Dextroamphetamine[note 1] is a potent central nervous system (CNS) stimulant and amphetamine stereoisomer prescribed for the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. Dextroamphetamine is also widely used by military air forces as a 'go-pill' during fatigue-inducing mission profiles such as night-time bombing missions. Preparations containing dextroamphetamine were also used in World War II as a treatment against fatigue.
The amphetamine molecule has two stereoisomers:[note 2] levoamphetamine and dextroamphetamine. Dextroamphetamine is the more active dextrorotatory, or "right-handed", enantiomer of the amphetamine molecule. Dextroamphetamine is available as a generic drug or under several brand names, including Dexedrine, Dextrostat, and Zenzedi. Dextroamphetamine is also available as the active metabolite of the prodrug[note 3] lisdexamfetamine.
Dextroamphetamine, like other amphetamines, elicits its stimulating effects via two distinct actions: first, it inhibits or reverses the transporter proteins for the monoamine neurotransmitters (namely the serotonin, norepinephrine and dopamine transporters) via trace amine-associated receptor 1 (TAAR1); and second, it releases these neurotransmitters from synaptic vesicles via vesicular monoamine transporter 2. It also shares many chemical and pharmacological properties with the human trace amine neurotransmiters, especially phenethylamine and N-methylphenethylamine, the latter being an isomer of amphetamine that is produced within the human body.
- 1 Uses
- 2 Contraindications
- 3 Side effects
- 4 Overdose
- 5 Pharmacology
- 6 History, society, and culture
- 7 Notes
- 8 Reference notes
- 9 References
- 10 External links
Dextroamphetamine is used to treat attention deficit hyperactivity disorder (ADHD) and narcolepsy (a sleep disorder), and is sometimes prescribed off-label for its past medical indications, such as depression, obesity, and nasal congestion. Long-term amphetamine exposure in some animal species is known to produce abnormal dopamine system development or nerve damage, but, in humans with ADHD, pharmaceutical amphetamines appear to improve brain development and nerve growth. 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.
Reviews of clinical stimulant research have established the safety and effectiveness of long-term amphetamine use for ADHD. Controlled trials spanning two years have demonstrated treatment effectiveness and safety. 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.
Current models of ADHD suggest that it is associated with functional impairments in some of the brain's neurotransmitter systems; these functional impairments involve impaired dopamine neurotransmission in the mesocorticolimbic projection and norepinephrine neurotransmission in the locus coeruleus and prefrontal cortex. Psychostimulants like methylphenidate and amphetamine are effective in treating ADHD because they increase neurotransmitter activity in these systems. Approximately 80% of those who use these stimulants see improvements in ADHD symptoms. 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. The Cochrane Collaboration's review[note 4] 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. 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.
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; 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. Therapeutic doses of amphetamine also enhance cortical network efficiency, an effect which mediates improvements in working memory in all individuals. Amphetamine and other ADHD stimulants also improve task saliency (motivation to perform a task) and increase arousal (wakefulness), in turn promoting goal-directed behavior. 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. Based upon studies of self-reported illicit stimulant use, 5–35% of college students use diverted ADHD stimulants, which are primarily used for performance enhancement rather than as recreational drugs. However, high amphetamine doses that are above the therapeutic range can interfere with working memory and other aspects of cognitive control.
Amphetamine is used by some athletes for its psychological and performance-enhancing effects, such as increased stamina and alertness; however, its use is prohibited at sporting events regulated by collegiate, national, and international anti-doping agencies. In healthy people at oral therapeutic doses, amphetamine has been shown to increase physical strength, acceleration, stamina, and endurance, while reducing reaction time. Amphetamine improves stamina, endurance, and reaction time primarily through reuptake inhibition and effluxion of dopamine in the central nervous system. At therapeutic doses, the adverse effects of amphetamine do not impede athletic performance; however, at much higher doses, amphetamine can induce effects that severely impair performance, such as rapid muscle breakdown and elevated body temperature.
