Adderall

Combination of
Dextroamphetamine	Psychostimulant
Amphetamine	Psychostimulant
Identifiers
CAS number	51-64-9 300-62-9
ATC code	N06BA02 N06BA01
PubChem	5826
DrugBank	DB01576
ChemSpider	13852819
Therapeutic considerations
Licence data	US Daily Med:link
Pregnancy cat.	C(US)
Legal status	Schedule II(US)
Dependence Liability	High
Routes	Oral

Adderall is a brand-name psychostimulant medication composed of amphetamine and dextroamphetamine, which is thought to work by increasing the amount of dopamine and norepinephrine in the brain.^[1] Adderall is widely reported to increase alertness, libido, concentration and overall cognitive performance while decreasing user fatigue. It is available in two formulations: IR (Instant Release) and XR (eXtended Release). The immediate release formulation is indicated for use in Attention Deficit Hyperactivity Disorder (ADHD) and narcolepsy,^[2] while the XR formulation is only approved for use in ADHD.^[1] In the United States, Adderall is a Schedule II drug under the Controlled Substance Act due to having addiction potential and potent effects on blood pressure.

[edit] History

Adderall is available as an instant release ("IR") as well as an extended release ("XR") drug. Adderall instant release is manufactured today by Teva and Barr Pharmaceuticals. Shire Pharmaceuticals, the creator of Adderall IR, no longer produces it. However, Shire Pharmaceuticals does continue to manufacture the extended release version of Adderall ("Adderall XR"). Shire Pharmaceuticals introduced the Adderall brand in 1996 in the form of a multi-dose, instant-release tablet derived from an original formula of the weight management drug Obetrol. In 2006, Shire agreed to sell rights to the Adderall name for this instant-release medication to Duramed Pharmaceuticals^[3] Ultimately, DuraMed Pharmaceuticals was acquired by Teva Pharmaceuticals in 2008 when Teva completed its acquisition of Barr Pharmaceuticals (including Barr's Duramed Pharmaceuticals division).^[4] Therefore, following its acquisition of Duramed, Teva Pharmaceuticals is in the somewhat unusual position of manufacturing both a generic formulation of Adderall instant release (under its Barr Division) as well as "brand name" Adderall (under its DuraMed division.)

Reflecting the change in manufacturers from Shire Pharmaceuticals to Teva's DuraMed Pharmaceuticals, the "imprint" on Adderall instant release tablets has changed. One side of the instant release tablets now bears the DuraMed Pharmaceuticals imprint, a lower case letter "d" over a lower case letter "p". This is a change from the previous upper case "AD" imprint on the tablets.

The active ingredients of Adderall include a combination of dextroamphetamine and racemic DL-amphetamine salts.^[5] In 2001, Shire Pharmaceuticals introduced an extended-release preparation of these ingredients in a variety of dosages under the brand name "Adderall XR," on which Shire retains exclusive patent rights until the patent expires, expected in 2018.^[6] However, due to issues with Shire's inability to evergreen (extend the patent life by either obtaining a new FDA indication or application of other patent life) the patent for Adderall XR, the drug has become available in a generic form.^[7] In 2009, Barr Pharmaceuticals and Shire reached a settlement agreement permitting Barr to offer a generic form of the drug beginning April 1, 2009.^[8]

[edit] Chemistry

Instant Release 30 mg Adderall Tablets

Adderall's effects are similar to other CNS stimulants of the same class and preparation. (See amphetamine for details.)

Urinary and stomach pH levels can have a strong effect on DL-amphetamine excretion and absorption.^[9] An acidic stomach and GI pH will decrease the absorption of Adderall,^[10] and acidic urine levels will decrease the reabsorption of the drug through the renal system.^[11] Co-administration of acidic substances (e.g. citric acid) causes decreased renal reabsorption of DL-amphetamine, while alkaline agents (e.g. antacids) may cause a marked increase in renal tubular reabsorption. The increased reabsorption can increase the retention of amphetamines, potentially resulting in dangerously high serum levels.^[11]

[edit] Adderall XR

Specifically, Adderall XR consists of the following amphetamine compounds in equal proportions; dextroamphetamine saccharate, dextroamphetamine sulfate, racemic amphetamine aspartate monohydrate, and racemic amphetamine sulfate.^[1] Breakdown rates are affected by many factors including urinary and stomach pH,^[9][10] weight, gender, other medications being taken, and age. Alkalinity increases bioavailability and acidity causes the drug to be excreted sooner. Manufacturers claim that the mixture of salts in Adderall XR makes its effects smoother (that is, makes softer highs and lows).^[12]

[edit] Dosing and administration

Adderall XR capsules

Adderall is marketed as either an immediate-release tablet, Adderall, or an extended-release capsule, Adderall XR. Doses of immediate-release Adderall are available in 5, 7.5, 10, 12.5, 15, 20, and 30 mg.^[2] Adderall XR is available in 5, 10, 15, 20, 25, and 30 mg doses.^[1]

