates), and social function (e.g., peer nomination scores, social skills, and quality of peer, family, and romantic relationships).[32]
Long-term combination therapy for ADHD (i.e., treatment with both a stimulant and behavioral therapy) produces even larger effect sizes for outcome improvements and improves a larger proportion of outcomes across each domain compared to long-term stimulant therapy alone.[32] These findings were further supported by a 2025 review of interventions for adolescents, which concluded that medications and cognitive-behavioral treatments (CBT) provide complementary benefits. Medications demonstrated strong short-term efficacy on core symptoms, while CBT contributed modest to strong, and sometimes long-lasting, improvements in functional impairments and executive skills when used as part of combination therapy.[33]
^Cochrane reviews are high quality meta-analytic systematic reviews of randomized controlled trials.[42]
^4-Hydroxyamphetamine has been shown to be metabolized into 4-hydroxynorephedrine by dopamine beta-hydroxylase (DBH) in vitro and it is presumed to be metabolized similarly in vivo.[115][119] Evidence from studies that measured the effect of serum DBH concentrations on 4-hydroxyamphetamine metabolism in humans suggests that a different enzyme may mediate the conversion of 4-hydroxyamphetamine to 4-hydroxynorephedrine;[119][121] however, other evidence from animal studies suggests that this reaction is catalyzed by DBH in synaptic vesicles within noradrenergic neurons in the brain.[122][123]
^For uniformity, molar masses were calculated using the Lenntech Molecular Weight Calculator[126] and were within 0.01 g/mol of published pharmaceutical values.
^Amphetamine base percentage = molecular massbase / molecular masstotal. Amphetamine base percentage for Adderall = sum of component percentages / 4.
^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 sulfate. Due to pharmacological differences between these medications (e.g., differences in the release, absorption, conversion, concentration, differing effects of enantiomers, half-life, etc.), the listed values should not be considered equipotent doses.
^ abMillichap JG (2010). "Chapter 9: Medications for ADHD". In Millichap JG (ed.). Attention Deficit Hyperactivity Disorder Handbook: A Physician's Guide to ADHD (2nd ed.). New York, USA: Springer. p. 112. ISBN978-1-4419-1396-8. 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]
^ abBrams M, Mao AR, Doyle RL (September 2008). "Onset of efficacy of long-acting psychostimulants in pediatric attention-deficit/hyperactivity disorder". Postgraduate Medicine. 120 (3): 69–88. doi:10.3810/pgm.2008.09.1909. PMID18824827. S2CID31791162. 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
^Drugs of Abuse(PDF). Drug Enforcement Administration • U.S. Department of Justice. 2017. p. 22. Retrieved 16 April 2019.
^Stuhec M, Lukić P, Locatelli I (February 2019). "Efficacy, Acceptability, and Tolerability of Lisdexamfetamine, Mixed Amphetamine Salts, Methylphenidate, and Modafinil in the Treatment of Attention-Deficit Hyperactivity Disorder in Adults: A Systematic Review and Meta-analysis". The Annals of Pharmacotherapy. 53 (2): 121–133. doi:10.1177/1060028018795703. PMID30117329. S2CID52019992.
^ abcdHuang 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. PMID21699268. S2CID3449435. Several other studies,[97-101] including a meta-analytic review[98] and a retrospective study,[97] suggested that stimulant therapy in childhood is associated with a reduced risk of subsequent substance use, cigarette smoking and alcohol use disorders. ... Recent studies have demonstrated that stimulants, along with the non-stimulants atomoxetine and extended-release guanfacine, are continuously effective for more than 2-year treatment periods with few and tolerable adverse effects. The effectiveness of long-term therapy includes not only the core symptoms of ADHD, but also improved quality of life and academic achievements. The most concerning short-term adverse effects of stimulants, such as elevated blood pressure and heart rate, waned in long-term follow-up studies. ... The current data do not support the potential impact of stimulants on the worsening or development of tics or substance abuse into adulthood. In the longest follow-up study (of more than 10 years), lifetime stimulant treatment for ADHD was effective and protective against the development of adverse psychiatric disorders.
^ abcMillichap JG (2010). "Chapter 9: Medications for ADHD". In Millichap JG (ed.). Attention Deficit Hyperactivity Disorder Handbook: A Physician's Guide to ADHD (2nd ed.). New York, US: Springer. pp. 121–123, 125–127. ISBN9781441913968. 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.
^Sibley MH, Flores S, Murphy M, Basu H, Stein MA, Evans SW, et al. (January 2025). "Research Review: Pharmacological and non-pharmacological treatments for adolescents with attention deficit/hyperactivity disorder - a systematic review of the literature". Journal of Child Psychology and Psychiatry, and Allied Disciplines. 66 (1): 132–149. doi:10.1111/jcpp.14056. PMID39370392. The main efficacy-related conclusions of this review are: (a) medications demonstrated the strongest and most consistent effects on core ADHD symptoms (especially inattention), (b) heterogeneous C/BTs demonstrated inconsistent effects on ADHD symptoms, strong consistent effects on impairment and executive function skills, and modest consistent effects on internalizing symptoms and analogue note-taking performance, (c) C/BTs demonstrated consistent maintenance effects for executive function skills and impairment up to 6 months and possibly 3 years post-treatment, (d) though comparing the efficacy of two C/BTs rarely led to significant differences, which C/BT worked best for whom could be reliably predicted from patient- and provider-level moderators ... Thus, maximal therapeutic benefit (in terms of breadth of response and maintenance of effects) might be achieved by combining medication and C/BTs, a recommendation generally reflected in current practice parameters (AACAP, 2007; AADPA, 2022; NICE, 2018; Wolraich et al., 2019).