Dextroamphetamine is also used recreationally as a euphoriant and aphrodisiac, and like other amphetamines is used by dancers at raves for its stimulative and euphoric high. Often taken in higher doses than those prescribed by doctors, Dextroamphetamine is considered to have a high potential for misuse in a recreational manner. Dexedrine capsules can be opened and the contents crushed and snorted, or dissolved in water and injected. Injection into the bloodstream can be dangerous because insoluble fillers within the tablets can block small blood vessels. Abusing amphetamines over time can induce severe drug dependence.
According to the International Programme on Chemical Safety (IPCS) and United States Food and Drug Administration (USFDA),[note 5] amphetamine is contraindicated in people with a history of drug abuse, heart disease, severe agitation, or severe anxiety. It is also contraindicated in people currently experiencing arteriosclerosis (hardening of the arteries), glaucoma (increased eye pressure), hyperthyroidism (excessive production of thyroid hormone), or hypertension. People who have experienced allergic reactions to other stimulants in the past or who are taking monoamine oxidase inhibitors (MAOIs) are advised not to take amphetamine. These agencies also state that anyone with anorexia nervosa, bipolar disorder, depression, hypertension, liver or kidney problems, mania, psychosis, Raynaud's phenomenon, seizures, thyroid problems, tics, or Tourette syndrome should monitor their symptoms while taking amphetamine. Evidence from human studies indicates that therapeutic amphetamine use does not cause developmental abnormalities in the fetus or newborns (i.e., it is not a human teratogen), but amphetamine abuse does pose risks to the fetus. Amphetamine has also been shown to pass into breast milk, so the IPCS and USFDA advise mothers to avoid breastfeeding when using it. Due to the potential for reversible growth impairments,[note 6] the USFDA advises monitoring the height and weight of children and adolescents prescribed an amphetamine pharmaceutical.
At normal therapeutic doses, the physical side effects of amphetamine vary widely by age and from person to person. 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). Sexual side effects in males may include erectile dysfunction, frequent erections, or prolonged erections. Abdominal side effects may include stomach pain, loss of appetite, nausea, and weight loss. 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.
Amphetamine stimulates the medullary respiratory centers, producing faster and deeper breaths. In a normal person at therapeutic doses, this effect is usually not noticeable, but when respiration is already compromised, it may be evident. 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. The effects of amphetamine on the gastrointestinal tract are unpredictable. If intestinal activity is high, amphetamine may reduce gastrointestinal motility (the rate at which content moves through the digestive system); however, amphetamine may increase motility when the smooth muscle of the tract is relaxed. Amphetamine also has a slight analgesic effect and can enhance the pain relieving effects of opioids.
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]
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. 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. Amphetamine psychosis (e.g., delusions and paranoia) can occur in heavy users. Although very rare, this psychosis can also occur at therapeutic doses during long-term therapy. According to the USFDA, "there is no systematic evidence" that stimulants produce aggressive behavior or hostility.
Amphetamine has also been shown to produce a conditioned place preference in humans taking therapeutic doses, meaning that individuals acquire a preference for spending time in places where they have previously used amphetamine.
An amphetamine overdose can lead to many different symptoms, but is rarely fatal with appropriate care. The severity of overdose symptoms increases with dosage and decreases with drug tolerance to amphetamine. 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. Symptoms of a moderate and extremely large overdose are listed below; fatal amphetamine poisoning usually also involves convulsions and coma. 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 7]
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. 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. Once nucleus accumbens ΔFosB is sufficiently overexpressed, it begins to increase the severity of addictive behavior (i.e., compulsive drug-seeking) with further increases in its expression. 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. Sustained aerobic exercise on a regular basis also appears to be an effective treatment for amphetamine addiction; 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.
|System||Minor or moderate overdose||Severe overdose[sources 4]|
|• 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. 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.
