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Amphetamine or amfetamine is a psychostimulant drug that is known to produce increased wakefulness and focus in association with decreased fatigue and appetite. Amphetamine is related to drugs such as methamphetamine and lisdexamfetamine which are a group of potent drugs that act by increasing levels of dopamine and norepinephrine in the brain, inducing euphoria. The group includes prescription CNS drugs commonly used to treat attention-deficit hyperactivity disorder. It is also used to treat symptoms of traumatic brain injury and the daytime drowsiness symptoms of narcolepsy, Postural Orthostatic Tachycardia Syndrome 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, or metabolize into, amphetamine include Adderall, Vyvanse, and Dexedrine, as well as Benzedrine in the past.
The drug is also used recreationally and as a performance enhancer. Recreational users of amphetamine have coined numerous euphemisms for amphetamine, such as speed and crank. 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. The name amphetamine is derived from its chemical name: alpha-methylphenethylamine.
Amphetamine was first synthesized in 1887 by the Romanian chemist 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 1927, 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 amphetamine 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 amphetamine 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 pharmaceutical Pervitin was a tablet of 3 mg methamphetamine which was available in Germany from 1938 and widely used in the Wehrmacht, 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.
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 most experienced biochemical investigators and the discoverer of many new psychotropic substances, has tried to contact the Texas A&M researchers and verify their findings. The authors of the paper have not responded; natural amphetamine remains most likely a false discovery.
Amphetamine elevates cardiac output and blood pressure making it dangerous for use by patients with a history of heart disease or hypertension. Amphetamine can cause a life-threatening complication in patients taking MAOI antidepressants. The use of amphetamine and amphetamine-like drugs is contraindicated in patients with narrow-angle glaucoma or anatomically narrow angles. Like other sympathomimetic amines, amphetamine can induce transient mydriasis. In patients with narrow angles, pupillary dilation can provoke an acute attack of angle-closure glaucoma. These agents should also be avoided in patients with other forms of glaucoma, as mydriasis may occasionally increase intraocular pressure.
Amphetamine has been shown to pass through into breast milk. Because of this, mothers taking amphetamine are advised to avoid breastfeeding during their course of treatment. Many women who use amphetamine find that their periods become irregular or even stop. Both amphetamine and the pill increase blood pressure which in the long term can affect the heart, blood vessels and liver. Furthermore, amphetamine can inhibit the effects of the contraceptive pill which may cause it to work less effectively. The weight loss sometimes associated with amphetamine use may also cause the contraceptive cap or diaphragm to be less effective as it will not fit as well.
Major neurobiological mechanisms
Amphetamine exerts its behavioral effects by modulating 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 amphetamine influences neurotransmitter activity specifically in regions implicated in reward provides insight into the behavioral consequences of the drug, such as the stereotyped onset of euphoria. A better understanding of the specific mechanisms by which amphetamine operates may increase our ability to treat amphetamine addiction, as the brain’s reward circuitry has been widely implicated in addictions of many types.
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.
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 amphetamine affects 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 amphetamine result in rapid increases of cytosolic dopamine concentrations. Amphetamine is believed to interact with dopamine-containing synaptic vesicles in the axon terminal. Amphetamine is a substrate for a specific neuronal synaptic vesicle uptake transporter called VMAT2. When amphetamine is taken up by VMAT2, the vesicle releases dopamine molecules into the cytosol in exchange. 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. The activity of DAT is believed to depend on specific phosphorylating kinases, such as protein kinase c, specifically 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.
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 ions, 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.
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 and MDMA known as ecstasy, to the N-methylated form, methamphetamine known as 'meth', and to decongestants such as ephedrine. Amphetamine is a homologue of phenethylamine.
At first, the medical drug came as the salt racemic-amphetamine sulfate. Attention disorders are often treated using Adderall or a generic equivalent, a formulation of mixed amphetamine and dextroamphetamine salts that contain
1/4 dextro-amphetamine saccharate
Amphetamine has been shown to both diffuse through the cell membrane and travel via the dopamine transporter to increase concentrations of dopamine in the neuronal terminal.