^Bellato A, Perrott NJ, Marzulli L, Parlatini V, Coghill D, Cortese S (30 May 2024). "Systematic Review and Meta-Analysis: Effects of Pharmacological Treatment for Attention-Deficit/Hyperactivity Disorder on Quality of Life". Journal of the American Academy of Child and Adolescent Psychiatry: S0890–8567(24)00304–6. doi:10.1016/j.jaac.2024.05.023. PMID38823477. We conducted the first systematic review and meta-analysis investigating the effects of medication for ADHD on quality of life (QoL) in parallel or crossover RCTs. Overall, we found that methylphenidate, amphetamines, and atomoxetine were significantly more efficacious than placebo in improving QoL in people with ADHD. ... Four studies on amphetamines (950 participants with ADHD in total; 45% adults) reported relevant data for effect sizes to be computed. The meta-analysis on 14 effect sizes showed that amphetamines led to better QoL than placebo in individuals with ADHD.
^ abcMalenka RC, Nestler EJ, Hyman SE (2009). "Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York, US: McGraw-Hill Medical. pp. 154–157. ISBN9780071481274.
^ abcdefMalenka RC, Nestler EJ, Hyman SE (2009). "Chapter 13: Higher Cognitive Function and Behavioral Control". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York, US: McGraw-Hill Medical. pp. 318, 321. ISBN9780071481274. 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.
^Millichap JG (2010). "Chapter 9: Medications for ADHD". In Millichap JG (ed.). Attention Deficit Hyperactivity Disorder Handbook: A Physician's Guide to ADHD (2nd ed.). New York, US: Springer. pp. 111–113. ISBN9781441913968.
^ abcdHeal DJ, Smith SL (June 2022). "Prospects for new drugs to treat binge-eating disorder: Insights from psychopathology and neuropharmacology". Journal of Psychopharmacology. 36 (6): 680–703. doi:10.1177/02698811211032475. PMC9150143. PMID34318734. BED subjects have substantial decrements in their ventral striatal reward pathways and diminished ability to recruit fronto-cortical impulse-control circuits to implement dietary restraint. ... There is not only substantial overlap between the psychopathology of BED and ADHD but also a clear association between these two disorders. Lisdexamfetamine's ability to reduce impulsivity and increase cognitive control in ADHD supports the hypothesis that efficacy in BED is dependent on treating its core obsessive, compulsive and impulsive behaviours.
^ abcdeMcElroy SL (2017). "Pharmacologic Treatments for Binge-Eating Disorder". The Journal of Clinical Psychiatry. 78 (Suppl 1): 14–19. doi:10.4088/JCP.sh16003su1c.03. PMID28125174. Genetic polymorphisms associated with abnormal dopaminergic signaling have been found in individuals who exhibit binge-eating behavior, and the binge-eating episodes,which often involve the consumption of highly palatable food, further stimulate the dopaminergic system. This ongoing stimulation may contribute to progressive impairments in dopamine signaling. Lisdexamfetamine is hypothesized to reduce binge-eating behavior by normalizing dopaminergic activity. ... After 12 weeks, both studies found significant reductions in the number of binge-eating days per week in the active treatment group compared with placebo (P < .001 for both studies; Figure 1). Lisdexamfetamine was also found to be superior to placebo on a number of secondary outcome measures including global improvement, binge-eating cessation for 4 weeks, and reduction of obsessive-compulsive binge-eating symptoms, body weight, and triglycerides.
^ abcdRodan SC, Bryant E, Le A, Maloney D, Touyz S, McGregor IS, et al. (July 2023). "Pharmacotherapy, alternative and adjunctive therapies for eating disorders: findings from a rapid review". Journal of Eating Disorders. 11 (1): 112. doi:10.1186/s40337-023-00833-9. PMC10327007. PMID37415200. LDX is commonly used in the treatment of ADHD, and is the only treatment for BED that is currently approved by the Food and Drug Administration (FDA) and the Therapeutic Goods Administration (TGA). LDX, like all amphetamine stimulants, has direct appetite suppressant effects that may be therapeutically useful in BED, although long-term neuroadaptations in dopaminergic and noradrenergic systems caused by LDX may also be relevant, leading to improved regulation of eating behaviours, attentional processes and goal-directed behaviours. ... Evidently, there is a substantial volume of trials with high-quality evidence supporting the efficacy of LDX in reducing binge eating frequency in treatment of adults with moderate to severe BED at 50–70 mg/day.
^ abcdeBoswell RG, Potenza MN, Grilo CM (January 2021). "The Neurobiology of Binge-eating Disorder Compared with Obesity: Implications for Differential Therapeutics". Clinical Therapeutics. 43 (1): 50–69. doi:10.1016/j.clinthera.2020.10.014. PMC7902428. PMID33257092. Stimulant medications may be especially effective for individuals with BED because of dual effects on reward and executive function systems. Indeed, the only FDA-approved pharmacotherapy for BED is LDX, a d-amphetamine prodrug. ... In humans, RCTs found that LDX reduced binge eating and impulsivity/compulsivity symptoms. Notably, there is a strong correlation between compulsivity symptoms and severity/frequency of binge eating episodes observed in LDX trials. Further, in individuals with BED, changes in prefrontal brain systems associated with LDX treatment were related to treatment outcome.
