History
Amphetamine was first synthesized in 1887 by Lazar Edeleanu at the University of Berlin. He called the compound "phenylisopropylamine". It was one of a series of compounds related to the plant derivative Ephedrine, which had been purified two years previously by Nagayoshi Nagai. No pharmacological use was found for amphetamine until 1927, when pioneer psychopharmacologist Gordon Alles resynthesized it. Alles was part of a group of researchers looking for an ephedrine substitute. It was then introduced in most of the world in the form of the pharmaceutical Benzedrine. This drug was used by the militaries of several nations, especially the air forces, to fight fatigue and increase alertness among servicemen. After decades of reported abuse, the FDA banned Benzedrine inhalers, and limited amphetamines to prescription use in 1959, but illegal use became common.
The related compound methamphetamine was first synthesized from ephedrine in Japan in 1893 by chemist Nagayoshi Nagai. In 1919, crystallized methamphetamine was synthesized by Akira Ogata via reduction of ephedrine using red phosphorus and iodine. The German military was notorious for their use of methamphetamine in World War Two. The German pharmaceutical Pervitin is an oral pill of 3mg which became available in 1938, by mid-1941 it became a controlled substance because of the amount of time needed for a soldier to rest and recover after use. Military doctors were then given guidelines on how they should issue it.
In 1997 and 1998, 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.
Chemistry
Amphetamine is a chiral compound. The racemic mixture can be divided into its optical antipodes: levo- and dextro-amphetamine. Amphetamine is the parent compound of its own structural class, comprising a broad range of psychoactive derivatives, e.g., MDMA (Ecstasy) and the N-methylated form, methamphetamine. Amphetamine is a homologue of phenethylamine.
Traditionally the medical drug came in the racemic salt d, l-amphetamine sulfate (racemic amphetamine contains levo- and dextro-form in equal amounts). Today, dextroamphetamine sulphate is the predominant form of the drug used;[citation needed] it consists entirely of the d-isomer. Attention disorders are often treated using Adderall or a generic equivalent, a formulation of mixed amphetamine salts that contain both d/l-amphetamine and d-amphetamine in the sulfate and saccharate forms mixed to a final ratio of 3 parts d-amphetamine to 1 part l-amphetamine.
Pharmacology
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. The primary reinforcing and behavioral-stimulant effects of amphetamine, however, are linked to enhanced dopaminergic activity, primarily in the mesolimbic DA system.
Amphetamine and other amphetamine type stimulants principally act to release dopamine into the synaptic cleft. Amphetamine has been shown to both diffuse through the intracellular membrane and travel via the DopAmine Transporter (DAT) to increase concentrations of amphetamine in the neuronal terminal. 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 (DAT) into the synapse In addition, amphetamine binds reversibly to the dopamine transporter (DAT) 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.
Research published in the Journal of Pharmacology And Experimental Therapeutics (2007), indicates that 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.
Medicinal use
Indicated for:
Diet suppressant
ADD
ADHD
Narcolepsy
Treatment-resistant depression
Recreational uses:
Stimulant popular with British subcultures, such as the mods,punks and goths since late 1950s
Other uses:
Used by the U.S. military to combat fatigue and increase wakefulness
Contraindications:
CNS Stimulants
MAOI use
Side effects:
Dizziness
Decrease in appetite/weight loss
Euphoria
Insomnia
Aggressiveness
Cardiovascular:
Vasoconstriction
Tachycardia
Ear, nose, and throat:
Decongestant
Eye:
Mydriasis
Relaxation of Ciliary muscle
Gastrointestinal:
Decreased Secretions
Decreased Peristalsis
Neuropharmacology:
Indirect Dopamine Agonist
Indirect Norepinephrine Agonist
Indirect Serotonin Agonist(lesser)
MAOI
Respiratory:
Bronchodilation
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, and decreased irritability. These effects can be dramatic, particularly in young children. 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. They 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.
Effects of use
Amphetamines release stores of norepinephrine and dopamine from nerve endings by converting the respective molecular transporters into open channels. Amphetamine also releases stores of serotonin from synaptic vesicles when taken in relatively high doses. This effect is more pronounced in methamphetamine use. Like methylphenidate (Ritalin), amphetamines also prevent the monoamine transporters for dopamine and norepinephrine from recycling them (called reuptake inhibition), which leads to increased amounts of dopamine and norepinephrine in synaptic clefts.