Current models of addiction from chronic drug use involve alterations in gene expression in certain parts of the brain, particularly the nucleus accumbens. The most important transcription factors[note 8] that produce these alterations are ΔFosB, cAMP response element binding protein (CREB), and nuclear factor kappa B (NFκB). 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 9] for most of the behavioral and neural adaptations that arise from addiction. Once ΔFosB is sufficiently overexpressed, it induces an addictive state that becomes increasingly more severe with further increases in ΔFosB expression. It has been implicated in addictions to alcohol, cannabinoids, cocaine, methylphenidate, nicotine, opioids, phencyclidine, propofol, and substituted amphetamines, among others.[sources 5]
ΔJunD, a transcription factor, and G9a, a histone methyltransferase enzyme, both directly oppose the induction of ΔFosB in the nucleus accumbens (i.e., they oppose increases in its expression). 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). ΔFosB also plays an important role in regulating behavioral responses to natural rewards, such as palatable food, sex, and exercise. 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. 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. These sex addictions are associated with a dopamine dysregulation syndrome which occurs in some patients taking dopaminergic drugs.
The effects of amphetamine on gene regulation are both dose- and route-dependent. Most of the research on gene regulation and addiction is based upon animal studies with intravenous amphetamine administration at very high doses. 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. This suggests that medical use of amphetamine does not significantly affect gene regulation.
As of May 2014[update], there is no effective pharmacotherapy for amphetamine addiction. Amphetamine addiction is largely mediated through increased activation of dopamine receptors and co-localized NMDA receptors[note 10] in the nucleus accumbens; magnesium ions inhibit NMDA receptors by blocking the receptor calcium channel. One review suggested that, based upon animal testing, pathological (addiction-inducing) amphetamine use significantly reduces the level of intracellular magnesium throughout the brain. Supplemental magnesium[note 11] treatment has been shown to reduce amphetamine self-administration (doses given to oneself) in humans, but it is not an effective monotherapy for amphetamine addiction.
Cognitive behavioral therapy is currently the most effective clinical treatment for psychostimulant addiction. 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. Exercise leads to better treatment outcomes when used as an adjunct treatment, particularly for psychostimulant addictions. 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. This is the opposite of pathological stimulant use, which induces decreased striatal DRD2 density.
|Form of neural or behavioral plasticity||Type of reinforcer||Sources|
|Opiates||Psychostimulants||High fat or sugar food||Sexual reward||Physical exercise
|ΔFosB expression in
nucleus accumbens D1-type MSNs
|Escalation of intake||Yes||Yes||Yes|||
conditioned place preference
|Reinstatement of drug-seeking behavior||↑||↑||↓||↓|||
in the nucleus accumbens
|Sensitized dopamine response
in the nucleus accumbens
|Altered striatal dopamine signaling||↓DRD2, ↑DRD3||↑DRD1, ↓DRD2, ↑DRD3||↑DRD1, ↓DRD2, ↑DRD3||↑DRD2||↑DRD2|||
|Altered striatal opioid signaling||↑μ-opioid receptors||↑μ-opioid receptors
|↑μ-opioid receptors||↑μ-opioid receptors||No change||No change|||
|Changes in striatal opioid peptides||↑dynorphin||↑dynorphin||↓enkephalin||↑dynorphin||↑dynorphin|||
|Mesocorticolimbic synaptic plasticity|
|Number of dendrites in the nucleus accumbens||↓||↑||↑|||
|Dendritic spine density in
the nucleus accumbens
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." 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. 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. The review indicated that withdrawal symptoms are associated with the degree of dependence, suggesting that therapeutic use would result in far milder discontinuation symptoms. Manufacturer prescribing information does not indicate the presence of withdrawal symptoms following discontinuation of amphetamine use after an extended period at therapeutic doses.
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. There is no evidence that amphetamine is directly neurotoxic in humans. However, large doses of amphetamine may cause indirect neurotoxicity as a result of increased oxidative stress from reactive oxygen species and autoxidation of dopamine.