^Malenka RC, Nestler EJ, Hyman SE, Holtzman DM (2015). "Chapter 14: Higher Cognitive Function and Behavioral Control". Molecular neuropharmacology: a foundation for clinical neuroscience (3rd ed.). New York: McGraw-Hill Medical. ISBN9780071827706. Because behavioral responses in humans are not rigidly dictated by sensory inputs and drives, behavioral responses can instead be guided in accordance with short- or long-term goals, prior experience, and the environmental context. The response to a delicious-looking dessert is different depending on whether a person is alone staring into his or her refrigerator, is at a formal dinner party attended by his or her punctilious boss, or has just formulated the goal of losing 10 lb. ... Adaptive responses depend on the ability to inhibit automatic or prepotent responses (eg, to ravenously eat the dessert or run from the snake) given certain social or environmental contexts or chosen goals and, in those circumstances, to select more appropriate responses. In conditions in which prepotent responses tend to dominate behavior, such as in drug addiction, where drug cues can elicit drug seeking (Chapter 16), or inattention deficit hyperactivity disorder (ADHD; described below), significant negative consequences can result.
^ abcdefgSchneider E, Higgs S, Dourish CT (December 2021). "Lisdexamfetamine and binge-eating disorder: A systematic review and meta-analysis of the preclinical and clinical data with a focus on mechanism of drug action in treating the disorder"(PDF). European Neuropsychopharmacology. 53: 49–78. doi:10.1016/j.euroneuro.2021.08.001. PMID34461386. Our meta-analysis of the four RCT data sets (Guerdjikova et al., 2016; McElroy et al., 2015b; McElroy et al., 2016a) showed an overall significant effect of LDX on binge-eating symptom change. ... BED has been described as an impulse control disorder since one of the key symptoms of the disorder is a lack of control over eating (American Psychiatric Association, 2013) and it is possible that LDX may be effective in treating BED at least in part by reducing impulsivity, compulsivity, and the repetitive nature of binge eating. There is extensive evidence that loss of impulse control in BED is a causal factor in provoking bingeing symptoms (Colles et al., 2008; Galanti et al., 2007; Giel et al., 2017; McElroy et al., 2016a; Nasser et al., 2004; Schag et al., 2013). More specifically, BED is associated with motor impulsivity and non-planning impulsivity which could initiate and maintain binge eating (Nasser et al., 2004). Neuroimaging studies using the Stroop task to measure impulse control have shown that BED patients have decreased BOLD fMRI activity in brain areas involved in self-regulation and impulse control including VMPFC, inferior frontal gyrus (IFG), and insula during performance of the task compared to lean and obese controls (Balodis et al., 2013b). ... It is conceivable that in BED patients a low 30 mg dose of LDX could reduce food intake by suppressing appetite or enhancing satiety and higher (50 and 70 mg) doses of the drug may have a dual suppressant effect on food intake and binge-eating frequency.
^Branis NM, Wittlin SD (2015). "Amphetamine-Like Analogues in Diabetes: Speeding towards Ketogenesis". Case Reports in Endocrinology. 2015: 917869. doi:10.1155/2015/917869. PMC4417573. PMID25960894. Peripheral norepinephrine concentration rises as well. As demonstrated after Dextroamphetamine administration, plasma norepinephrine can rise up to 400 pg/mL, a level comparable to that achieved during mild physical activity. Cumulative effect on norepinephrine concentration is likely when amphetamine-type medications are given in the setting of acute illness or combined with activities leading to catecholamine release, such as exercise. ... The primary effect of norepinephrine on ketogenesis is mediated through increased substrate availability. As shown by Krentz et al., at high physiological concentrations, norepinephrine induces accelerated lipolysis and increases NEFA formation significantly. Secondly, norepinephrine stimulates ketogenesis directly at the hepatocyte level. As reported by Keller et al., norepinephrine infusion increased ketone bodies concentration to a greater degree when compared to NEFA concentration (155 ± 30 versus 57 ± 16%), suggesting direct hepatic ketogenic effect.
^Muratore AF, Attia E (July 2022). "Psychopharmacologic Management of Eating Disorders". Current Psychiatry Reports. 24 (7): 345–351. doi:10.1007/s11920-022-01340-5. PMC9233107. PMID35576089. An 11-week, double-blind RCT examined the effects of three doses of lisdexamfetamine (30 mg/day, 50 mg/day, 70 mg/day) and placebo on binge eating frequency. Results indicated that 50 mg and 70 mg doses were superior to placebo in reducing binge eating. Two follow-up 12-week RCTs confirmed the superiority of 50 and 70 mg doses to placebo in improving binge eating and secondary outcome measures, including obsessive–compulsive symptoms, body weight, and global improvement. ... Subsequent studies of lisdexamfetamine provided further support for the medication's safety and efficacy and provided additional evidence that continued use may be better than placebo in preventing relapse. While it is considered safe and effective, lisdexamfetamine's side effect profile and risk for misuse may make it inappropriate for certain patients.
