Dextroamphetamine

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Dextroamphetamine
Systematic (IUPAC) name
(2S)-1-phenylpropan-2-amine
Identifiers
CAS number	300-62-9
ATC code	N06BA01
PubChem	5826
DrugBank	APRD00480
Chemical data
Formula	C9H13N
Mol. weight	135.206 g/mol
Pharmacokinetic data
Bioavailability	>75%
Metabolism	Hepatic
Half life	10–28 hours (Average ~12 hours)
Excretion	Renal: ~45%
Therapeutic considerations
Pregnancy cat.	B3(AU) C(US)
Legal status	Schedule III(CA) Class B(UK) Schedule II(US)
Routes	Oral

Dextroamphetamine is a powerful psychostimulant which produces increased wakefulness, energy and self-confidence in association with decreased fatigue and appetite. It works primarily by inducing the release of the neurotransmitters dopamine and norepinephrine from their storage areas in nerve terminals. Other common names for dextroamphetamine include d-amphetamine, dexamphetamine, (S)-(+)-amphetamine, and brand names such as Dexedrine and Dextrostat.

Contents 1 Overview 2 History 3 Clinical uses 4 Other uses 5 Side effects 5.1 Overdose 5.2 Chronic use 6 Time course and elimination 7 Popular culture 8 Notable users 9 See also 10 References 11 Footnotes

[edit] Overview

Dextroamphetamine, commonly abbreviated as d-amphetamine, is the dextrorotary stereoisomer of the amphetamine molecule, which can take two different forms. Its stimulant properties are similar to those of Ritalin and methamphetamine, though with a slower onset of action and a duration that lies somewhere between the two. It is perhaps the archetypal euphoric stimulant, and other drugs with similar structures or psychoactive properties are often referred to as "amphetamine analogues" or as having "amphetamine-like effects".

Both dopamine and norepinephrine are significant in dextroamphetamine's mechanism of action. In broad terms, dopamine is responsible for boosting mental focus and mood, while norepinephire causes the typical fight-or-flight effects of appetite-suppression, reduced sense of fatigue, dry mouth and increased blood pressure.^[1]

Dextroamphetamine is most often prescribed as dextroamphetamine sulfate, available as 5 mg and 10 mg tablets, as well as 5 mg, 10 mg, and 15 mg time-release capsules. Other forms of the drug include the popular ADHD medication Adderall and its generic derivatives which contain equal proportions, by weight, of dextroamphetamine sulfate, dextroamphetamine saccharate and the sulfate and Aspartate Monohydrate salts of racemic d,l-amphetamine). The aspartate, saccharate and sulfate forms differ pharmacokinetically in the rate at which they are metabolized by the body.

[edit] History

Amphetamine was first synthesized under the chemical name "phenylisopropylamine" in 1887 by the Romanian chemist Lazar Edeleanu. It was not widely marketed until 1932, when the pharmaceutical company Smith, Kline, and French (currently known as GlaxoSmithKline) introduced it in the form of the "Benzedrine Inhaler," for combating cold symptoms. Notably, the chemical form of Benzedrine in the inhaler was the purely basic form (i.e., it was not a chloride or sulfate salt). In free-base form, amphetamine is a volatile oil, hence the efficacy of the inhalers.

Three years later, in 1935, the medical community became aware of the stimulant properties of amphetamine, specifically dextroamphetamine, and in 1937 Smith, Kline, and French introduced Dexedrine tablets, which consisted of pure dextroamphetamine sulfate (a salt of the basic form of D-amphetamine), under the tradename Dexedrine. In the United States, Dexedrine tablets were approved to treat narcolepsy, attention disorders, depression, and obesity. Dextroamphetamine was marketed in various other forms in the following decades, primarily by Smith, Kline, and French, such as several combination medications including a mixture of dextroamphetamine and amobarbital (a barbiturate) sold under the tradename Dexamyl and, in the 1950s, an extended release capsule (the "Spansule").

It quickly became apparent that Dexedrine and other amphetamines had a high potential for abuse, although they were not heavily controlled until 1970, when the Comprehensive Drug Abuse Prevention and Control Act was passed by the United States Congress. Dexedrine, along with other sympathomimetics, was eventually classified as schedule II, the most restrictive category possible for a drug with recognized medical uses.

