Amphetamine

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Amphetamine
Clinical data
Other names(±)-alpha-methylbenzeneethanamine, alpha-methylphenethylamine, beta-phenyl-isopropylamine
Routes of
administration		Oral, intravenous, vaporization, insufflation, suppository, sublingual
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityOral "good"[2]; nasal 75%; rectal 95–99%; intravenous 100%
Protein binding15–40%
MetabolismHepatic (CYP2D6[3])
Elimination half-life10 hours for d-isomer, 13 hours for l-isomer
ExcretionRenal; significant portion unaltered
Identifiers
  • 1-phenylpropan-2-amine
CAS Number
PubChem CID
DrugBank
CompTox Dashboard (EPA)
ECHA InfoCard100.005.543 Edit this at Wikidata
Chemical and physical data
FormulaC9H13N
Molar mass135.2084 g·mol−1
3D model (JSmol)
Melting point280 to 281 °C (536 to 538 °F)
Solubility in water50–100 mg/mL (16C°) mg/mL (20 °C)
  • CC(CC1=CC=CC=C1)N

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.[4] It includes prescription CNS drugs commonly used to treat attention-deficit disorder (ADD) and 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 it was more popularly used to diminish the appetite and to control weight.

Brand names of the drugs that contain amphetamine include Vyvanse, Adderall, and Dexedrine. The drug is also used illegally as a recreational club drug and as a performance enhancer. The name amphetamine is derived from its chemical name: alpha-methylphenethylamine. Some biochemistry textbooks also claim that the name 'amphetamine' is derived from an abbreviation for "amphoteric amine," indicating that the compound can act as both an acid (proton donor) and a base (proton acceptor) depending upon its chemical environment. This origin seems unlikely, however, as there is no unique structural feature that makes amphetamine amphoteric; indeed, all primary amines are amphoteric. The name is also used to refer to the class of compounds derived from amphetamine, often referred to as the substituted amphetamines.

History

Amphetamine was first synthesized in 1887 by Lazăr Edeleanu in Berlin, Germany.[5] 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.[6] 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 under the name Benzedrine Inhaler, useful as a decongestant (and readily usable for non-medical purposes too).[7] 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”.[8] 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. It is also rumored that Adolf Hitler was receiving daily shots of a medicine secretly named "vitamultine" that contained certain essential vitamins and amphetamines. 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 ever less frequently, and with increasing discrimination as the war progressed onwards towards Nazi Germany's and the Axis' eventual defeat in 1945.[9]

In 1997 and 1998,[10][11] researchers at Texas A&M University reported finding 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.[12]

Indications

Indicated for:
Contraindications:
  • CNS Stimulants
  • Agitated states
  • Patients with a history of drug abuse
  • Glaucoma
  • MAOI use
Adverse effects:
Other information:

Neuropharmacology:

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 (Ritalin, Concerta, etc.), 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.[13]

Major neurobiological mechanisms

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 does not appear to be non-specific;[14] 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.[14]

The major neural systems affected by amphetamine are largely implicated in the brain’s reward circuitry. Moreover, neurotransmitters involved various reward pathways of the brain appear to be the primary targets of amphetamine.[15] 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 caudate putamen, the nucleus accumbens, and the ventral striatum—have been found to be primary sites of amphetamine action.[16][17]

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 of euphoria.[17] A better understanding of the specific mechanisms by which amphetamines operate may increase our ability to treat amphetamine addiction, as the brain’s reward circuitry has been widely implicated in addictions of many types.[18]

Endogenous amphetamines

Amphetamine has been found to have several endogenous analogues; that is, molecules of a similar structure found naturally in the brain.[19] 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.[20] 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.[21][19] 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.[22][23][24][25]

The difference between amphetamine & cocaine with regard to DAT1 receptor reuptake blocking. Amphetamines phosphorylate and invert the transporter internally within the cell, whereas cocaine binds externally to the DAT1 transporter.