^ abcBarateau L, Pizza F, Plazzi G, Dauvilliers Y (August 2022). "Narcolepsy". Journal of Sleep Research. 31 (4): e13631. doi:10.1111/jsr.13631. PMID35624073. Narcolepsy type 1 was called "narcolepsy with cataplexy" before 2014 (AASM, 2005), but was renamed NT1 in the third and last international classification of sleep disorders (AASM, 2014). ... A low level of Hcrt-1 in the CSF is very sensitive and specific for the diagnosis of NT1. ... All patients with low CSF Hcrt-1 levels are considered as NT1 patients, even if they report no cataplexy (in about 10–20% of cases), and all patients with normal CSF Hcrt-1 levels (or without cataplexy when the lumbar puncture is not performed) as NT2 patients (Baumann et al., 2014). ... In patients with NT1, the absence of Hcrt leads to the inhibition of regions that suppress REM sleep, thus allowing the activation of descending pathways inhibiting motoneurons, leading to cataplexy.
^ abcdefghMignot EJ (October 2012). "A practical guide to the therapy of narcolepsy and hypersomnia syndromes". Neurotherapeutics. 9 (4): 739–752. doi:10.1007/s13311-012-0150-9. PMC3480574. PMID23065655. At the pathophysiological level, it is now clear that most narcolepsy cases with cataplexy, and a minority of cases (5–30 %) without cataplexy or with atypical cataplexy-like symptoms, are caused by a lack of hypocretin (orexin) of likely an autoimmune origin. In these cases, once the disease is established, the majority of the 70,000 hypocretin-producing cells have been destroyed, and the disorder is irreversible. ... Amphetamines are exceptionally wake-promoting, and at high doses also reduce cataplexy in narcoleptic patients, an effect best explained by its action on adrenergic and serotoninergic synapses. ... The D-isomer is more specific for DA transmission and is a better stimulant compound. Some effects on cataplexy (especially for the L-isomer), secondary to adrenergic effects, occur at higher doses. ... Numerous studies have shown that increased dopamine release is the main property explaining wake-promotion, although norepinephrine effects also contribute.
^ abMalenka RC, Nestler EJ, Hyman SE, Holtzman DM (2015). "Chapter 10: Neural and Neuroendocrine Control of the Internal Milieu". Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (3rd ed.). New York: McGraw-Hill Medical. pp. 456–457. ISBN9780071827706. More recently, the lateral hypothalamus was also found to play a central role in arousal. Neurons in this region contain cell bodies that produce the orexin (also called hypocretin) peptides (Chapter 6). These neurons project widely throughout the brain and are involved in sleep, arousal, feeding, reward,aspects of emotion, and learning. In fact, orexin is thought to promote feeding primarily by promoting arousal. Mutations in orexin receptors are responsible for narcolepsy in a canine model, knockout of the orexin gene produces narcolepsy in mice, and humans with narcolepsy have low or absent levels of orexin peptides in cerebrospinal fluid (Chapter 13). Lateral hypothalamus neurons have reciprocal connections with neurons that produce monoamine neurotransmitters (Chapter 6).
^ abcMalenka RC, Nestler EJ, Hyman SE, Holtzman DM (2015). "Chapter 13: Sleep and Arousal". Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (3rd ed.). McGraw-Hill Medical. p. 521. ISBN9780071827706. The ARAS consists of several different circuits including the four main monoaminergic pathways discussed in Chapter 6. The norepinephrine pathway originates from the LC and related brainstem nuclei; the serotonergic neurons originate from the RN within the brainstem as well; the dopaminergic neurons originate in the ventral tegmental area (VTA); and the histaminergic pathway originates from neurons in the tuberomammillary nucleus (TMN) of the posterior hypothalamus. As discussed in Chapter 6, these neurons project widely throughout the brain from restricted collections of cell bodies. Norepinephrine, serotonin,dopamine, and histamine have complex modulatory functions and, in general, promote wakefulness. The PT in the brainstem is also an important component of the ARAS. Activity of PT cholinergic neurons (REM-on cells) promotes REM sleep, as noted earlier. During waking, REM-on cells are inhibited by a subset of ARAS norepinephrine and serotonin neurons called REM-off cells.
^Shneerson JM (2009). Sleep medicine a guide to sleep and its disorders (2nd ed.). John Wiley & Sons. p. 81. ISBN9781405178518. All the amphetamines enhance activity at dopamine, noradrenaline and 5HT synapses. They cause presynaptic release of preformed transmitters, and also inhibit the re-uptake of dopamine and noradrenaline. These actions are most prominent in the brainstem ascending reticular activating system and the cerebral cortex.
^ abSchwartz JR, Roth T (2008). "Neurophysiology of sleep and wakefulness: basic science and clinical implications". Current Neuropharmacology. 6 (4): 367–378. doi:10.2174/157015908787386050. PMC2701283. PMID19587857. Alertness and associated forebrain and cortical arousal are mediated by several ascending pathways with distinct neuronal components that project from the upper brain stem near the junction of the pons and the midbrain. ... Key cell populations of the ascending arousal pathway include cholinergic, noradrenergic, serotoninergic, dopaminergic, and histaminergic neurons located in the pedunculopontine and laterodorsal tegmental nucleus (PPT/LDT), locus coeruleus, dorsal and median raphe nucleus, and tuberomammillary nucleus (TMN), respectively. ... The mechanism of action of sympathomimetic alerting drugs (eg, dextro- and methamphetamine, methylphenidate) is direct or indirect stimulation of dopaminergic and noradrenergic nuclei, which in turn heightens the efficacy of the ventral periaqueductal grey area and locus coeruleus, both components of the secondary branch of the ascending arousal system. ... Sympathomimetic drugs have long been used to treat narcolepsy
^ abcdeMaski K, Trotti LM, Kotagal S, Robert Auger R, Rowley JA, Hashmi SD, et al. (September 2021). "Treatment of central disorders of hypersomnolence: an American Academy of Sleep Medicine clinical practice guideline". Journal of Clinical Sleep Medicine. 17 (9): 1881–1893. doi:10.5664/jcsm.9328. PMC8636351. PMID34743789. The TF identified 1 double-blind RCT, 1 single-blind RCT, and 1 retrospective observational long-term self-reported case series assessing the efficacy of dextroamphetamine in patients with narcolepsy type 1 and narcolepsy type 2. These studies demonstrated clinically significant improvements in excessive daytime sleepiness and cataplexy.