[edit] Clinical uses

Dextroamphetamine is commonly used for treatment of attention deficit hyperactivity disorder (ADHD) or well-established narcolepsy, generally where non-pharmacological measures have proved insufficient. In some localities it has replaced methylphenidate as the first-choice medication for ADHD, a role in which it is considered highly effective. It is occasionally prescribed for weight-loss in cases of extreme obesity. Dextroamphetamine is contraindicated for patients with a history of substance abuse.

Though such use remains out of the mainstream, dextroamphetamine has been successfully applied in the treatment of certain categories of depression as well as other psychiatric syndromes.^[2] Such alternate uses include reduction of fatigue in cancer patients, antidepressant treatment for HIV patients with depression and debilitating fatigue,^[3] early stage physiotherapy for severe stroke victims,^[4] and replacement therapy for those with methamphetamine addiction.

[edit] Other uses

The U.S. Air Force uses dextroamphetamine as its "go-pill," given to pilots on long missions to help them remain focused and alert. Other branches of the U.S. military (as well as the armed forces of other nations) commonly use or have dispensed dextroamphetamine to troops to prevent or treat fatigue in combat situations. Because of the propensity of dextroamphetamine to cause behavioral side effects, this use is viewed as controversial; newer stimulant medications with fewer side effects, like modafinil are being investigated for this reason. NASA has also used dextroamphetamine to combat fatigue in astronauts near the end of a mission.

Along with Ritalin, illicit use of dextroamphetamine is popular among students, both as a study aid, and for purely recreational purposes. According to the National Institute on Drug Abuse, 4% of American college students reported non-prescription stimulant use in 2004.^[5] Those with a prescription for dextroamphetamine may give it to friends, or sell it for a profit.

[edit] Side effects

Possible adverse effects of dextroamphetamine include sleeplessness, reduced appetite, dependence, nervousness, restlessness, irritability, and euphoria that may be followed by fatigue and depression. There may be dryness of mouth, abdominal cramps, headache, dizziness, tremor, sweating, palpitations, increased or sometimes decreased blood pressure and altered libido.

[edit] Overdose

The Physician's 1991 Drug Handbook reports: "Symptoms of overdose include restlessness, tremor, hyperreflexia, tachypnea, confusion, aggressiveness, hallucinations, and panic." Dilated pupils ("doll's eyes") are common with high doses.

The fatal dose in humans is not precisely known, but in various species of rat generally ranges between 50 and 100 mg/kg, or a factor of 100 over what is required to produce noticeable psychological effects.^[6][7] This suggests a wide therapeutic range, in contrast to such drugs as morphine and heroin, where effective doses may be as much as 50% of a fatal dose. Although the symptoms seen in a fatal overdose are similar to those of methamphetamine, their mechanisms are not identical, as some substances which inhibit d-amphetamine toxicity do not do so for methamphetamine.^[8][9]

An extreme symptom of overdose is amphetamine psychosis, characterized by vivid visual, auditory, and sometimes tactile hallucinations. Many of its symptoms are identical to the psychosis-like state which follows long-term sleep deprivation, so it remains unclear whether these are solely the effect of the drug, or due to the long periods of sleep deprivation which are often undergone by the chronic user or abuser. "In apparently sensitive individuals, psychosis may be produced by 55 to 75 mg of dextroamphetamine. With high enough doses, psychosis can probably be induced in anyone."^[10]

[edit] Chronic use

While continuous dosing with amphetamine causes tolerance, intermittent dosing produces "reverse tolerance" or sensitization to its psychological effects.^[11][12] As a result, regular users commonly experience a quick decrease of unwanted side effects, 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.

There have also been reports of growth retardation of children with long-term use, although this effect can be reduced by periods of abstinence, referred to as "drug holidays".