The former hypothesis is backed by data demonstrating that injections of amphetamines result in rapid increases of cytosolic dopamine concentrations.[25] 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.[19] Calcium may be a key molecule involved in the interactions between amphetamine and VMATs.[26]

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 PCK-β.[25] Upon phosphorylation, DAT undergoes a conformational change that results in the transportation of DAT-bound dopamine from the extracellular to the intracellular environment.[27] 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.[22] Thus, beyond inhibiting reuptake of dopamine, amphetamine also stimulates the release of dopamine molecules into the synapse.[28]

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.[25] 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.[29] Like DAT, the serotonin transporter SERT can be induced to operate in reverse upon stimulation by amphetamine.[30] This mechanism is thought to rely on the actions of calcium molecules, as well as on the proximity of certain transporter proteins.[30]

The interaction between amphetamine and serotonin is only apparent in particular regions of the brain, such as the mesocorticalimbic 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.[29] 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.[29]

The proposed ability of amphetamine to increase excitability of glutamatergic pathways may be of significance when considering serotonin-mediated addiction.[29] An additional behavioral consequence may be the stereotyped locomotor stimulation that occurs in response to amphetamine exposure.[20]

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.[16]

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.[31]

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.[32]

Pharmacology

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 ecstacy, 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. The increased amphetamine concentration 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.[32] 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).[33] TAAR are a newly discovered receptor system which seems to be affected by a range of amphetamine-like substances called trace amines.

Effects

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 high doses or chronic use convulsions, dry or itchy skin, acne, pallor can occur.[34][35][36][37]

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,[38] 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.[39]

Psychological effects

Psychological effects of amphetamine can include anxiety and/or general nervousness (by increased norepinephrine),[40] 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.[41] 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.[42]

Dependence and addiction

Tolerance is developed rapidly in amphetamine abuse, therefore increasing the amount of the drug that is needed to satisfy the addiction.[43] 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.[44][45][46][47][48][49] 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 peeled and then injected.[citation needed] Amphetamines are still produced in the United States: those prescribed for narcolepsy, attention-deficit hyperactivity disorder, treatment-resistant depression, and extreme obesity.[citation needed]

Performance-enhancing use

Amphetamine is used by college and high-school students as a study and test-taking aid.[50] Amphetamine increases energy levels, concentration, and motivation, 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. [51]

Amphetamines have been, and are still, used by militaries around the world. British troops used 72 million amphetamine tablets in the second world war[52] and the RAF used so many that "Methedrine won the Battle of Britain" according to one report[53]. American bomber pilots use amphetamines ("go pills") to stay awake during long missions. The Tarnak Farm incident, in which an American F16-pilot killed several friendly 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 professional,[54] collegiate[55] and high school[55] 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.[56] The use of amphetamine during strenuous physical activity can be extremely dangerous, 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".[57] 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.[58][59][60]

Truck drivers, especially long-haul drivers, often take amphetamine[61] to combat symptoms of somnolence and to increase their concentration on driving.

Cultural impact of amphetamines

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 and casuals in all night soul and ska dances, punk concerts, basement shows and fighting on the terraces by casuals. Amphetamine is also used by homosexual men, and in the rave culture, to break down inhibitions, as well as keep dancing or having sex for prolonged periods (though in these subcultures, methamphetamine is arguably equally as popular).[citation needed]

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 mods, being working class, were often opposed to the slower, more contemplative, meditative ideals and lifestyle of the hippies. Amphetamines therefore suited their high energy and aggressive aesthetics and lifestyle, whether it was dancing to soul music at all night parties, or fighting rockers.[citation needed]

In literature

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 provided 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 (including amphetamine) 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.

  • Sherlock Holmes' nemesis Dr. Moriarity may have been a figment of Holmes' paranoid delusions which may have been brought on by his use of cocaine. "The man pervades London, and no one has heard of him. That's what puts him on a pinnacle in the records of crime."[62]

In music

Many songs have been written about amphetamine, but it has also influenced the aesthetics of many rock'n'roll bands (especially in the punk/hardcore, gothic rock and extreme heavy metal genres). The Jesus And Mary Chain's use of distortion and feedback was heavily influenced by their use of amphetamines, along with their highly confrontational stage shows early in their existence.This lead them to be banned from venues, even starting riots.

Black Metal band Cradle of Filth's song, Nymphetamine, is a pun on the word "amphetamine" itself. The lyrics liken the submission to a succubus to amphetamine addiction, though it could also be seen as a reference to amphetamine psychosis through the hallucinations and paranoia that are a symptom of the condition.