^ abcdBarateau L, Lopez R, Dauvilliers Y (October 2016). "Management of Narcolepsy". Current Treatment Options in Neurology. 18 (10): 43. doi:10.1007/s11940-016-0429-y. PMID27549768. The usefulness of amphetamines is limited by a potential risk of abuse, and their cardiovascular adverse effects (Table 1). That is why, even though they are cheaper than other drugs, and efficient, they remain third-line therapy in narcolepsy. Three class II studies showed an improvement of EDS in that disease. ... Despite the potential for drug abuse or tolerance using stimulants, patients with narcolepsy rarely exhibit addiction to their medication. ... Some stimulants, such as mazindol, amphetamines, and pitolisant, may also have some anticataplectic effects.
^Dauvilliers Y, Barateau L (August 2017). "Narcolepsy and Other Central Hypersomnias". Continuum. 23 (4, Sleep Neurology): 989–1004. doi:10.1212/CON.0000000000000492. PMID28777172. Recent clinical trials and practice guidelines have confirmed that stimulants such as modafinil, armodafinil, or sodium oxybate (as first line); methylphenidate and pitolisant (as second line [pitolisant is currently only available in Europe]); and amphetamines (as third line) are appropriate medications for excessive daytime sleepiness.
^Thorpy MJ, Bogan RK (April 2020). "Update on the pharmacologic management of narcolepsy: mechanisms of action and clinical implications". Sleep Medicine. 68: 97–109. doi:10.1016/j.sleep.2019.09.001. PMID32032921. The first agents used to treat EDS (ie, amphetamines, methylphenidate) are now considered second- or third-line options because newer medications have been developed with improved tolerability and lower abuse potential (eg, modafinil/armodafinil, solriamfetol, pitolisant)
^ abSpencer RC, Devilbiss DM, Berridge CW (June 2015). "The Cognition-Enhancing Effects of Psychostimulants Involve Direct Action in the Prefrontal Cortex". Biological Psychiatry. 77 (11): 940–950. doi:10.1016/j.biopsych.2014.09.013. PMC4377121. PMID25499957. The procognitive actions of psychostimulants are only associated with low doses. Surprisingly, despite nearly 80 years of clinical use, the neurobiology of the procognitive actions of psychostimulants has only recently been systematically investigated. Findings from this research unambiguously demonstrate that the cognition-enhancing effects of psychostimulants involve the preferential elevation of catecholamines in the PFC and the subsequent activation of norepinephrine α2 and dopamine D1 receptors. ... This differential modulation of PFC-dependent processes across dose appears to be associated with the differential involvement of noradrenergic α2 versus α1 receptors. Collectively, this evidence indicates that at low, clinically relevant doses, psychostimulants are devoid of the behavioral and neurochemical actions that define this class of drugs and instead act largely as cognitive enhancers (improving PFC-dependent function). ... In particular, in both animals and humans, lower doses maximally improve performance in tests of working memory and response inhibition, whereas maximal suppression of overt behavior and facilitation of attentional processes occurs at higher doses.
^Devous MD, Trivedi MH, Rush AJ (April 2001). "Regional cerebral blood flow response to oral amphetamine challenge in healthy volunteers". Journal of Nuclear Medicine. 42 (4): 535–542. PMID11337538.
^Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 10: Neural and Neuroendocrine Control of the Internal Milieu". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York, US: McGraw-Hill Medical. p. 266. ISBN9780071481274. Dopamine acts in the nucleus accumbens to attach motivational significance to stimuli associated with reward.
^Clemow DB, Walker DJ (September 2014). "The potential for misuse and abuse of medications in ADHD: a review". Postgraduate Medicine. 126 (5): 64–81. doi:10.3810/pgm.2014.09.2801. PMID25295651. S2CID207580823. 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.
^ abcLiddle DG, Connor DJ (June 2013). "Nutritional supplements and ergogenic AIDS". Primary Care: Clinics in Office Practice. 40 (2): 487–505. doi:10.1016/j.pop.2013.02.009. PMID23668655. 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
^Westfall DP, Westfall TC (2010). "Miscellaneous Sympathomimetic Agonists". In Brunton LL, Chabner BA, Knollmann BC (eds.). Goodman & Gilman's Pharmacological Basis of Therapeutics (12th ed.). New York, US: McGraw-Hill. ISBN9780071624428.
^ abcdParr JW (July 2011). "Attention-deficit hyperactivity disorder and the athlete: new advances and understanding". Clinics in Sports Medicine. 30 (3): 591–610. doi:10.1016/j.csm.2011.03.007. PMID21658550. 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.
^ abcRoelands B, de Koning J, Foster C, Hettinga F, Meeusen R (May 2013). "Neurophysiological determinants of theoretical concepts and mechanisms involved in pacing". Sports Medicine. 43 (5): 301–311. doi:10.1007/s40279-013-0030-4. PMID23456493. S2CID30392999. 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.