A severe amphetamine overdose can result in a stimulant psychosis that may involve a variety of symptoms, such as paranoia and delusions. A Cochrane Collaboration review on treatment for amphetamine, dextroamphetamine, and methamphetamine psychosis states that about 5–15% of users fail to recover completely. According to the same review, there is at least one trial that shows antipsychotic medications effectively resolve the symptoms of acute amphetamine psychosis. Psychosis very rarely arises from therapeutic use.
Amphetamine and its enantiomers have been identified as potent full agonists of trace amine-associated receptor 1 (TAAR1), a GPCR, discovered in 2001, that is important for regulation of monoaminergic systems in the brain. Activation of TAAR1 increases cAMP production via adenylyl cyclase activation and inhibits the function of the dopamine transporter, norepinephrine transporter, and serotonin transporter, as well as inducing the release of these monoamine neurotransmitters (effluxion). Amphetamine enantiomers are also substrates for a specific neuronal synaptic vesicle uptake transporter called VMAT2. When amphetamine is taken up by VMAT2, the vesicle releases (effluxes) dopamine, norepinephrine, and serotonin, among other monoamines, into the cytosol in exchange.
Dextroamphetamine (the dextrorotary enantiomer) and levoamphetamine (the levorotary enantiomer) have identical pharmacodynamics, but their binding affinities to their biomolecular targets vary. Dextroamphetamine is a more potent agonist of TAAR1 than levoamphetamine. Consequently, dextroamphetamine produces roughly three to four times more central nervous system (CNS) stimulation than levoamphetamine; however, levoamphetamine has slightly greater cardiovascular and peripheral effects.
Related endogenous compounds
Amphetamine has a very similar structure and function to the endogenous trace amines, which are naturally occurring neurotransmitter molecules produced in the human body and brain. Among this group, the most closely related compounds are phenethylamine, the parent compound of amphetamine, and N-methylphenethylamine, an isomer of amphetamine (i.e., it has an identical molecular formula). In humans, phenethylamine is produced directly from L-phenylalanine by the aromatic amino acid decarboxylase (AADC) enzyme, which converts L-DOPA into dopamine as well. In turn, N‑methylphenethylamine is metabolized from phenethylamine by phenylethanolamine N-methyltransferase, the same enzyme that metabolizes norepinephrine into epinephrine. Like amphetamine, both phenethylamine and N‑methylphenethylamine regulate monoamine neurotransmission via TAAR1; unlike amphetamine, both of these substances are broken down by monoamine oxidase B, and therefore have a shorter half-life than amphetamine.
Amphetamine is well absorbed from the gut, and bioavailability is typically over 75% for dextroamphetamine. However, oral availability varies with gastrointestinal pH. Dextroamphetamine is a weak base with a pKa of 9–10; 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. Conversely, an acidic pH means the drug is predominantly in its water-soluble cationic form, and less is absorbed.
The half-life of dextroamphetamine varies with urine pH. At normal urine pH, the half-life of dextroamphetamine is 9–11 hours. An acidic diet will reduce the half-life to 8–11 hours, while an alkaline diet will increase the range to 16–31 hours. The immediate-release and extended release variants of dextroamphetamine salts reach peak plasma concentrations at 3 hours and 7 hours post-dose respectively. Dextromphetamine is eliminated via the kidneys, with 30–40% of the drug being excreted unchanged at normal urinary pH. When the urinary pH is basic, more of the drug is in its poorly water-soluble free base form, and less is excreted. When urine pH is abnormal, the urinary recovery of amphetamine may range from a low of 1% to as much as 75%, depending mostly upon whether urine is too basic or acidic, respectively. Amphetamine is usually eliminated within two days of the last oral dose. Apparent half-life and duration of effect increase with repeated use and accumulation of the drug.
