Amphetamine
In 1887, Romanian chemist Lazăr Edeleanu synthesized a new chemical compound in Germany and named it phenylisopropylamine. The substance remained a laboratory curiosity for decades until Gordon Alles independently resynthesized the drug in 1927. Alles reported that the compound possessed sympathomimetic properties, meaning it mimicked the effects of the sympathetic nervous system. Pharmaceutical companies began testing its potential uses shortly after this discovery. By late 1933, Smith, Kline and French introduced the first amphetamine pharmaceutical under the brand name Benzedrine. This product was originally sold as an inhaler to treat nasal congestion. Three years later, Benzedrine sulfate became available as a tablet form used to treat narcolepsy, obesity, low blood pressure, and chronic pain. During World War II, both Allied and Axis forces distributed amphetamine extensively to soldiers. Military personnel relied on the stimulant to maintain alertness during long campaigns and to enhance physical performance. As the addictive nature of the drug became clear, governments worldwide began implementing strict controls over its sale and distribution. In the early 1970s, the United States classified amphetamine as a schedule II controlled substance under the Controlled Substances Act.
Modern medicine utilizes amphetamine to treat attention deficit hyperactivity disorder, narcolepsy, obesity, and binge eating disorder through the prodrug lisdexamfetamine. Clinical reviews indicate that approximately 80% of patients using these stimulants experience improvements in ADHD symptoms. Long-term studies suggest that continuous treatment reduces core symptoms like hyperactivity, inattention, and impulsivity while enhancing quality of life. A nine-month randomized controlled trial found that children receiving amphetamine treatment gained an average of 4.5 IQ points compared to control groups. Reviews of magnetic resonance imaging scans show that long-term use decreases abnormalities in brain structure and function found in subjects with ADHD. The American Academy of Sleep Medicine conditionally recommends dextroamphetamine for treating type 1 and type 2 narcolepsy. Evidence suggests this medication produces clinically significant reductions in daytime sleepiness for many patients. FDA-commissioned studies from 2011 found no association between serious adverse cardiovascular events and medical use of amphetamine in children or adults. A 2022 meta-analysis sampling nearly four million participants corroborated these findings regarding safety across all age groups. As of July 2024, lisdexamfetamine remains the only USFDA- and TGA-approved pharmacotherapy specifically for binge eating disorder.
Amphetamine exerts its behavioral effects by altering monoamine neurotransmission primarily within dopamine and norepinephrine pathways. The drug enters presynaptic neurons through active transporters or passive diffusion across neuronal membranes. Once inside the cytosol, it triggers signaling cascades that activate protein kinases such as PKA and PKC. These enzymes phosphorylate transporter proteins to induce reverse transport of dopamine into the synaptic cleft. Amphetamine also acts as a full agonist of trace amine-associated receptor 1, which modulates monoamine transporter function. This interaction leads to competitive reuptake inhibition and non-competitive reuptake inhibition at specific synapses. Dextroamphetamine displays higher binding affinity for the dopamine transporter than levoamphetamine does. Consequently, dextroamphetamine produces roughly three to four times more stimulation of dopamine release compared to its counterpart. Levoamphetamine retains slightly stronger cardiovascular and peripheral effects despite lower dopaminergic potency. The drug inhibits vesicular monoamine transporters VMAT1 and VMAT2, causing the collapse of vesicular pH gradients. This process releases stored monoamines from synaptic vesicles into the neuronal cytosol for subsequent efflux. Amphetamine activates seven human carbonic anhydrase enzymes, four of which are highly expressed in the brain.
Athletes utilize amphetamine to increase endurance, alertness, reaction time, and muscle strength during competition. At therapeutic doses, the drug delays fatigue onset while improving power output at fixed levels of perceived exertion. It overrides a physiological safety switch that normally limits core body temperature access to reserve capacity. International anti-doping agencies prohibit non-medical use of amphetamine at collegiate, national, and sporting events. Healthy individuals taking oral therapeutic doses show increased acceleration and anaerobic performance capabilities. However, much higher doses can induce rapid muscle breakdown and elevated body temperature that severely impair athletic function. A 2015 systematic review found that low therapeutic doses produce modest yet unambiguous improvements in working memory and attention for normal healthy adults. Studies indicate that about 30% of college students use diverted ADHD stimulants primarily for academic enhancement rather than recreation. These cognitive effects stem from indirect activation of dopamine D1 receptors and alpha-2-adrenergic receptors in the prefrontal cortex. Therapeutic doses enhance cortical network efficiency, mediating improvements in task saliency and goal-directed behavior. The adverse effects of standard pharmaceutical dosages do not impede athletic performance under normal conditions.