^Parker KL, Lamichhane D, Caetano MS, Narayanan NS (October 2013). "Executive dysfunction in Parkinson's disease and timing deficits". Frontiers in Integrative Neuroscience. 7: 75. doi:10.3389/fnint.2013.00075. PMC3813949. PMID24198770. 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.
^Rattray B, Argus C, Martin K, Northey J, Driller M (March 2015). "Is it time to turn our attention toward central mechanisms for post-exertional recovery strategies and performance?". Frontiers in Physiology. 6: 79. doi:10.3389/fphys.2015.00079. PMC4362407. PMID25852568. 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)
^Roelands B, De Pauw K, Meeusen R (June 2015). "Neurophysiological effects of exercise in the heat". Scandinavian Journal of Medicine & Science in Sports. 25 (Suppl 1): 65–78. doi:10.1111/sms.12350. PMID25943657. S2CID22782401. 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.
^ abcdefghDolder PC, Strajhar P, Vizeli P, Hammann F, Odermatt A, Liechti ME (2017). "Pharmacokinetics and Pharmacodynamics of Lisdexamfetamine Compared with D-Amphetamine in Healthy Subjects". Front Pharmacol. 8: 617. doi:10.3389/fphar.2017.00617. PMC5594082. PMID28936175. Inactive lisdexamfetamine is completely (>98%) converted to its active metabolite D-amphetamine in the circulation (Pennick, 2010; Sharman and Pennick, 2014). When lisdexamfetamine is misused intranasally or intravenously, the pharmacokinetics are similar to oral use (Jasinski and Krishnan, 2009b; Ermer et al., 2011), and the subjective effects are not enhanced by parenteral administration in contrast to D-amphetamine (Lile et al., 2011) thus reducing the risk of parenteral misuse of lisdexamfetamine compared with D-amphetamine. Intravenous lisdexamfetamine use also produced significantly lower increases in "drug liking" and "stimulant effects" compared with D-amphetamine in intravenous substance users (Jasinski and Krishnan, 2009a).
^"Elvanse Adult 30mg Hard Capsules". Retrieved 26 February 2022. 2. Qualitative and quantitative composition. 30 mg Capsules: Each capsule contains 30 mg lisdexamfetamine dimesylate, equivalent to 8.9 mg of dexamfetamine. 50 mg Capsules: Each capsule contains 50 mg lisdexamfetamine dimesylate, equivalent to 14.8 mg of dexamfetamine. 70 mg Capsules: Each capsule contains 70 mg lisdexamfetamine dimesylate, equivalent to 20.8 mg of dexamfetamine.
^Sulzer D, Cragg SJ, Rice ME (August 2016). "Striatal dopamine neurotransmission: regulation of release and uptake". Basal Ganglia. 6 (3): 123–148. doi:10.1016/j.baga.2016.02.001. PMC4850498. PMID27141430. Despite the challenges in determining synaptic vesicle pH, the proton gradient across the vesicle membrane is of fundamental importance for its function. Exposure of isolated catecholamine vesicles to protonophores collapses the pH gradient and rapidly redistributes transmitter from inside to outside the vesicle. ... Amphetamine and its derivatives like methamphetamine are weak base compounds that are the only widely used class of drugs known to elicit transmitter release by a non-exocytic mechanism. As substrates for both DAT and VMAT, amphetamines can be taken up to the cytosol and then sequestered in vesicles, where they act to collapse the vesicular pH gradient.
^Ledonne A, Berretta N, Davoli A, Rizzo GR, Bernardi G, Mercuri NB (July 2011). "Electrophysiological effects of trace amines on mesencephalic dopaminergic neurons". Front. Syst. Neurosci. 5: 56. doi:10.3389/fnsys.2011.00056. PMC3131148. PMID21772817. Three important new aspects of TAs action have recently emerged: (a) inhibition of firing due to increased release of dopamine; (b) reduction of D2 and GABAB receptor-mediated inhibitory responses (excitatory effects due to disinhibition); and (c) a direct TA1 receptor-mediated activation of GIRK channels which produce cell membrane hyperpolarization.
^"TAAR1". GenAtlas. University of Paris. 28 January 2012. Retrieved 29 May 2014. • tonically activates inwardly rectifying K(+) channels, which reduces the basal firing frequency of dopamine (DA) neurons of the ventral tegmental area (VTA)
^Underhill SM, Wheeler DS, Li M, Watts SD, Ingram SL, Amara SG (July 2014). "Amphetamine modulates excitatory neurotransmission through endocytosis of the glutamate transporter EAAT3 in dopamine neurons". Neuron. 83 (2): 404–416. doi:10.1016/j.neuron.2014.05.043. PMC4159050. PMID25033183. AMPH also increases intracellular calcium (Gnegy et al., 2004) that is associated with calmodulin/CamKII activation (Wei et al., 2007) and modulation and trafficking of the DAT (Fog et al., 2006; Sakrikar et al., 2012). ... For example, AMPH increases extracellular glutamate in various brain regions including the striatum, VTA and NAc (Del Arco et al., 1999; Kim et al., 1981; Mora and Porras, 1993; Xue et al., 1996), but it has not been established whether this change can be explained by increased synaptic release or by reduced clearance of glutamate. ... DHK-sensitive, EAAT2 uptake was not altered by AMPH (Figure 1A). The remaining glutamate transport in these midbrain cultures is likely mediated by EAAT3 and this component was significantly decreased by AMPH
^Vaughan RA, Foster JD (September 2013). "Mechanisms of dopamine transporter regulation in normal and disease states". Trends Pharmacol. Sci. 34 (9): 489–496. doi:10.1016/j.tips.2013.07.005. PMC3831354. PMID23968642. AMPH and METH also stimulate DA efflux, which is thought to be a crucial element in their addictive properties [80], although the mechanisms do not appear to be identical for each drug [81]. These processes are PKCβ– and CaMK–dependent [72, 82], and PKCβ knock-out mice display decreased AMPH-induced efflux that correlates with reduced AMPH-induced locomotion [72].