CYP2D6, dopamine β-hydroxylase, flavin-containing monooxygenase, butyrate-CoA ligase, and glycine N-acyltransferase are the enzymes known to metabolize amphetamine or its metabolites in humans. Amphetamine has a variety of excreted metabolic products, including 4-hydroxyamfetamine, 4-hydroxynorephedrine, 4-hydroxyphenylacetone, benzoic acid, hippuric acid, norephedrine, and phenylacetone. Among these metabolites, the active sympathomimetics are 4‑hydroxyamphetamine, 4‑hydroxynorephedrine, and norephedrine.
History, society, and culture
Racemic amphetamine was first synthesized under the chemical name "phenylisopropylamine" in Berlin, 1887 by the Romanian chemist Lazar Edeleanu. It was not widely marketed until 1932, when the pharmaceutical company Smith, Kline & French (now known as GlaxoSmithKline) introduced it in the form of the Benzedrine inhaler for use as a bronchodilator. Notably, the amphetamine contained in the Benzedrine inhaler was the liquid free-base,[note 12] not a chloride or sulfate salt.
Three years later, in 1935, the medical community became aware of the stimulant properties of amphetamine, specifically dextroamphetamine, and in 1937 Smith, Kline, and French introduced tablets under the tradename Dexedrine. In the United States, Dexedrine was approved to treat narcolepsy, attention disorders, depression, and obesity. In Canada, epilepsy and parkinsonism were also approved indications. Dextroamphetamine was marketed in various other forms in the following decades, primarily by Smith, Kline, and French, such as several combination medications including a mixture of dextroamphetamine and amobarbital (a barbiturate) sold under the tradename Dexamyl and, in the 1950s, an extended release capsule (the "Spansule"). Preparations containing dextroamphetamine were also used in World War II as a treatment against fatigue.
It quickly became apparent that dextroamphetamine and other amphetamines had a high potential for misuse, although they were not heavily controlled until 1970, when the Comprehensive Drug Abuse Prevention and Control Act was passed by the United States Congress. Dextroamphetamine, along with other sympathomimetics, was eventually classified as Schedule II, the most restrictive category possible for a drug with a government-sanctioned, recognized medical use. Internationally, it has been available under the names AmfeDyn (Italy), Curban (US), Obetrol (Switzerland), Simpamina (Italy), Dexedrine/GSK (US & Canada), Dexedrine/UCB (United Kingdom), Dextropa (Portugal), and Stild (Spain).
The U.S. Air Force uses dextroamphetamine as one of its "go pills", given to pilots on long missions to help them remain focused and alert. Conversely, "no-go pills" are used after the mission is completed, to combat the effects of the mission and "go-pills". The Tarnak Farm incident was linked by media reports to the use of this drug on long term fatigued pilots. The military did not accept this explanation, citing the lack of similar incidents. Newer stimulant medications or awakeness promoting agents with different side effect profiles, such as modafinil, are being investigated and sometimes issued for this reason.
In the United States, immediate release (IR) formulations of dextroamphetamine sulfate are available generically as 5 mg and 10 mg tablets, marketed by Barr (Teva Pharmaceutical Industries), Mallinckrodt Pharmaceuticals, Wilshire Pharmaceuticals, Aurobindo Pharmaceutical USA and CorePharma. Previous IR tablets sold by the brand names of Dexedrine and Dextrostat have been discontinued but in 2015 IR tablets became available by the brand name Zenzedi, offered as 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg and 30 mg tablets. Dextroamphetamine sulfate is also available as a controlled-release (CR) capsule preparation in strengths of 5 mg, 10 mg, and 15 mg under the brand name Dexedrine Spansule, with generic versions marketed by Barr and Mallinckrodt. A bubblegum flavored oral solution is available under the brand name ProCentra, manufactured by FSC Pediatrics, which is designed to be an easier method of administration in children who have difficulty swallowing tablets, each 5 mL contains 5 mg dextroamphetamine. The conversion rate between dextroamphetamine sulfate to amphetamine free base is .728.
