Amphetamine and related drugs such as methamphetamine are a group of drugs that act by increasing levels of norepinephrine, serotonin, and dopamine in the brain. The group includes prescription CNS drugs commonly used to treat attention-deficit hyperactivity disorder (ADHD) in adults and children. It is also used to treat symptoms of traumatic brain injury and the daytime drowsiness symptoms of narcolepsy and chronic fatigue syndrome. Initially, amphetamine was more popularly used to diminish the appetite and to control weight.

Brand names of the drugs that contain amphetamine include Adderall, Vyvanse, and Dexedrine. The drug is also used illegally as a recreational drug and as a performance enhancer. The name amphetamine is derived from its chemical name: alpha-methylphenethylamine.

The name is also used to refer to the class of compounds derived from amphetamine, often referred to as the substituted amphetamines.

Recreational users of amphetamine have coined numerous nicknames for amphetamine, some of the more common street names for amphetamine include speed, crank, and whizz. The European Monitoring Centre for Drugs and Drug Addiction reports the typical retail price of amphetamine in Europe varied between 10£ and 15£ a gram in half of the reporting countries.

History

Amphetamine was first synthesized in 1887 by the Romanian Lazăr Edeleanu in Berlin, Germany.  He named the compound phenylisopropylamine. It was one of a series of compounds related to the plant derivative ephedrine, which had been isolated from Ma-Huang that same year by Nagayoshi Nagai. No pharmacological use was found for amphetamine until 1929, when pioneer psychopharmacologist Gordon Alles resynthesized and tested it on himself, in search of an artificial replacement for ephedrine. From 1933 or 1934 Smith, Kline and French began selling the volatile base form of the drug as an inhaler under the trade name Benzedrine, useful as a decongestant but readily usable for non-medical purposes. One of the first attempts at using amphetamines as a scientific study was done by M. H. Nathanson, a Los Angeles physician, in 1935. He studied the subjective effects of amphetamine in 55 hospital workers who were each given 20 mg of Benzedrine. The two most commonly reported drug effects were "a sense of well being and a feeling of exhilaration" and "lessened fatigue in reaction to work". During World War II amphetamine was extensively used to combat fatigue and increase alertness in soldiers. After decades of reported abuse, the FDA banned Benzedrine inhalers, and limited amphetamines to prescription use in 1965, but non-medical use remained common. Amphetamine became a schedule II drug under the Controlled Substances Act in 1971.

The related compound methamphetamine was first synthesized from ephedrine in Japan in 1918 by chemist Akira Ogata, via reduction of ephedrine using red phosphorus and iodine. The German military was notorious for their use of methamphetamine in World War II. Adolf Hitler received daily shots of a medicine his doctor called "vitamultine", which contained various essential vitamins in addition to methamphetamine. The pharmaceutical Pervitin was a tablet of 3 mg methamphetamine which was available in Germany from 1938 and widely used in theWehrmacht, but by mid-1941 it became a controlled substance, partly because of the amount of time needed for a soldier to rest and recover after use and partly because of abuse. For the rest of the war, military doctors continued to issue the drug, but less frequently and with increasing discrimination as the war progressed onwards towards Nazi Germany's and the Axis' eventual defeat in 1945.

In 1997 and 1998, researchers at Texas A&M University claimed to have found amphetamine and methamphetamine in the foliage of two Acacia species native to Texas, A. berlandieri and A. rigidula. Previously, both of these compounds had been thought to be human inventions. These findings have never been duplicated, and the analyses are believed by many biochemists to be the result of experimental error, and as such the validity of the report has come into question. Alexander Shulgin, one of the more experimented biochemical investigator and creator of hundred of new substances of that chemical family, tried to contact and verify that finding but the authors of the paper never answered, so natural amphetamine remains most likely a false discovery.

Amphetamines were still in use in the US Air Force as of 2003. They are believed to have played a role in the deaths of four Canadian soldiers in Afghanistan involved in a friendly fire incident.