Heavy recreational use of amphetamine carries a serious risk of addiction compared to long-term medical use at therapeutic doses. Chronic high-dose self-administration gradually increases the level of accumbal Delta FBJ murine osteosarcoma viral oncogene homolog B protein. This molecular switch acts as master control for addiction behaviors including compulsive drug-seeking. Individuals who frequently take large amounts develop tolerance requiring increasingly larger doses to achieve the same effect. Withdrawal symptoms occur in roughly 88% of chronic heavy users within 24 hours of their last dose. Symptoms include anxiety, depressed mood, fatigue, increased appetite, sleeplessness, and lucid dreams. A marked crash phase typically occurs during the first week of discontinuation. Amphetamine psychosis involving delusions and paranoia can arise in heavy users but rarely occurs at therapeutic doses even during long-term therapy. Tolerant individuals have been known to consume up to 5 grams of amphetamine in a single day. This amount represents roughly 100 times the maximum daily therapeutic dose. In 2013, overdose on amphetamine and related compounds resulted in an estimated 3,788 deaths worldwide. No effective pharmacotherapy currently exists for treating amphetamine addiction, though sustained aerobic exercise appears to reduce the risk.
The most common synthetic route employs a non-metal reduction known as the Leuckart reaction using phenylacetone and formamide. This process yields an intermediate that is hydrolyzed with hydrochloric acid and basified to produce the free base. The free base then precipitates out as sulfate salt when treated with sulfuric acid. Chiral resolution remains the most economical method for obtaining optically pure dextroamphetamine on a large scale. Racemic amphetamine can be separated into its optical isomers levoamphetamine and dextroamphetamine through fractional crystallization. Substituted derivatives include stimulants like methamphetamine, serotonergic empathogens like MDMA, and decongestants like ephedrine. These compounds contain amphetamine as a backbone structure formed by replacing hydrogen atoms with substituents. Amphetamine itself serves as the parent compound of its own structural class within organic chemistry. It functions as an excellent chiral ligand for stereoselective synthesis processes. Frequently prepared solid salts include amphetamine adipate, aspartate, hydrochloride, phosphate, saccharate, sulfate, and tannate. Dextroamphetamine sulfate stands as the most common enantiopure salt available today. Alternative synthetic routes involve Friedel-Crafts alkylation or Ritter reactions depending on the desired output.
The United Nations 1971 Convention on Psychotropic Substance classified amphetamine as a schedule II controlled substance in all 183 state parties. Consequently, the drug remains heavily regulated across most nations worldwide. Some countries such as South Korea and Japan have banned substituted amphetamines even for medical use. Brazil classifies it as a class A3 drug while Canada lists it under schedule I. The Netherlands designates it as a List I drug and the United States maintains it as schedule II. Australia schedules it as category 8 and Thailand categorizes it as a narcotic under category 1. The United Kingdom regulates it as a class B drug. Among European Union member states, approximately 11.9 million adults aged 15 to 64 have used amphetamine or methamphetamine at least once in their lives. About 1.7 million of these individuals used either substance within the last year. During 2012, authorities seized approximately 5.9 metric tons of illicit amphetamine within EU borders. The street price ranged from unspecified amounts per gram during that same period. Outside Europe, the illicit market for amphetamine is much smaller than markets for methamphetamine and MDMA. Clandestine labs continue to synthesize the drug illegally for sale on black markets primarily located in European countries.
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Common questions
Who synthesized amphetamine in 1887?
Romanian chemist Lazăr Edeleanu synthesized the chemical compound phenylisopropylamine, now known as amphetamine, in Germany during 1887. Gordon Alles independently resynthesized the drug later in 1927 and reported its sympathomimetic properties.
When did Smith Kline and French introduce Benzedrine?
Smith Kline and French introduced the first amphetamine pharmaceutical under the brand name Benzedrine by late 1933. Three years after this initial release, Benzedrine sulfate became available as a tablet form to treat narcolepsy, obesity, low blood pressure, and chronic pain.
What is the current legal status of amphetamine in the United States?
The United States classified amphetamine as a schedule II controlled substance under the Controlled Substances Act in the early 1970s. The United Nations 1971 Convention on Psychotropic Substance also classified amphetamine as a schedule II controlled substance in all 183 state parties.
How does dextroamphetamine compare to levoamphetamine in terms of stimulation?
Dextroamphetamine produces roughly three to four times more stimulation of dopamine release compared to levoamphetamine due to higher binding affinity for the dopamine transporter. Levoamphetamine retains slightly stronger cardiovascular and peripheral effects despite lower dopaminergic potency.
What are the withdrawal symptoms experienced by chronic heavy users of amphetamine?
Withdrawal symptoms occur in roughly 88% of chronic heavy users within 24 hours of their last dose and include anxiety, depressed mood, fatigue, increased appetite, sleeplessness, and lucid dreams. A marked crash phase typically occurs during the first week of discontinuation.