Amphetamine, both as d-amphetamine and l-amphetamine, 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. 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, thereby increasing intra-neuronal concentrations of transmitter. This increase in concentration effectively reverses transport of dopamine via the dopamine transporter 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 and to a lesser extent serotonin.
In addition, amphetamine binds to a group of receptors called Trace Amine Associated Receptors. TAAR are a newly discovered receptor system which seems to be affected by a range of amphetamine-like substances called trace amines.
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, and arrhythmia. 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 in which the penis when flaccid appears to have shrunk due to vasoconstriction. Upon erection the penis returns to normal size.
Young adults who abuse amphetamine 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 can include euphoria, anxiety, increased libido, alertness, concentration, energy, self-esteem, self-confidence, sociability, irritability, aggression, psychosomatic disorders, psychomotor agitation, hubris, excessive feelings of power and superiority, repetitive and obsessive behaviors, paranoia, and with chronic and/or high doses, amphetamine psychosis can occur.
Amphetamine use in adolescence may impair adult working memory.
Withdrawal from chronic use of amphetamine can include anxiety, depression, agitation, fatigue, excessive sleeping, increased appetite, short temper, psychosis and suicidal thoughts.
An amphetamine overdose is rarely fatal but can lead to a number of different symptoms, including psychosis, chest pain, and hypertension.
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, thereby the amount of the drug that is needed to satisfy the addiction needs to be increased at regular intervals.
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 abusers of amphetamine often insufflate, smoke or inject the drug in order to experience a rush, with extra risks for infection, vein damage and overdose.
Amphetamine is used by some college and high-school students as a study and test-taking aid. Amphetamine works by increasing energy levels, concentration, and motivation, thus allowing students to study for an extended period of time. This drug is often acquired through ADHD prescriptions to students and peers, rather than illicitly produced drugs.
Amphetamine has been, and is 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 amphetamine 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 amphetamine. The ban is enforced through periodic drug-testing. 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.
Amphetamine was formerly in widespread use by truck drivers to combat symptoms of somnolence and to increase their concentration during driving, especially in the decades prior to the signing by former president Ronald Reagan of Executive Order 12564, which initiated mandatory random drug testing of all truck drivers and employees of other DOT-regulated industries. Although implementation of the order on the trucking industry was kept to a gradual rate in consideration of its projected effects on the national economy, in the decades following the order, amphetamine and other drug abuse by truck drivers has since dropped drastically.
Cultural impact of amphetamine
The social and cultural impact of amphetamine has been, and continues to be, quite extensive.
From the 1960s onward, amphetamine has been popular with many youth subcultures in Britain (and other parts of the world) as a recreational drug. It has been commonly used by mods, skinheads, punks, goths, gangstas, and casuals in all night soul and ska dances, punk concerts, basement shows and fighting on the terraces by casuals.
The hippie counterculture was very critical of amphetamines due to the behaviors they cause; beat writer Allen Ginsberg wrote that users ran the risk of becoming a "Frankenstein speed freak".
The writers of the Beat Generation used amphetamine extensively, mainly under the Benzedrine brand name. Jack Kerouac was a particularly avid user of amphetamine, which was said to provide him with the stamina needed to work on his novels for extended periods of time.
Scottish author Irvine Welsh often portrays drug use in his novels, though in one of his journalism works he comments on how drugs have become part of consumerism and how his novels Trainspotting and Porno reflect the changes in drug use and culture during the years that elapse between the two texts.
Amphetamine is frequently mentioned in the work of American journalist Hunter S. Thompson. Speed appears not only amongst the astoundingly diverse and voluminous inventory of drugs Thompson consumed for what could broadly be defined as recreational purposes, but also receives frequent, explicit mention as an essential component of his writing toolkit, such as in his "Author's Note" in Fear and Loathing on the Campaign Trail '72.
"One afternoon about three days ago showed up at my door with no warning, and loaded about forty pounds of supplies into the room: two cases of Mexican beer, four quarts of gin, a dozen grapefruits, and enough speed to alter the outcome of six Super Bowls. ... Meanwhile, with the final chapter still unwritten and the presses scheduled to start rolling in twenty-four hours . . . . unless somebody shows up pretty soon with extremely powerful speed, there might not be a final chapter. About four fingers of king-hell Crank would do the trick, but I am not optimistic."
