Amphetamine, a CYP2D6 substrate, is widely used by truck Reproduction ( photocopying) of editorial content of this journal is prohibited without publisher’s. Journal of Analytical Toxicology, Vol. 24, September cutoff concentration is required for amphetamine (AMP) reporting, there is no requirement for. pharmacological effect but also in chemical structure: the amphetamine-type stimulants clandestine manufacture of [email protected], Journal of Forensic.
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Amphetamine stimulants have been used medically since early in the twentieth century, but they have a high abuse potential and can be neurotoxic. Although jurnnal have long been used effectively to treat attention deficit hyperactivity disorder ADHD in children and jutnal, amphetamines are now being prescribed increasingly as maintenance therapy for ADHD and narcolepsy in adults, considerably extending the period of potential exposure.
Effects of prolonged stimulant treatment have not been fully explored, and iurnal such effects is a research priority 1. Because the pharmacokinetics of amphetamines differ between children and adults, reevaluation of the potential for adverse effects of chronic treatment of adults is essential.
Despite information on the effects of stimulants in laboratory animals, profound species differences in susceptibility to stimulant-induced neurotoxicity underscore the need for systematic studies of prolonged human exposure. Early amphetamine treatment has been linked to slowing in height and weight growth in some children.
Because the number of prescriptions for amphetamines has increased several-fold over the past decade, amfetamiin amphetamine-containing formulation is the most commonly prescribed stimulant in North America, and it is noteworthy that amphetamines are also the most abused prescription medications.
Although early treatment does not increase risk for substance abuse, few studies have tracked the compliance and usage profiles of individuals who began amphetamine treatment as adults. Overall, there is concern about risk for slowed growth in young patients who are dosed continuously, and for substance abuse in patients first medicated in late ajfetamin or adulthood.
Although most adult patients also use amphetamines effectively and safely, occasional case reports indicate that prescription use can produce marked psychological adverse events, including stimulant-induced psychosis. Assessments of central toxicity and adverse psychological effects during late adulthood and senescence of adults who receive prolonged courses of amphetamine treatment are warranted.
Finally, identification of the biological factors that confer risk and those that offer protection are also needed to better specify the parameters of safe, long-term, therapeutic amfeyamin of amphetamines to adults. Amphetamine was initially synthesized in Berlin in as 1-methylphenethylamine.
For years, amphetamine was thought to be a human invention, but the compound was found inalong with methamphetamine, nicotine and mescaline, within two species of Texas acacia bushes 34. Amphetamine is one of the most potent sympathomimetic drugs, producing its effects by increasing synaptic levels of the biogenic amines, dopamine, norepinephrine and kurnal, through multiple mechanisms 56.
Although amphetamine binds to all monoamine transporters, its behavioral stimulant effects are mediated primarily through dopamine and depend on the dopamine transporter DAT 7. Amphetamine blocks the ability of DAT to clear the neurotransmitter from the synapse and facilitates reverse movement of dopamine across the cell membrane i.
These actions further promote cytoplasmic accumulation of monoamines, which can then be transported into the synapse. Other molecular mechanisms by which amphetamine mediates monoamine release have also been implicated. These include amphetamine-induced exchange diffusion, channel-like transport, disruption of vesicular storage by the weak base properties of amphetamine, phosphorylation, and transporter trafficking 2.
Amphetamine is presumed to amplify both tonic and phasic dopamine release through such mechanisms.
Potential Adverse Effects of Amphetamine Treatment on Brain and Behavior: A Review
Noradrenergic amfdtamin of amphetamine are less well studied, but are also believed to exist at clinically relevant plasma levels of the drug 8. Amphetamine exists as two stereoisomers that differ in effects 5. The l – enantiomer levoamphetamine produces more cardiovascular and peripheral effects than the d – enantiomer dextroamphetamine.
At low doses, levoamphetamine produces greater arousal than dextroamphetamine, acting primarily on norepinephrine.
At higher doses, dextroamphetamine has stimulant properties that are three- to four times as strong as those of levoamphetamine, and acts primarily on dopamine.
Few clinical studies of ADHD, however, have documented differences among d – l – and racemic amphetamine. Just as dextroamphetamine has more central and less peripheral action than levoamphetamine, jutnal, which is equipotent to dextroamphetamine in producing behavioral stimulant effects 9has even fewer peripheral effects than dextroamphetamine 5. Although primarily valued for their use in the treatment of ADHD, amphetamines are also effective in combating the excessive daytime sleepiness associated with narcolepsy.
