Amphetamine
Amphetamine is a central nervous system stimulant that is used in the treatment of attention deficit hyperactivity disorder, narcolepsy, and obesity; it is also used to treat binge eating disorder in the form of lisdexamfetamine. Historically, it has been used to treat nasal congestion and depression. Amphetamine is also used as an athletic performance enhancer and cognitive enhancer, and recreationally as an aphrodisiac and euphoriant. It is a prescription drug in many countries, and unauthorized possession and distribution of amphetamine are often tightly controlled due to the significant health risks associated with recreational use.
Amphetamine was discovered as a chemical in 1887 by Lazăr Edeleanu, and then as a drug in the late 1920s. It exists as two enantiomers: levoamphetamine and dextroamphetamine. The first amphetamine pharmaceutical was Benzedrine. [|Pharmaceutical amphetamine] is prescribed as racemic amphetamine, Adderall, dextroamphetamine, or lisdexamfetamine. Amphetamine increases monoamine and excitatory neurotransmission in the brain, with its most pronounced effects targeting the norepinephrine and dopamine neurotransmitter systems.
At therapeutic doses, amphetamine causes emotional and cognitive effects such as euphoria, change in desire for sex, increased wakefulness, and improved cognitive control. It induces physical effects such as improved reaction time, fatigue resistance, decreased appetite, elevated heart rate, and increased muscle strength. Larger doses of amphetamine may impair cognitive function and induce rapid muscle breakdown. Addiction is a serious risk with heavy recreational amphetamine use, but is unlikely to occur from long-term medical use at therapeutic doses. Very high doses can result in psychosis, which rarely occurs at therapeutic doses even during long-term use. Recreational doses are generally much larger than prescribed therapeutic doses and carry a far greater risk of serious side effects.
Amphetamine belongs to the phenethylamine class. It is also the parent compound of its own structural class, the substituted amphetamines, which includes prominent substances such as bupropion, cathinone, MDMA, and methamphetamine. As a member of the phenethylamine class, amphetamine is also chemically related to the naturally occurring trace amine neuromodulators, specifically phenethylamine and, both of which are produced within the human body. Phenethylamine is the parent compound of amphetamine, while is a positional isomer of amphetamine that differs only in the placement of the methyl group.
Uses
Medical
ADHD
Long-term amphetamine exposure at sufficiently high doses in some animal species is known to produce abnormal dopamine system development or nerve damage, but, in humans with ADHD, long-term use of pharmaceutical amphetamines at therapeutic doses appears to improve brain development and nerve growth. Reviews of magnetic resonance imaging 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 continuous amphetamine use for the treatment of ADHD. Randomized controlled trials of continuous stimulant therapy for the treatment of ADHD spanning 2 years have demonstrated treatment effectiveness and safety. Two reviews have indicated that long-term continuous stimulant therapy for ADHD is effective for reducing the core symptoms of ADHD, enhancing quality of life and academic achievement, and producing improvements in a large number of functional outcomes across 9 categories of outcomes related to academics, antisocial behavior, driving, non-medicinal drug use, obesity, occupation, self-esteem, service use, and social function. Additionally, a 2024 meta-analytic systematic review reported moderate improvements in quality of life when amphetamine treatment is used for ADHD. 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. 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.
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 noradrenergic projections from the locus coeruleus to the prefrontal cortex. Stimulants 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 reviews 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. However, a 2025 meta-analytic systematic review of 113 randomized controlled trials found that stimulant medications were the only intervention with robust short-term efficacy, and were associated with lower all-cause treatment discontinuation rates than non-stimulant medications. 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.
Binge eating disorder
is characterized by recurrent and persistent episodes of compulsive binge eating. These episodes are often accompanied by marked distress and a feeling of loss of control over eating. 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. As of July 2024, lisdexamfetamine is the only USFDA- and TGA-approved pharmacotherapy for BED. 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.Lisdexamfetamine's therapeutic effects for BED primarily involve direct action in the central nervous system after conversion to its pharmacologically active metabolite, dextroamphetamine. Dextroamphetamine increases dopaminergic and noradrenergic neurotransmission in prefrontal cortex, a region of the brain that regulates cognitive control of behavior. 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. Dextroamphetamine is also a full agonist of trace amine-associated receptor 1, a G-protein coupled receptor that regulates monoaminergic systems in the brain; activation of TAAR1 may restore impaired dopaminergic signaling in the prefrontal cortex and thereby correct deficits in inhibitory control associated with binge eating behaviors. Alongside its effect on cognitive control, appetite suppression is a common side effect of lisdexamfetamine and is associated with reduced food intake. Amphetamines are believed to dampen the sensation of hunger through actions in the lateral hypothalamus; this is thought to involve increased catecholaminergic signaling and the induction of cocaine- and amphetamine-regulated transcript, a hypothalamic neuropeptide involved the regulation of food intake. While appetite suppression may influence the magnitude of reductions in food intake, three medical reviews indicate that lisdexamfetamine's enhancement of cognitive control is the primary therapeutic effect for reducing binge-eating symptoms and is likely required for addressing the disorder's underlying psychopathology. This view is supported by the failure of anti-obesity medications and other appetite suppressants to significantly reduce BED symptom severity, despite their ability to produce weight loss.
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. 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. 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. 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. Lisdexamfetamine, like all pharmaceutical amphetamines, has direct appetite suppressant effects that may be therapeutically useful in both BED and its comorbidities. Based on reviews of neuroimaging studies involving BED-diagnosed participants, therapeutic 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.