Famous mathematician Paul Erdős took amphetamine, and once won a bet from his friend Ron Graham, who bet him $500 that he could not stop taking the drug for a month. Erdős won the bet, but complained during his abstinence that mathematics had been set back by a month: "Before, when I looked at a piece of blank paper my mind was filled with ideas. Now all I see is a blank piece of paper." After he won the bet, he promptly resumed his amphetamine habit.
Many songs have been written about amphetamine, for example in the track entitled "St. Ides Heaven" from singer/songwriter, Elliott Smith's self-titled album. Semi Charmed Life by Third Eye Blind also references amphetamine. It has also influenced the aesthetics of many rock'n'roll bands. Husker Du, Jesus And Mary Chain's and The Who were keen amphetamine users early in their existence. Land Speed Record is an allusion to Husker Du's amphetamine use.
The Who's 1965 iconic Mod/youth anthem "My Generation" famously re-creates, in Roger Daltrey's vocals, the effect of amphetamine on the ability to speak. The pills accelerate the brain's processes to the degree that ideas flow faster than the ability to communicate them by speech, resulting in the characteristic stuttering of words. At various times, in the period 1965-66, either to avoid controversy or to keep the true drug-related reason a secret among "those in the know", Pete Townshend stated the stuttering was a protest at the government's poor record of national education opportunities.
Many rock'n'roll bands have named themselves after amphetamine and drug slang surrounding it. For example Mod revivalists, The Purple Hearts named themselves after the amphetamine tablets popular with mods during the 1960s, as did the Australian band of the same name during the mid 1960's. The Amphetameanies, a ska-punk band, are also named after amphetamine, but also imitate its' effects. Dexy's Midnight Runners, of number one hit "Come On Eileen" are named after Dexedrine. Motorhead named themselves after the slang for an amphetamine addict. Interestingly, Lemmy Kilmister said amphetamine was the only drug that he found any benefit in using, saying:
" first got into speed because it was a utilitarian drug and kept you awake when you needed to be awake, when otherwise you'd just be flat out on your back. If you drive to Glasgow for nine hours in the back of a sweaty truck you don't really feel like going onstage feeling all bright and breezy... It's the only drug I've found that I can get on with, and I've tried them all — except smack and morphine: I've never fixed anything."
In MASH, an announcement is made over the intercom stating that "Corporal Judson has informed the colonel's office that three cases of amphetamine sulfate are unaccounted for again. This is the third occurrence of this type in the last month. It must stop by order of Colonel Blake's office, 4077th M*A*S*H unit."
Producer David O. Selznick was an amphetamine user, and would often dictate long and rambling memos under the influence of amphetamine to his directors. The documentary Shadowing The Third Man relates that Selznick introduced Third Man director Carol Reed to the use of amphetamine, which allowed Reed to bring the picture in below budget and on schedule by filming nearly 22 hours at a time.
Garrett Scott's documentary Cul-de-Sac: A Suburban War Story has a brief history of the manufacture and spread of amphetamine, and of its effects.
In the movie Requiem for a Dream Ellen Burstyn portrays Sara Goldfarb, an elderly widow who became addicted with weight-loss amphetamine pills, and after suffering from amphetamine psychosis, was hospitalized against her will, undergoes painful electro-convulsive therapy, and later on was confined at a mental asylum.
The movie Ciao! Manhattan was riddled with amphetamine usage and is based on the life of Edie Sedgwick who was a socialite, Andy Warhol's superstar, model, actress, and 'It' girl of 1965. She died before the movie's release on November 16, 1971.
In the movie Empire Records Liv Tyler's character, Corey, ingests amphetamine in several scenes, using the drug to both be alert so she'll do well in school to please her father and to calm herself in stressful situations.
The title of the movie Amphetamine by director Scud (Hongkong 2010) plays on the double meaning of the word in Chinese - besides the name for the drug it also means 'isn't this his fate?' and tells a story of love, drugs and fate. The straight fitness trainer Kafka meets the successful gay executive Daniel. The two men fatefully fall in love and believe that their love can bridge anything, even their difference in sexuality and Kafka's severe drug habits.
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.
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