In Australia, dexamphetamine is available in bottles of 100 instant release 5 mg tablets as a generic drug. or slow release dextroamphetamine preparations may be compounded by individual chemists. Similarly, in the United Kingdom it is only available in 5 mg instant release sulfate tablets under the generic name dextroamphetamine sulphate having had been available under the brand name Dexedrine prior to UCB Pharma disinvesting the product to another pharmaceutical company (Auden Mckenzie).
Dextroamphetamine is the active metabolite of the prodrug lisdexamfetamine (L-lysine-dextroamphetamine), available by the brand name Vyvanse (lisdexamfetamine dimesylate). Lisdexamfetamine is metabolised in the gastrointestinal tract, while dextroamphetamine's metabolism is hepatic. Lisdexamfetamine is therefore an inactive compound until it is converted into an active compound by the digestive system. Vyvanse is marketed as once-a-day dosing as it provides a slow release of dextroamphetamine into the body. Vyvanse is available as capsules, and in six strengths; 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, and 70 mg. The conversion rate between lisdexamfetamine dimesylate (Vyvanse) to amphetamine free base is 29.48%.
Another pharmaceutical that contains dextroamphetamine is commonly known by the brand name Adderall. The drug formulation of Adderall, including both the immediate release (IR) and extended release (XR) forms, is:
Adderall has a total amphetamine base equivalence of 63%. Of this 63% amphetamine base equivalence, roughly three-quarters (72.7%) is dextroamphetamine, (the remaining percentage is levoamphetamine). The salt ratio, as noted above, is 75%:25% or 3:1 dextroamphetamine to levoamphetamine.
- Synonyms and alternate spellings include dexamphetamine (AAN) and dexamfetamine (INN and BAN).
- which are mirror images of the same molecule
- that is, an inactive drug that is metabolised in the body into another more biologically-active drug
- Cochrane Collaboration reviews are high quality meta-analytic systematic reviews of randomized controlled trials.
- The statements supported by the USFDA come from prescribing information, which is the copyrighted intellectual property of the manufacturer and approved by the USFDA.
- In individuals who experience sub-normal height and weight gains, a rebound to normal levels is expected to occur if stimulant therapy is briefly interrupted. The average reduction in final adult height from continuous stimulant therapy over a 3 year period is 2 cm.
- The 95% confidence interval indicates that there is a 95% probability that the true number of deaths lies between 3,425 and 4,145.
- Transcription factors are proteins that increase or decrease the expression of specific genes.
- 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.
- 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.
- The review indicated that magnesium L-aspartate and magnesium chloride produce significant changes in addictive behavior; other forms of magnesium were not mentioned.
- Free-base form amphetamine is a volatile oil, hence the efficacy of the inhalers.
- "Dextromphetamine". DrugBank. Retrieved 5 November 2013.
- "Adderall XR Prescribing Information" (PDF). United States Food and Drug Administration. December 2013. pp. 12–13. Retrieved 30 December 2013.
- Lemke TL, Williams DA, Roche VF, Zito W (2013). Foye's Principles of Medicinal Chemistry (7th ed. ed.). Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins. p. 648. ISBN 1609133455.
Alternatively, direct oxidation of amphetamine by DA β-hydroxylase can afford norephedrine.
- Krueger SK, Williams DE (June 2005). "Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism". Pharmacol. Ther. 106 (3): 357–387. doi:10.1016/j.pharmthera.2005.01.001. PMC 1828602. PMID 15922018.
- "butyrate-CoA ligase". BRENDA. Technische Universität Braunschweig. Retrieved 7 May 2014.
- "glycine N-acyltransferase". BRENDA. Technische Universität Braunschweig. Retrieved 7 May 2014.
- Millichap JG (2010). "Chapter 9: Medications for ADHD". In Millichap JG. Attention Deficit Hyperactivity Disorder Handbook: A Physician's Guide to ADHD (2nd ed.). New York, USA: Springer. p. 112. ISBN 9781441913968.