Indications

Along with methylphenidate (Ritalin, Concerta, etc.), amphetamine is one of the standard treatments for ADHD. Beneficial effects for ADHD can include improved impulse control, improved concentration, decreased sensory overstimulation, decreased irritability and decreased anxiety. These effects on productivity can be dramatic in both young children and adults. The ADHD medication Adderall is composed of four different amphetamine salts, and Adderall XR is a timed-release formulation of these same salt forms.

When used within the recommended doses, side-effects like loss of appetite tend to decrease over time. However, amphetamines last longer in the body than methylphenidate and tend to have stronger side-effects on appetite and sleep.

Amphetamines are also a standard treatment for narcolepsy, as well as other sleeping disorders. If used within therapeutic limits, amphetamines are generally effective over long periods of time without producing addiction or physical dependence.

Amphetamines are sometimes used to augment anti-depressant therapy in treatment-resistant depression.

Medical use for weight loss is still approved in some countries, but is regarded as obsolete and dangerous in others.

Contraindications

Stimulants such as amphetamines elevate cardiac output and blood pressure making them dangerous for use by patients with a history of heart disease or hypertension. Also, patients with a history of drug dependence or anorexia should not be treated with amphetamines due to their addictive and appetite suppressing properties. Amphetamines can cause a life-threatening complication in patients taking MAOI antidepressants. Amphetamine is not suitable for patients with a history of glaucoma.

Amphetamines have also been shown to pass through into breast milk. Because of this, mothers taking medications containing amphetamines are advised to avoid breastfeeding during their course of treatment.

Primary sites of action

Amphetamine exerts its behavioral effects by modulating the behavior of several key neurotransmitters in the brain, including dopamine, serotonin, and norepinephrine. However, the activity of amphetamine throughout the brain appears to be specific; certain receptors that respond to amphetamine in some regions of the brain tend not to do so in other regions. For instance, dopamine D2 receptors in the hippocampus, a region of the brain associated with forming new memories, appear to be unaffected by the presence of amphetamine.

The major neural systems affected by amphetamine are largely implicated in the brain's reward circuitry. Moreover, neurotransmitters involved in various reward pathways of the brain appear to be the primary targets of amphetamine. One such neurotransmitter is dopamine, a chemical messenger heavily active in the mesolimbic and mesocortical reward pathways. Not surprisingly, the anatomical components of these pathways - including the striatum, the nucleus accumbens, and the ventral striatum - have been found to be primary sites of amphetamine action.

The fact that amphetamines influence neurotransmitter activity specifically in regions implicated in reward provides insight into the behavioral consequences of the drug, such as the stereotyped onset ofeuphoria.  A better understanding of the specific mechanisms by which amphetamines operate may increase our ability to treat amphetamineaddiction, as the brain's reward circuitry has been widely implicated in addictions of many types.

Endogenous amphetamines

Amphetamine has been found to have several endogenous analogues; that is, molecules of a similar structure found naturally in the brain. l-Phenylalanine and β-Phenethylamine are two examples, which are formed in the peripheral nervous system as well as in the brain itself. These molecules are thought to modulate levels of excitement and alertness, among other related affective states.

Dopamine

Perhaps the most widely studied neurotransmitter with regard to amphetamine action is dopamine, the "reward neurotransmitter" that is highly active in numerous reward pathways of the brain. Various studies have shown that in select regions, amphetamine increases the concentrations of dopamine in the synaptic cleft, thereby heightening the response of the post-synaptic neuron. This specific action hints at the hedonic response to the drug as well as to the drug's addictive quality.

The specific mechanisms by which amphetamines affect dopamine concentrations have been studied extensively. Currently, two major hypotheses have been proposed, which are not mutually exclusive. One theory emphasizes amphetamine's actions on the vesicular level, increasing concentrations of dopamine in the cytosol of the pre-synaptic neuron. The other focuses on the role of the dopamine transporter DAT, and proposes that amphetamine may interact with DAT to induce reverse transport of dopamine from the presynaptic neuron into the synaptic cleft.

The former hypothesis is backed by data demonstrating that injections of amphetamines result in rapid increases of cytosolic dopamine concentrations. Amphetamine is believed to interact with dopamine-containing vesicles in the axon terminal, called VMATs, in a way that releases dopamine molecules into the cytosol. The redistributed dopamine is then believed to interact with DAT to promote reverse transport. Calcium may be a key molecule involved in the interactions between amphetamine and VMATs.