It was also noted in the s that amphetamines had reinforcing properties, leading to widespread prescription drug abuse see below. Therefore, by most countries that regulate drug use had severely restricted legal use of amphetamines, but the number of prescriptions, and prescription abuse, continued to grows, particularly in North America. During there were eight billion amphetamine-containing tablets manufactured in the United States; and both licit and illicit use of amphetamines increased greatly in subsequent years.
Schedule II drugs have an accepted medical use, but are tightly monitored due to a potential for abuse that can lead to severe psychological and physiological dependence. Despite recommendations that amphetamines be restricted to use for narcolepsy murnal ADHD, with very limited use for obesity, some physicians have continued to write off-label prescriptions for other medical uses, such as adjuvant medications in treatment of depression and post-stroke cognitive impairment.
Inthere were still fewer thanannual prescriptions written for amphetamine in the US. Over the ensuing decade and a half, however, the amount of amphetamine produced and the number of prescriptions written in the United States increased dramatically. Events in the early ‘s likely influenced the utilization of amphetamine as a prescribed treatment.
This act mandates a comprehensive behavioral, educational and medical evaluation of children suspected of having an educational disability. A physician visit is not required, but the school district is obligated to provide any diagnostic services that are needed at no cost to parents Over the next 2 years, ADHD diagnoses tripled, from one to three million. Other concurrent factors included heightened awareness of the biological basis of ADHD 13reports supporting the view that the disorder was a neuropsychiatric syndrome 14books about ADHD in the lay press, and a variety of reports on its persistence and associated impairment.
Newer formulations of amphetamine also reached the market. In addition, 1, kg of methamphetamine was used primarily for treatment of obesity, although it was also approved for treatment of ADHD Methamphetamine is less frequently used in clinical preparations, and is primarily discussed amfetamun a comparative drug. Methylphenidate, an amphetamine-like phenethylamine stimulant and catecholamine reuptake inhibitor, is the most common alternative to treatment with amphetamine, both for ADHD and for narcolepsy.
In the s, longer acting forms of amphetamine were developed using capsules of mixed d – and l – salts in both immediate release pellets and enteric-coated, delayed-release beads. The different salts and beads are metabolized at different amfetaminn, resulting in a less dramatic onset and termination of therapeutic action. Amphetamine is most amfetamjn administered twice daily in immediate-release formulations Dexedrine, DextroStat, or Adderall IR amfetamior once a day in sustained-release formulations Dexedrine or Adderal XR capsules, Vyvanse tablets.
Plasma profiles of d – and l – amphetamine are similar after a single dose of 20 mg Adderall XR or two mg doses of Adderal IR, given 4 h apart.
Maximum plasma concentration for Adderall XR is achieved about 6 h after ingestion Amphetamine is approved for ADHD in doses of 2. Amphetamine in an extended-release XR formulation has a maximum approved dosage of 30 mg per day for children. Vyvanse contains a conditionally bioreversible derivative of dextroamphetamine, which has lower pharmacokinetic variability and slightly longer duration than other delayed-release amphetamine medications, but requires higher doses.
It is manufactured in tablets ranging in dose from 20 mg to 70 mg, and is approved for up to 70 mg per day for school-age children For adults, Adderall XR is approved at doses up to 20 mg per day, due to lack of evidence for clearly superior benefits from higher doses.
After a report that daily Vyvanse dosages of 30 mg, 50 mg and 70 mg all improved ADHD symptoms in a sample of adults 17the FDA approved the drug for adult treatment in April There is evidence suggesting that some adults require higher doses of stimulant medications than the approved maximum levels to achieve maximal benefit 18 – Effects of prolonged stimulant treatment in adults, however, have not been fully explored, and this is a current research priority 1.
Methamphetamine is approved for obesity at a dose of 5 mg taken before meals for patients at age 12 and over. Some physicians continue to write off-label prescriptions for other uses of these drugs. Most pharmaceutical amphetamine is used in treatment of ADHD. Although the therapeutic mode of action is not fully known, amphetamine is highly efficacious for the reduction of core Amfdtamin symptoms in children, adolescents, and adults. In the very few studies that have compared the efficacy and safety of amphetamine directly to those of methylphenidate, amphetamine was equivalent or superior to methylphenidate on standard efficacy endpoints.