These combined effects rapidly increase the concentrations of the respective neurotransmitters in the synaptic cleft, which promotes nerve impulse transmission in neurons that have those receptors.
Physical effects
Short-term physiological effects vary greatly, depending on dosage used and the method in which the drug is taken. At therapeutic levels these effects could include decreased appetite, increased stamina and physical energy, increased sexual drive/response and in some cases bruxism (teeth grinding). When the drug is abused effects could include involuntary bodily movements, hyperhidrosis, hyperactivity, jitteriness, nausea, itchy, blotchy or greasy skin, tachycardia, irregular heart rate, hypertension, and headaches. Fatigue can often follow the dose's period of effectiveness. Overdose can be treated with chlorpromazine.
Long-term abuse or overdose effects can include tremor, restlessness, changed sleep patterns, anxiety and increase in pre-existing anxiety, poor skin condition, hyperreflexia, tachypnea, gastrointestinal narrowing, and weakened immune system. Fatigue and depression can follow the excitement stage. Erectile dysfunction, heart problems, stroke, and liver, kidney and lung damage can result from prolonged abuse. When insufflated, amphetamine can lead to a deterioration of the lining of the nostrils.
Psychological effects
Short-term psychological effects of the drug at therapeutic levels could include alertness, euphoria, increased concentration, rapid talking, increased confidence, and increased social responsiveness. Effects of the drug when abused could include, nystagmus (eye wiggles), hallucinations, and loss of REM sleep the night after use.
Long-term amphetamine abuse can induce psychological effects that include insomnia, mental states resembling schizophrenia, aggressiveness (not associated with schizophrenia), addiction or dependence with accompanying withdrawal symptoms, irritability, confusion, and panic. Chronic and/or extensively-continuous use can lead to amphetamine psychosis, which causes delusions and paranoia, but this is uncommon when taken as prescribed. The abuse of an amphetamine is highly-psychologically addictive, and, with chronic abuse, tolerance develops very quickly. Withdrawal, although not physiologically threatening, is an unpleasant experience (including paranoia, depression, difficult breathing, dysphoria, gastric fluctuations and/or pain, and lethargia). This commonly leads chronic users to re-dose amphetamine frequently, explaining tolerance and increasing the possibility of addiction.
Addiction
Tolerance is developed rapidly in amphetamine abuse, therefore increasing the amount of the drug that is needed to satisfy the addiction. Many abusers 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. Chronic abusers of amphetamines typically snort or resort to 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. While continuous dosing with amphetamine causes tolerance, intermittent use can produce "reverse tolerance" or sensitization to some psychological effects. As a result, regular use commonly results in a quick decrease of unwanted side effects, but without an equivalent loss of its stimulant properties. Notably, the sensitization is induced more quickly, and persists far longer than withdrawal-related effects, suggesting a phenomenon more complex than a simple tolerance-induced withdrawal syndrome.
Because of the abuse of amphetamines in the U.S., most brands were discontinued by the 90's including the highly abused brand names such as Biphetamine (known as black beauties), and Preludin known on the street as Bams, which the coating was peeled and then injected. Only a few brands of amphetamines are still produced in the United States which are prescribed for narcolepsy, hyperactivity in children, or for extremely obese people.
Harm reduction approach to amphetamine use
Proponents of the harm reduction philosophy seek to minimize the harms that arise from the recreational use of amphetamines. Safer means of taking the drug—smoked, nasal, oral, and rectal—are encouraged due to the lower risk of overdose, infection, and contraction of bloodborne viruses associated with drug injection. Smoking drugs reveals their effects roughly as fast as injection, as blood directly picks up the drug at the lungs. Amphetamine, in contrast to methamphetamine, isn't smokable.
Where the strength of the drug is unknown, users are encouraged to try a small amount first to gauge the strength, to minimize the risks of overdose. For the same reason the use of two or more drugs at the one time is discouraged. Users are also discouraged from using amphetamines by themselves, as friends can assist in the event of an overdose or amphetamine psychosis.
Amphetamine users who choose to inject should always use new needles and syringes where possible, and not share these with other users. Governments that support a harm reduction approach often supply new needles and syringes on a confidential basis, as well as education on proper filtering prior to injection, safer injection techniques, and safe disposal of used injecting gear.
Amphetamine Long Term Physiological
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