The latter hypothesis postulates a direct interaction between amphetamine and the DAT transporter. The activity of DAT is believed to depend on specific phosphorylating kinases, such as PKC-β. Upon phosphorylation, DAT undergoes a conformational change that results in the transportation of DAT-bound dopamine from the extracellular to the intracellular environment. In the presence of amphetamine, however, DAT has been observed to function in reverse, spitting dopamine out of the presynaptic neuron and into the synaptic cleft. Thus, beyond inhibiting reuptake of dopamine, amphetamine also stimulates the release of dopamine molecules into the synapse.

In support of the above hypothesis, it has been found that PKC-β inhibitors eliminate the effects of amphetamine on extracellular dopamine concentrations in the striatum of rats. This data suggests that the PKC-β kinase may represent a key point of interaction between amphetamine and the DAT transporter.

Serotonin

Amphetamine has been found to exert similar effects on serotonin as on dopamine. Like DAT, the serotonin transporter SERT can be induced to operate in reverse upon stimulation by amphetamine. This mechanism is thought to rely on the actions of calcium molecules, as well as on the proximity of certain transporter proteins.

The interaction between amphetamine and serotonin is only apparent in particular regions of the brain, such as the mesocorticolimbic projection. Recent studies additionally postulate that amphetamine may indirectly alter the behavior of glutamatergic pathways extending from the ventral tegmental area to the prefrontal cortex. Glutamatergic pathways are strongly correlated with increased excitability at the level of the synapse. Increased extracellular concentrations of serotonin may thus modulate the excitatory activity of glutamatergic neurons.

The proposed ability of amphetamine to increase excitability of glutamatergic pathways may be of significance when considering serotonin-mediated addiction. An additional behavioral consequence may be the stereotyped locomotor stimulation that occurs in response to amphetamine exposure.

Other relevant neurotransmitters

Several other neurotransmitters have been linked to amphetamine activity. For instance, extracellular levels of glutamate, the primary excitatory neurotransmitter in the brain, have been shown to increase upon exposure to amphetamine. Consistent with other findings, this effect was found in the areas of the brain implicated in reward; namely, the nucleus accumbens, striatum, and prefrontal cortex.

Additionally, several studies demonstrate increased levels of norepinephrine, a neurotransmitter related to adrenaline, in response to amphetamine. This is believed to occur via reuptake blockage as well as via interactions with the norepinephrine neuronal transport carrier.

Long-term neurological effects

The long-term effects of amphetamine remain unknown to a large extent, though some literature on the topic does exist. Several of the postulated effects include reductions in dopamine content, DAT density, and tyrosine hydroxylase (the dopamine synthesizing enzyme) in the striatum and nearby areas.

Chemical properties

Amphetamine is a chiral compound. The racemic mixture can be divided into its optical isomers: levo- and dextro-amphetamine. Amphetamine is the parent compound of its own structural class, comprising a broad range of psychoactive derivatives, from empathogens, MDA (3,4-Methylenedioxyamphetamine) and MDMA (3,4-Methylenedioxy-N-methamphetamine) known as ecstasy, to the N-methylated form, methamphetamine known as 'meth', and to decongestants such as ephedrine (EPH) . Amphetamine is a homologue of phenethylamine.

At first, the medical drug came as the salt racemic-amphetamine sulfate (racemic-amphetamine contains both isomers in equal amounts). Attention disorders are often treated using Adderall or a generic equivalent, a formulation of mixed amphetamine and dextroamphetamine salts that contain

• 1/4 dextroamphetamine saccharate
• 1/4 dextroamphetamine sulfate
• 1/4 (racemic dextro/laevo-amphetamine) aspartate monohydrate
• 1/4 (racemic dextro/laevo-amphetamine) sulfate

Pharmacodynamics

Amphetamine has been shown to both diffuse through the cell membrane and travel via the dopamine transporter (DAT) to increase concentrations of dopamine in the neuronal terminal.