Some research also suggests that a few individuals who do not respond to methylphenidate treatment for ADHD experience significant benefit from amphetamine and vice versa 8. Nurnal remain among the most effective appetite suppressants. jurnwl
International Scholarly Research Notices
Amphetamines readily cross the blood-brain barrier to reach their primary sites of action in the brain. The acute administration of amphetamine produces a wide range of dose-dependent behavioral changes, including increased arousal or wakefulness, anorexia, hyperactivity, perseverative movements, and, in particular, a state of pleasurable affect, elation, and euphoria, which can lead to the abuse of the drug.
Adverse effects listed in drug labels of prescription amphetamines include disturbances of mood and behavior in addition to cardiac and gastrointestinal effects. The most common drug-related effects are loss of appetite, insomnia, emotional lability, nervousness and fever The American Academy of Pediatrics 24 also lists jitteriness and social withdrawal as common side-effects of amphetamines in children.
Although limited in scope, a few studies have compared the types and rates of adverse events associated with administration of amphetamine and methylphenidate to children with ADHD.
In general, these studies found similar side effect profiles for the two drugs. Unfortunately, the extant studies on side effect risk of the stimulants used for ADHD treatment have many limitations. All have been restricted to relatively short durations of exposure; and most are based on an assumption that a dose of methylphenidate is equivalent to half of an equal dose of amphetamine.
Most studies have not incorporated measurement of plasma drug level achieved although few relationships between these common adverse events and plasma levels have been noted Nevertheless, it is potentially important that treatment within approved dose ranges with amphetamines, especially newer extended-release formulations, have produced residual low, but detectable, steady-state blood levels up to 24 h after administration.
Thus many individuals experience some degree of continuous drug exposure. Although not tested, this finding suggests that cardiovascular complications, which have been associated with both normal aging and amphetamine abuse in young addicts, may appear earlier in older adults receiving maintenance amphetamine treatment Regarding the detection of risk for uncommon or rare severe psychological or behavioral reactions to stimulants, controlled studies have not been large enough to pinpoint risk factors or determine differential risk by treatment assignment.
Finally, a common observation across studies of the pharmacokinetics, pharmacodynamics, and safety profiles of amphetamine is the high degree of interindividual variability across most measures and endpoints. This variability calls for additional caution in application of the increasingly common practice of prescribing stimulants concurrent with use of other psychotropic medications 27 ADHD is the most common reason for mental health, special education or behavioral referral in pediatric medicine, and community studies yield prevalence rates from 1.
The prescription of chronic stimulant medication for maintenance therapy has long been the most effective treatment for ADHD 31and stimulant use has continued to increase over the last decade. Despite this increase, estimates suggest that roughly half of children and adolescents with ADHD do not receive medical treatment for the disorder 29and even fewer adults with ADHD receive any intervention directed at its amelioration.
ADHD treatment forms the bulk of the total prescriptions for pharmaceutical amphetamines. This frequency of amphetamine use parallels regional differences in the prevalence estimates of ADHD However, as methylphenidate was approved for government subsidies in lateits use has probably since increased The frequency of diagnoses increases steeply from age 3 to about age 8, and increases at a slower rate or plateaus through the teen years. In a study of almost 10, Australian children taking medicinal stimulants, the highest prevalence of ADHD was 5.
The proportion of total stimulant prescriptions written for adults has not been documented, but adult diagnosis of ADHD has increased over recent years, attaining a census-adjusted visit rate of 0.
Amphetamine treatment lasted for a median of days, longer than treatment periods associated with methylphenidate 99 daysor atomoxetine 86 days. Adults can receive higher amphetamine doses than children, with evidence that doses of up to 0. In addition, the elimination half-life of amphetamine in adults is two to three times as long as that observed in children Because the treatment of adult ADHD could theoretically be quite prolonged if symptoms persist, the careful evaluation of the potential for adverse effects of cumulative amphetamines in adults is needed.
Narcolepsy is a less common disorder than attention deficit disorder, with prevalence estimates ranging from 0. It is characterized by excessive daytime sleepiness, cataplexy, and hypnagogic hallucinations. Narcolepsy is most typically diagnosed in the second or third decade of life. As it is a chronic disorder, treatment needs are essentially life-long.
It is remarkable that the prevalence of problematic use of amphetamine has been rising in the elderly, and that prescription substance abuse in this population may augment associated risks and require unique considerations for diagnosis and treatment