Table 9.2 Dextroamphetamine formulations of stimulant medication
Dexedrine [Peak:2–3 h] [Duration:5–6 h] ...
Adderall [Peak:2–3 h] [Duration:5–7 h]
Dexedrine spansules [Peak:7–8 h] [Duration:12 h] ...
Adderall XR [Peak:7–8 h] [Duration:12 h]
Vyvanse [Peak:3–4 h] [Duration:12 h]
- Brams M, Mao AR, Doyle RL (September 2008). "Onset of efficacy of long-acting psychostimulants in pediatric attention-deficit/hyperactivity disorder". Postgrad. Med. 120 (3): 69–88. doi:10.3810/pgm.2008.09.1909. PMID 18824827.
Onset of efficacy was earliest for d-MPH-ER at 0.5 hours, followed by d, l-MPH-LA at 1 to 2 hours, MCD at 1.5 hours, d, l-MPH-OR at 1 to 2 hours, MAS-XR at 1.5 to 2 hours, MTS at 2 hours, and LDX at approximately 2 hours. ... MAS-XR, and LDX have a long duration of action at 12 hours postdose
- "Adderall IR Prescribing Information" (PDF). United States Food and Drug Administration. Barr Laboratories, Inc. March 2007. pp. 4–5. Retrieved 2 November 2013.
- "Biological Half-Life". AMPHETAMINE. United States National Library of Medicine – Toxnet. Hazardous Substances Data Bank. Retrieved 5 January 2014.
Concentrations of (14)C-amphetamine declined less rapidly in the plasma of human subjects maintained on an alkaline diet (urinary pH > 7.5) than those on an acid diet (urinary pH < 6). Plasma half-lives of amphetamine ranged between 16-31 hr & 8-11 hr, respectively, & the excretion of (14)C in 24 hr urine was 45 & 70%.
- Mignot 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. PMC 3480574. PMID 23065655.
- "dextrostat (dextroamphetamine sulfate) tablet [Shire US Inc.]". DailyMed. Wayne, PA: Shire US Inc. August 2006. Retrieved 8 November 2013.
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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.
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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.
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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.
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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.
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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.
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Dopamine acts in the nucleus accumbens to attach motivational significance to stimuli associated with reward.
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misuse of prescription stimulants has become a serious problem on college campuses across the US and has been recently documented in other countries as well. ... Indeed, large numbers of students claim to have engaged in the nonmedical use of prescription stimulants, which is reflected in lifetime prevalence rates of prescription stimulant misuse ranging from 5% to nearly 34% of students.
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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.
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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
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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.
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Table 2. Decongestants Causing Rhinitis Medicamentosa
– Nasal decongestants:
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A minority of individuals who use amphetamines develop full-blown psychosis requiring care at emergency departments or psychiatric hospitals. In such cases, symptoms of amphetamine psychosis commonly include paranoid and persecutory delusions as well as auditory and visual hallucinations in the presence of extreme agitation. More common (about 18%) is for frequent amphetamine users to report psychotic symptoms that are sub-clinical and that do not require high-intensity intervention ...
About 5–15% of the users who develop an amphetamine psychosis fail to recover completely (Hofmann 1983) ...
Findings from one trial indicate use of antipsychotic medications effectively resolves symptoms of acute amphetamine psychosis.
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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.
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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.
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Amphetamine use disorders ... 3,788 (3,425–4,145)
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ΔFosB serves as one of the master control proteins governing this structural plasticity.
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Currently, cognitive–behavioral therapies are the most successful treatment available for preventing the relapse of psychostimulant use.
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When oral formulations of psychostimulants are used at recommended doses and frequencies, they are unlikely to yield effects consistent with abuse potential in patients with ADHD.
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Despite concerted efforts to identify a pharmacotherapy for managing stimulant use disorders, no widely effective medications have been approved.
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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
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