The amphetamine molecule has two stereoisomers (which are mirror images of the same molecule): 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 and Dextrostat. Dextroamphetamine is also the active metabolite of the prodrug (that is, a drug that is metabolised in the body into another more biologically-active drug) lisdexamfetamine.
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 continuous treatment effectiveness and safety. One review highlighted a 9 month randomized controlled trial in children that found an average increase of 4.5 IQ points and continued improvements in attention, disruptive behaviors, and hyperactivity.
Current models of ADHD suggest that it is associated with functional impairments in some of the brain's neurotransmitter systems,[note 2] particularly those involving dopamine and norepinephrine. Psychostimulants like methylphenidate and amphetamine possess efficacy in treating ADHD because they increase neurotransmitter activity in these systems. Approximately 70% 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, generally perform better in school, are less distractible and impulsive, and have longer attention spans. The Cochrane Collaboration's review[note 3] on the treatment of adult ADHD with amphetamines stated that amphetamines improve short-term symptoms, but have higher discontinuation rates than non-stimulant medications due to their adverse effects.
A Cochrane Collaboration review on the treatment of ADHD in children with tic disorders indicated that stimulants in general do not make tics worse, but high doses of dextroamphetamine in such people should be avoided. Other Cochrane reviews on the use of amphetamine for improving recovery following stroke or acute brain injury indicated that it may improve recovery, but further research is needed to confirm this.
Therapeutic doses of amphetamine improve cortical network efficiency, resulting in higher performance on working memory tests in all individuals. Amphetamine and other ADHD stimulants also improve task saliency and increase arousal. 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, performance-enhancing use, rather than abuse as a recreational drug, is the primary reason that students use stimulants. High amphetamine doses, above the therapeutic range, can interfere with working memory and cognitive control.
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 1]
Addiction is a serious risk with heavy recreational amphetamine use; it is unlikely to arise from typical medical use.Tolerance develops rapidly in amphetamine abuse, so periods of extended use require increasing doses of the drug in order to achieve the same effect.
A Cochrane Collaboration review on amphetamine and methamphetamine dependence and abuse indicates that the current evidence on effective treatments is extremely limited. The review indicated that fluoxetine[note 5] and imipramine[note 6] have some limited benefits in treating abuse and addiction, but concluded, "no treatment has been demonstrated to be effective for the treatment of amphetamine dependence and abuse." A corroborating review indicated that amphetamine dependence is mediated through increased activation of dopamine receptors and co-localizedNMDA receptors in the mesolimbic pathway. This review also noted that magnesium ions, which inhibit NMDA receptor calcium channels, and serotonin have inhibitory effects on NMDA receptors. It also suggested that, based upon animal testing, pathological amphetamine use significantly reduces the level of intracellular magnesium throughout the brain. Supplemental magnesium,[note 7] like fluoxetine treatment, has been shown to reduce self-administration in both humans and lab animals.
According to another Cochrane Collaboration review on withdrawal in highly dependent amphetamine and methamphetamine abusers, "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 suggested 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.
Current models of addiction from chronic drug use involve alterations in gene expression in certain parts of the brain. The most important transcription factors that produce these alterations are ΔFosB, cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), and nuclear factor kappa B (NFκB). ΔFosB is the most significant, since its overexpression in the nucleus accumbens is necessary and sufficient for many of the neural adaptations seen in drug addiction; it has been implicated in addictions to alcohol, cannabinoids, cocaine, nicotine, phenylcyclidine, and substituted amphetamines.ΔJunD is the transcription factor which directly opposes ΔFosB. Increases in nucleus accumbens ΔJunD expression can reduce or, with a large increase, even block most of the neural 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 natural rewards, like drugs of abuse, induce ΔFosB, chronic acquisition of these rewards can result in a similar pathological addictive state. Consequently, ΔFosB is the key transcription factor involved in amphetamine addiction, especially amphetamine-induced sex addictions. ΔFosB inhibitors (drugs that oppose its action) may be an effective treatment for addiction and addictive disorders.
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.
Abuse of amphetamine can result in a stimulant psychosis that may present with a variety of symptoms (e.g., paranoia, hallucinations, delusions). A Cochrane Collaboration review on treatment for amphetamine, dextroamphetamine, and methamphetamine abuse-induced psychosis states that about 5–15% of users fail to recover completely. The same review asserts that, based upon at least one trial, antipsychotic medications effectively resolve the symptoms of acute amphetamine psychosis. Psychosis very rarely arises from therapeutic use.