Proto-punk band, The Velvet Underground, wrote White Light/White Heat referring directly to amphetamine use.

Mod revivalists Purple Hearts took their name from the amphetamine tablets popular with mods during the 1960's.

In film

Many films have been created that are either visually or aesthetically influenced by the perceived effects of amphetamine, or that portray amphetamine use in their plotlines. For example, the film Spun portrays the life of methamphetamine addicts, their social interactions, and the impact the drug has on their lives. In Requiem for a Dream, the character Sara Goldfarb suffers amphetamine psychosis after having been prescribed amphetamines as a weight loss drug; she imagines that her refrigerator is trying to devour her.

A Scanner Darkly (as well as the novel of the same name) contains a scene where the character Charles Freck suffers from formication.

In television

Several episodes of The Bill have been centered around an explosion at a meth lab in the fictional borough of Sunhill. In episode four of the television series Breaking Bad the character Jesse Pinkman apparently suffers from a brief episode of Amphetamine psychosis.

Advertising has also alluded to and portrayed the effects of amphetamine in both serious and humorous ways, especially in anti-drug campaigns. The Montana Meth Project has commissioned a series of public information films showing the effects of methamphetamine on both the user, and society in general. The Partnership for a Drug-Free America has also commissioned public information films depicting the of impact amphetamine use on communities, with both social and environmental consequences.

On the other hand, advertisements for Red bull energy drinks often allude to effects similar to amphetamine in a tongue-in-cheek manner, with the slogan "Red bull gives you wings". One American anti-drug public information film uses humor, parodying a Folgers coffee jingle to raise awareness of the effects of amphetamine abuse.[63]

Legal issues

  • In the United Kingdom, amphetamines are regarded as Class B drugs. The maximum penalty for unauthorised 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).[64]
  • 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 gelcapsules.
  • In the United States, amphetamine and methamphetamine are Schedule II drugs, classified as CNS (central nervous system) stimulants.[65] 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.[66]

A chart comparing the chemical structures of different amphetamine derivatives

See also

References and notes

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  8. ^ Iverson, Leslie. Speed, Ecstacy, Ritalin: the science of amphetamines. Oxford, New York. Oxford University Press, 2006.
  9. ^ Rasmussen, Nicolas (2008). "Ch. 4". On Speed: The Many Lives of Amphetamine. New York, New York: New York University Press. ISBN 0-8147-7601-9.
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  11. ^ Clement, Beverly A., Goff, Erik Allen Burt, Christina M. and Forbes, T. David A. (1997). Toxic amines and alkaloids from Acacia berlandieri. Phytochemistry 46(2), pp 249-254
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  13. ^ [1] FDA PDF 2004
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  28. ^ Moore, KE. “The actions of amphetamine on neurotransmitters: A brief review.” Biol Psychiatry 3 (1977): 451-62.
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  33. ^ jpet.aspetjournals.org Research published in the Journal of Pharmacology And Experimental Therapeutics (2007)
  34. ^ Erowid Amphetamines Vault : Effects
  35. ^ Amphetamine; Facts
  36. ^ Amphetamines - Better Health Channel
  37. ^ adderall xr, adderall medication, adderall side effects, adderall abuse
  38. ^ Westover AN, Nakonezny PA, Haley RW (2008). "Acute myocardial infarction in young adults who abuse amphetamines". Drug Alcohol Depend. 96 (1–2): 49–56. doi:10.1016/j.drugalcdep.2008.01.027. PMID 18353567. {{cite journal}}: Cite has empty unknown parameter: |unused_data= (help); Text "PubMed - in process" ignored (help)CS1 maint: multiple names: authors list (link)
  39. ^ Newswise: Study Finds Link Between Amphetamine Abuse and Heart Attacks in Young Adults Retrieved on June 3, 2008.
  40. ^ http://www.drugs.com/sfx/amphetamine-side-effects.html Amphetamine Side Effects drugs.com
  41. ^ Erowid Amphetamines Vault : Effects
  42. ^ Symptoms of Amphetamine withdrawal - WrongDiagnosis.com
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External links

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