Amphetamine, both as d-amphetamine (dextroamphetamine) and l-amphetamine (or a racemic mixture of the two isomers), is believed to exert its effects by binding to the monoamine transporters and increasing extracellular levels of the biogenic amines dopamine, norepinephrine (noradrenaline) and serotonin. It is hypothesized that d-amphetamine acts primarily on the dopaminergic systems, while l-amphetamine is comparatively norepinephrinergic (noradrenergic). The primary reinforcing and behavioral-stimulant effects of amphetamine, however, are linked to enhanced dopaminergic activity, primarily in the mesolimbic dopamine system.

Amphetamine and other amphetamine-type stimulants principally act to release dopamine into the synaptic cleft. Amphetamine, unlike similar dopamine acting stimulant cocaine, does not act as a ligand but does slow reuptake by a secondary acting mechanism through the phosphorylation of dopamine transporters. The primary action is through the increased amphetamine concentration which releases endogenous stores of dopamine from vesicular monoamine transporters (VMATs), thereby increasing intra-neuronal concentrations of transmitter. This increase in concentration effectively reverses transport of dopamine via the dopamine transporter (DAT) into the synapse. In addition, amphetamine binds reversibly to the DATs and blocks the transporter's ability to clear DA from the synaptic space. Amphetamine also acts in this way with norepinephrine (noradrenaline) and to a lesser extent serotonin.

In addition, amphetamine binds to a group of receptors called TrAce Amine Receptors (TAAR). TAAR are a newly discovered receptor system which seems to be affected by a range of amphetamine-like substances called trace amines.

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Physical effects

Physical effects of amphetamine can include reduced appetite, increased/distorted sensations, hyperactivity, dilated pupils, flushing, restlessness, dry mouth, erectile dysfunction, headache, tachycardia, increased breathing rate, increased blood pressure, fever, sweating, diarrhea, constipation, blurred vision, impaired speech, dizziness, uncontrollable movements or shaking, insomnia, numbness, palpitations, arrhythmia. In addition, increased awareness of one's body's sensations can cause the user to perceive certain physical effects, such as sudden hot or coldness, a flushed face, or very rapid heart rate. In high doses or chronic use convulsions, dry or itchy skin, acne, pallor can occur.

Occasionally amphetamine use in males can cause an odd and sometimes startling effect to occur in which the penis when flaccid appears to have shrunk. The reason this occurs is because amphetamine is a potent vasoconstrictor or an agent that constricts blood vessels. The rigidness of the erection and the size of the penis are in part by affected by the amount of blood flow to the penis. When amphetamine constricts the blood vessels enough it reduces blood flow to the penis and then can produce a penis that is slightly smaller and this effect is often coupled along with impotence and erectile dysfunction. Upon erection the penis returns to normal size.

Young adults who abuse amphetamines may be at greater risk of suffering a heart attack. In a study published in the journal Drug and Alcohol Dependence, researchers examined data from more than 3 million people between 18 and 44 years old hospitalized from 2000 through 2003 in Texas. After controlling for cocaine abuse, alcohol abuse, tobacco use, hypertension, diabetes mellitus, lipid disorders, obesity, congenital defects, and coagulation defects, they found a relationship between a diagnosis of amphetamine abuse and heart attack.

Psychological effects

Psychological effects of amphetamine can include anxiety and/or general nervousness (by increased norepinephrine), euphoria, metacognition, creative or philosophical thinking, perception of increased energy, increased sense of well being, increase of goal-orientated thoughts or organized behavior, repetitive behavior, increased concentration/mental sharpness, increased alertness, feeling of power or superiority, emotional lability, excitability, talkativeness, an increased expression of aggression or paranoia, and occasionally amphetamine psychosis, typically in a high and/or chronic doses. Effects are similar to other phenylethylamine stimulants and cocaine.

Withdrawal effects

Withdrawal from chronic recreational use of amphetamines can include anxiety, depression, agitation, fatigue, excessive sleeping, increased appetite, psychosis and suicidal thoughts.

Overdose

An amphetamine overdose can lead to a number of different symptoms. Some include psychosis, chest pain, and hypertension.