In rodents and primates, sufficiently high doses of amphetamine cause dopaminergic neurotoxicity, or damage to dopamine neurons, which is characterized as reduced transporter and receptor function. There is no evidence that amphetamine is directly neurotoxic in humans. High-dose amphetamine can cause indirect neurotoxicity as a result of increased oxidative stress from reactive oxygen species and autoxidation of dopamine.
Amphetamine enters the presynaptic neuron across the neuronal membrane or through DAT. Once inside, it binds to TAAR1 or enters synaptic vesicles through VMAT2. When amphetamine enters the synaptic vesicles through VMAT2, dopamine is released into the cytosol (yellow-orange area). When amphetamine binds to TAAR1, it reduces dopamine receptor firing rate via potassium channels and triggers protein kinase A (PKA) and protein kinase C (PKC) signaling, resulting in DAT phosphorylation. PKA-phosphorylation causes DAT to withdraw into the presynaptic neuron (internalize) and cease transport. PKC-phosphorylated DAT may either operate in reverse or, like PKA-phosphorylated DAT, internalize and cease transport.
Dextroamphetamine (the dextrorotaryenantiomer) 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.
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.
Approximately 15–40% of dextroamphetamine circulating in the bloodstream is bound to plasma proteins.
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.
The primary active metabolites of amphetamine are 4-hydroxyamphetamine and norephedrine; however, most of an administered dose is excreted as amphetamine itself and the inactive metabolites. Benzoic acid is metabolized by butyrate-CoA ligase into an intermediate product, benzoyl-CoA, which is then metabolized by glycine N-acyltransferase into hippuric acid.
Three years later, in 1935, the medical community became aware of the stimulant properties of amphetamine, specifically dexamfetamine, 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. Dexamfetamine 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 dexamfetamine 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 dexamfetamine 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. Dexamfetamine, 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).
In October 2010, GlaxoSmithKline sold the rights for Dexedrine Spansule to Amedra Pharmaceuticals (a subsidiary of CorePharma).
The U.S. Air Force uses dexamfetamine 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, an instant-release (IR) tablet preparation of dextroamphetamine sulfate is available under the brand name Dextrostat, in 5 mg and 10 mg strengths, with generic versions marketed by Barr (Teva Pharmaceutical Industries), Mallinckrodt Pharmaceuticals and Wilshire Pharmaceuticals. 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 dexamfetamine.
In Australia, dexamfetamine is available in bottles of 100 instant release 5 mg tablets as a generic drug. or slow release dexamfetamine 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 dexamfetamine sulphate having had been available under the brand name Dexedrine prior to UCB Pharma disinvesting the product to another pharmaceutical company (Auden Mckenzie).
Dexamfetamine 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 dexamfetamine 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 of Lisdexamfetamine dimesylate to dextroamphetamine base is 0.2948, thus a 30 mg-strength Vyvanse capsule is molecularly equivalent to 8.844 mg dexamfetamine base.
Amphetamine salts (Adderall)
Adderall 20 mg tablets, some broken in half, with a lengthwise-folded US dollar bill along the bottom
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 is roughly three-quarters dextroamphetamine, with it accounting for 72.7% of the amphetamine base in Adderall (the remaining percentage is levoamphetamine). The salt ratio, as noted above, is 75%:25% or 3:1 dextroamphetamine to levoamphetamine.
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^ abcdeMalenka RC, Nestler EJ, Hyman SE (2009). "Chapter 13: Higher Cognitive Function and Behavioral Control". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. p. 318. ISBN9780071481274. "Therapeutic (relatively low) doses of psychostimulants, such as methylphenidate and amphetamine, improve performance on working memory tasks both in in normal subjects and those with ADHD. Positron emission tomography (PET) demonstrates that methylphenidate decreases regional cerebral blood flow in the doroslateral prefrontal cortex and posterior parietal cortex while improving performance of a spacial working memory task. This suggests that cortical networks that normally process spatial working memory become more efficient in response to the drug. ... [It] is now believed that dopamine and norepinephrine, but not serotonin, produce the beneficial effects of stimulants on working memory. At abused (relatively high) doses, stimulants can interfere with working memory and cognitive control ... 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."
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