^ abcJasinski DR, Krishnan S (June 2009). "Abuse liability and safety of oral lisdexamfetamine dimesylate in individuals with a history of stimulant abuse". Journal of Psychopharmacology. 23 (4): 419–427. doi:10.1177/0269881109103113. PMID19329547. S2CID6138292.
^Ermer J, Homolka R, Martin P, Buckwalter M, Purkayastha J, Roesch B (September 2010). "Lisdexamfetamine dimesylate: linear dose-proportionality, low intersubject and intrasubject variability, and safety in an open-label single-dose pharmacokinetic study in healthy adult volunteers". Journal of Clinical Pharmacology. 50 (9): 1001–1010. doi:10.1177/0091270009357346. PMID20173084.
^Patel VB, Preedy VR, eds. (2022). Handbook of Substance Misuse and Addictions. Cham: Springer International Publishing. p. 2006. doi:10.1007/978-3-030-92392-1. ISBN978-3-030-92391-4. Amphetamine is usually consumed via inhalation or orally, either in the form of a racemic mixture (levoamphetamine and dextroamphetamine) or dextroamphetamine alone (Childress et al. 2019). In general, all amphetamines have high bioavailability when consumed orally, and in the specific case of amphetamine, 90% of the consumed dose is absorbed in the gastrointestinal tract, with no significant differences in the rate and extent of absorption between the two enantiomers (Carvalho et al. 2012; Childress et al. 2019). The onset of action occurs approximately 30 to 45 minutes after consumption, depending on the ingested dose and on the degree of purity or on the concomitant consumption of certain foods (European Monitoring Centre for Drugs and Drug Addiction 2021a; Steingard et al. 2019). It is described that those substances that promote acidification of the gastrointestinal tract cause a decrease in amphetamine absorption, while gastrointestinal alkalinization may be related to an increase in the compound's absorption (Markowitz and Patrick 2017).
^ abcde"Metabolism/Pharmacokinetics". Amphetamine. Hazardous Substances Data Bank. United States National Library of Medicine – Toxicology Data Network. Archived from the original on 2 October 2017. Retrieved 2 October 2017. Duration of effect varies depending on agent and urine pH. Excretion is enhanced in more acidic urine. Half-life is 7 to 34 hours and is, in part, dependent on urine pH (half-life is longer with alkaline urine). ... Amphetamines are distributed into most body tissues with high concentrations occurring in the brain and CSF. Amphetamine appears in the urine within about 3 hours following oral administration. ... Three days after a dose of (+ or -)-amphetamine, human subjects had excreted 91% of the (14)C in the urine
^ abcSantagati NA, Ferrara G, Marrazzo A, Ronsisvalle G (September 2002). "Simultaneous determination of amphetamine and one of its metabolites by HPLC with electrochemical detection". Journal of Pharmaceutical and Biomedical Analysis. 30 (2): 247–255. doi:10.1016/S0731-7085(02)00330-8. PMID12191709.
^"Compound Summary". p-Hydroxyamphetamine. PubChem Compound Database. United States National Library of Medicine – National Center for Biotechnology Information. Retrieved 15 October 2013.
^"Compound Summary". p-Hydroxynorephedrine. PubChem Compound Database. United States National Library of Medicine – National Center for Biotechnology Information. Retrieved 15 October 2013.
^"Compound Summary". Phenylpropanolamine. PubChem Compound Database. United States National Library of Medicine – National Center for Biotechnology Information. Retrieved 15 October 2013.
^"Pharmacology and Biochemistry". Amphetamine. Pubchem Compound Database. United States National Library of Medicine – National Center for Biotechnology Information. Retrieved 12 October 2013.
^ abGlennon RA (2013). "Phenylisopropylamine stimulants: amphetamine-related agents". In Lemke TL, Williams DA, Roche VF, Zito W (eds.). Foye's principles of medicinal chemistry (7th ed.). Philadelphia, US: Wolters Kluwer Health/Lippincott Williams & Wilkins. pp. 646–648. ISBN9781609133450. 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.
^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". Journal of Pharmacology and Experimental Therapeutics. 288 (3): 1251–1260. PMID10027866.
^ abcSjoerdsma A, von Studnitz W (April 1963). "Dopamine-beta-oxidase activity in man, using hydroxyamphetamine as substrate". British Journal of Pharmacology and Chemotherapy. 20 (2): 278–284. doi:10.1111/j.1476-5381.1963.tb01467.x. PMC1703637. PMID13977820. Hydroxyamphetamine was administered orally to five human subjects ... Since conversion of hydroxyamphetamine to hydroxynorephedrine occurs in vitro by the action of dopamine-β-oxidase, a simple method is suggested for measuring the activity of this enzyme and the effect of its inhibitors in man. ... The lack of effect of administration of neomycin to one patient indicates that the hydroxylation occurs in body tissues. ... a major portion of the β-hydroxylation of hydroxyamphetamine occurs in non-adrenal tissue. Unfortunately, at the present time one cannot be completely certain that the hydroxylation of hydroxyamphetamine in vivo is accomplished by the same enzyme which converts dopamine to noradrenaline.