Psychosis

Amphetamine psychosis usually occurs at large doses only, but it has been known to occur in children taking therapeutic doses for the treatment of ADHD.

Dependence and addiction

Tolerance is developed rapidly in amphetamine abuse, therefore increasing the amount of the drug that is needed to satisfy the addiction. Repeated amphetamine use can produce "reverse tolerance", or sensitization to some psychological effects. Amphetamine does not have the potential to cause physical dependence, though withdrawal can still be hard for a user. Many users will repeat the amphetamine cycle by taking more of the drug during the withdrawal. This leads to a very dangerous cycle and may involve the use of other drugs to get over the withdrawal process. Users will commonly stay up for 2 or 3 days to avoid the withdrawals then dose themselves with benzodiazepines, barbiturate, and in some cases heroin, to help them stay calm while they recuperate or simply to extend the positive effects of the drug. Chronic users of amphetamines sometimes snort or use drug injection to experience the full effects of the drug in a faster and more intense way, with the added risks of infection, vein damage, and higher risk of overdose with drug injection.

Because of the abuse of amphetamines in the U.S., brands discontinued by the 1990s, including Preludin, known on the street as "slams", whose coating was removed so that the waxy pill in the center could be processed and the active ingredient injected.Amphetamines are still produced in the United States: those prescribed for narcolepsy, attention-deficit hyperactivity disorder, treatment-resistant depression, and extreme obesity.

Performance-enhancing use

Amphetamines are used by some college and high-school students as a study and test-taking aid. Amphetamines work by increasing energy levels, concentration, and motivation, thus allowing students to study for an extended period of time. These drugs are often acquired through ADHD prescriptions to students and peers, rather than illicitly produced drugs.

Amphetamines have been, and are still, used by militaries around the world. British troops used 72 million amphetamine tablets in the second world war and the RAF used so many that "Methedrine won the Battle of Britain" according to one report. American bomber pilots use amphetamines ("go pills") to stay awake during long missions. The Tarnak Farm incident, in which an American F-16 pilot killed several friendly Canadian soldiers on the ground, was blamed by the pilot on his use of amphetamine. A nonjudicial hearing rejected the pilot's claim.

Amphetamine is also used by some professional, collegiate and high school athletes for its strong stimulant effect. Energy levels are perceived to be dramatically increased and sustained, which is believed to allow for more vigorous and longer play. However, at least one study has found that this effect is not measurable. The use of amphetamine during strenuous physical activity can be extremely dangerous, especially when combined with alcohol, and athletes have died as a result, for example, British cyclist Tom Simpson.

Amphetamine use has historically been especially common among Major League Baseball players and is usually known by the slang term "greenies". In 2006, the MLB banned the use of amphetamines. The ban is enforced through periodic drug-testing. If a player tests positive for amphetamine, the consequences are significant. However, the MLB has received some criticism because the consequences for amphetamine use are dramatically less severe than for anabolic steroid use, with the first offense bringing only a warning and further testing.

Some truck drivers, especially long-haul drivers, take amphetamine to combat symptoms of somnolence and to increase their concentration on driving.

Legal issues

• In the United Kingdom, amphetamines are regarded as Class B drugs. The maximum penalty for unauthorized possession is five years in prison and an unlimited fine. The maximum penalty for illegal supply is fourteen years in prison and an unlimited fine. Methamphetamine has recently been reclassified to Class A, penalties for possession of which are more severe (7 years in prison and an unlimited fine).
• In the Netherlands, amphetamine and methamphetamine are List I drugs of the Opium Law, but the dextro isomer of amphetamine is indicated for ADD/ADHD and narcolepsy and available for prescription as 5 and 10 mg generic tablets, and 5 and 10 mg gel capsules.
• In the United States, amphetamine and methamphetamine are Schedule II drugs, classified as CNS (central nervous system) stimulants. A Schedule II drug is classified as one that has a high potential for abuse, has a currently-accepted medical use and is used under severe restrictions, and has a high possibility of severe psychological and physiological dependence.

Internationally, amphetamine is a Schedule II drug under the Convention on Psychotropic Substances.

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