[edit] Time course and elimination

On average, about one half of a given dose is eliminated unchanged in the urine, while the other half is broken down into various metabolites (mostly benzoic acid).^[13] However, the drug's half-life is highly variable because the rate of excretion is very sensitive to urinary pH. Under alkaline conditions, direct excretion is negligible and 95%+ of the dose is metabolized. The main metabolic pathway is d-amphetamine phenylacetone benzoic acid hippuric acid. Another pathway, mediated by enzyme CYP2D6, is d-amphetamine p-hydroxyamphetamine p-hydroxynorephedrine. Although p-hydroxyamphetamine is a minor metabolite (~5% of the dose), it may may have significant physiological effects as a norepinephrine analogue.^[14]

Subjective effects are increased by larger doses, however, over the course of a given dose there is a noticeable divergence between such effects and drug concentration in the blood.^[15] In particular, mental effects peak before maximal blood levels are reached, and decline as blood levels remain stable or even continue to increase.^[16][17][18] This indicates a mechanism for development of acute tolerance, perhaps distinct from that seen in chronic use. Its slower onset of action as compared to methamphetamine and methylphenidate is presumably due to a somewhat lower effectiveness in crossing the blood-brain barrier.^[19]

[edit] Popular culture

• There is a widespread myth that, while Dexedrine acts as stimulant in people without ADHD, it causes the opposite reaction in those with the condition. This may have arisen due to a misconception that the drug is a sedative for hyper-active schoolchildren. Rather than true sedation, this is a result of increased mental alertness aiding the user in focusing on a given task for extended periods of time.
• The British band Dexys Midnight Runners derives their name from this drug.
• Jim Bouton makes mention of Dexedrine use in major league baseball (under the street name "greenies") in his book Ball Four (1970).
• Michael Herr's book Dispatches (1968) tells of a soldier in the Vietnam War using Dexedrine.
• In William Gibson's novel Neuromancer (1984), the main character, Case, is addicted to an amphetamine described as "Dex".^[20]
• Bob Fosse's film All That Jazz (1979) shows main character Joe Gideon using Dexedrine.
• The younger protagonists of Hubert Selby Jr.'s Requiem for a Dream take Dexedrine recreationally in both the novel and motion picture.
• In the beginning of the film Withnail and I, both Marwood and Withnail are in the midst of an amphetamine binge and the two escape to the countryside in an attempt to escape the "unusual" feelings brought on by the drug.
• The Velvet Underground's album White Light/White Heat includes several songs about the use of amphetamines, mentioning it explicitly in the final song, Sister Ray; at time 16:43, Lou Reed sings, "Now just like...just like...amphetamine".
• Catherine Wheel's album Chrome is essentially the narrative of an amphetamine-addicted individual. Songs such as "Crank" illustrate this point.
• The brand name Dexedrine should not be confused with Dexatrim, an over-the-counter weightloss supplement which does not contain amphetamine.
• In The Simpsons, there is an episode where Bart is put on "Focusin" to treat his hyper-activity.
• The character of Danny Crane in the hit series "Boston Legal" admits in court to using Dextroemphetamines to treat his memory problems, the early symptoms of Alzheimers, later in the episode he states he is no longer taking the drug.

[edit] Notable users

• Allen Ginsberg was a frequent user of amphetamines, including Dexedrine. When he died, pundit George Will wrote this of one his most famous poems, published in 1956: "He composed 'Howl' with the help of a cocktail of peyote, amphetamines and Dexedrine".^[21]
• Steven Watson, in The Birth of the Beat Generation (2002), reports that Jack Kerouac died in 1969 "addicted to Johnnie Walker Red and Dexedrine."^[22]
• Mathematician Paul Erdős was a heavy user of amphetamines in his later life. When a friend bet him he could not abstain for a month, Erdős won the bet but complained that the progress of mathematics had been delayed by a month.

[edit] See also

• ADHD
• Adderall
• Amphetamine
• Benzedrine
• Methamphetamine
• Methylphenidate (Ritalin)
• Dexmethylphenidate (Focalin)

[edit] References

• Poison Information Monograph (PIM 178: Dexamphetamine Sulphate)
• Physician's 1991 Drug Handbook
• Dexamphetamine GPnotebook 1845887055
• Package inserts: New Zealand., Canada.

[edit] Footnotes

Stimulants - edit
Adrafinil, Armodafinil, Caffeine, Modafinil, Nicotine
Sympathomimetic amines (R01, A08, and others) edit Aminorex, Amphetamine, Benzylpiperazine, Cathinone, CFT, Chlorphentermine, Clobenzorex, Cocaine, Cyclopentamine, Diethylpropion, Ephedrine, Fenfluramine, Mazindol, 4-Methyl-aminorex, Methylone, Methylphenidate, Pemoline, Phendimetrazine, Phenmetrazine, Phentermine, Phenylephrine, Propylhexedrine, Pseudoephedrine, Sibutramine, Synephrine See also amphetamines