^ abBadenhorst CP, van der Sluis R, Erasmus E, van Dijk AA (September 2013). "Glycine conjugation: importance in metabolism, the role of glycine N-acyltransferase, and factors that influence interindividual variation". Expert Opinion on Drug Metabolism & Toxicology. 9 (9): 1139–1153. doi:10.1517/17425255.2013.796929. PMID23650932. S2CID23738007. Figure 1. Glycine conjugation of benzoic acid. The glycine conjugation pathway consists of two steps. First benzoate is ligated to CoASH to form the high-energy benzoyl-CoA thioester. This reaction is catalyzed by the HXM-A and HXM-B medium-chain acid:CoA ligases and requires energy in the form of ATP. ... The benzoyl-CoA is then conjugated to glycine by GLYAT to form hippuric acid, releasing CoASH. In addition to the factors listed in the boxes, the levels of ATP, CoASH, and glycine may influence the overall rate of the glycine conjugation pathway.
^Horwitz D, Alexander RW, Lovenberg W, Keiser HR (May 1973). "Human serum dopamine-β-hydroxylase. Relationship to hypertension and sympathetic activity". Circulation Research. 32 (5): 594–599. doi:10.1161/01.RES.32.5.594. PMID4713201. S2CID28641000. The biologic significance of the different levels of serum DβH activity was studied in two ways. First, in vivo ability to β-hydroxylate the synthetic substrate hydroxyamphetamine was compared in two subjects with low serum DβH activity and two subjects with average activity. ... In one study, hydroxyamphetamine (Paredrine), a synthetic substrate for DβH, was administered to subjects with either low or average levels of serum DβH activity. The percent of the drug hydroxylated to hydroxynorephedrine was comparable in all subjects (6.5-9.62) (Table 3).
^Freeman JJ, Sulser F (December 1974). "Formation of p-hydroxynorephedrine in brain following intraventricular administration of p-hydroxyamphetamine". Neuropharmacology. 13 (12): 1187–1190. doi:10.1016/0028-3908(74)90069-0. PMID4457764. In species where aromatic hydroxylation of amphetamine is the major metabolic pathway, p-hydroxyamphetamine (POH) and p-hydroxynorephedrine (PHN) may contribute to the pharmacological profile of the parent drug. ... The location of the p-hydroxylation and β-hydroxylation reactions is important in species where aromatic hydroxylation of amphetamine is the predominant pathway of metabolism. Following systemic administration of amphetamine to rats, POH has been found in urine and in plasma. The observed lack of a significant accumulation of PHN in brain following the intraventricular administration of (+)-amphetamine and the formation of appreciable amounts of PHN from (+)-POH in brain tissue in vivo supports the view that the aromatic hydroxylation of amphetamine following its systemic administration occurs predominantly in the periphery, and that POH is then transported through the blood-brain barrier, taken up by noradrenergic neurones in brain where (+)-POH is converted in the storage vesicles by dopamine β-hydroxylase to PHN.
^Matsuda LA, Hanson GR, Gibb JW (December 1989). "Neurochemical effects of amphetamine metabolites on central dopaminergic and serotonergic systems". Journal of Pharmacology and Experimental Therapeutics. 251 (3): 901–908. PMID2600821. The metabolism of p-OHA to p-OHNor is well documented and dopamine-β hydroxylase present in noradrenergic neurons could easily convert p-OHA to p-OHNor after intraventricular administration.
^"Dyanavel XR Prescribing Information"(PDF). United States Food and Drug Administration. Tris Pharma, Inc. May 2017. pp. 1–14. Retrieved 4 August 2017. 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. The amphetamine base contains dextro- to levo-amphetamine in a ratio of 3.2:1, which is approximately the ratio in Adderall. The product uses an ion exchange resin to achieve extended release of the amphetamine base.
^Buoli M, Serati M, Cahn W (2016). "Alternative pharmacological strategies for adult ADHD treatment: a systematic review". Expert Review of Neurotherapeutics. 16 (2): 131–144. doi:10.1586/14737175.2016.1135735. PMID26693882. S2CID33004517.
^Rasmussen N (July 2006). "Making the first anti-depressant: amphetamine in American medicine, 1929-1950". J Hist Med Allied Sci. 61 (3): 288–323. doi:10.1093/jhmas/jrj039. PMID16492800.
^Brown AS, Gershon S (1993). "Dopamine and depression". J Neural Transm Gen Sect. 91 (2–3): 75–109. doi:10.1007/BF01245227. PMID8099801.
^"Lisdexamfetamine - Shionogi/Takeda". Adisinsight.springer.com. Retrieved 12 March 2022. Clinical development is underway in the US, for mood disorders in children and adolescents for binge eating disorder and ADHD.
^ abcdGiacobbe P, Rakita U, Lam R, Milev R, Kennedy SH, McIntyre RS (January 2018). "Efficacy and tolerability of lisdexamfetamine as an antidepressant augmentation strategy: A meta-analysis of randomized controlled trials". Journal of Affective Disorders. 226: 294–300. doi:10.1016/j.jad.2017.09.041. PMID29028590.
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