Adderall XR utilizes the Microtrol extended-release delivery system, incorporating two types of beads. The first dissolves immediately, releasing half of the medication, while the second type dissolves much more slowly releasing the remaining medication four hours later. Maximum plasma concentration is achieved in seven hours, compared to instant-release Adderall, which reaches maximum plasma concentration within three hours. As a result of its high bioavailability, Adderall XR's effectiveness is not altered by food absorption in the gastrointestinal tract. However, mean plasma concentration is prolonged by 2.5 hours (using a 900 calorie standard high-fat meal as the control). Medications that alter urinary pH will cause variations in amount and method of excretion and usage should be monitored when taken concurrently with Adderall.^[10]

Manufacturer's claims of instant release have been disputed. A US patent granted for Adderall^[13] was a pharmaceutical composition patent listing a rapid immediate release oral dosage form. No claim of increased or smooth drug delivery was made. A recent double-blind, placebo-controlled crossover study, conducted among children, indicated that patients behaved similarly to other immediate release amphetamines. The authors found that sustained-release dexamphetamine (the main isomeric-amphetamine component of Adderall) had a longer duration of action, though D-amphetamine was less effective in the first few hours.^[14]

[edit] Use as treatment for Attention-Deficit Hyperactivity Disorder (ADHD)

Adderall is commonly prescribed as a psychostimulant treatment for children and adults with Attention-Deficit Hyperactivity Disorder (ADHD). Depending on dosage, the beneficial effects of stimulant medications can last several hours, allowing improved performance throughout the day.^[15] Compared to the similar medication methylphenidate (sold under the brand name Ritalin and others) studies have suggested that Adderall is slightly more potent and has a longer period of efficacy, especially at lower doses.^[16] For those who experience adverse side effects to Ritalin or for whom Ritalin has become ineffective, Adderall is often recommended as a substitute.^[17][18]

[edit] Other uses

Apart from its most typical application in the treatment of ADHD, Adderall has also been used successfully to manage severe cases of treatment-resistant depression. Individuals who show little or no response to typical antidepressants, including SSRIs and tricyclic antidepressants, are more likely to respond to psychostimulant therapy. These patients, however, are the exception rather than the norm among those with depression and this is not an FDA-approved indication.

• Idiopathic Central Nervous System Hypersomnia established by recognized diagnostic criteria
• Drug-induced brain dysfunction
• Epilepsy
• Narcolepsy
• Senile apathetic behavior
• Psychiatric differential diagnosis of depression
• Obesity^[19]

[edit] Generic forms

Both Adderall and Adderall XR have generic preparations available for dispensing.^[20][21][22]

[edit] Mechanism of action

Molecular structure of amphetamine. (Methamphetamine has the same structure, with the addition of a methyl group attached to the nitrogen).

With respect to central stimulant actions, the S(+) isomer (i.e., dextroamphetamine) is several times more potent than its R(-)enantiomer (i.e., levoamphetamine); this is not necessarily the case with other actions produced by amphetamine, particularly those produced in the periphery such as its cardiovascular actions.^[23] Dextroamphetamine induces more euphoria, whereas levoamphetamine induces more depression. The overall greater potency of the dextro form to central actions suggests that this form may have a higher potential for abuse.^[24]

Adderall’s inclusion of levoamphetamine provides the pharmaceutical with a quicker onset and longer clinical effect compared to pharmaceuticals exclusively formulated of dextroamphetamine.^[25] Although it seems the human brain has a preference for dextroamphetamine over levoamphetamine, it has been reported that certain children have a better clinical response to levoamphetamine.^[26] Amphetamines are believed to exert their effects by binding to the monoamine transporters and increasing extracellular levels of the biogenic amines dopamine, norepinephrine, and serotonin.

It is hypothesized that D-amphetamine acts primarily on the dopaminergic (DA) systems, while L-amphetamine is comparatively norepinephrinergic (NE). The primary reinforcing and behavioral-stimulant effects of amphetamine, however, are linked to enhanced dopaminergic activity, primarily in the mesolimbic dopaminergic pathway. Amphetamine binds to the dopamine transporter (DAT) and blocks the transporter's ability to clear DA from the synaptic space. In addition, amphetamine is transported into the cell, which leads to dopamine efflux (DA is transported out of the cell and into the synaptic space via reverse transport of the DAT).

Amphetamine also possesses the ability to inhibit the enzymes monoamine oxidase A and B (MAO-A and MAO-B) in high doses. MAO-A is responsible for the break down of serotonin, dopamine, norepinephrine, and epinephrine. MAO-B is responsible for breaking down dopamine (more potently than MAO-A) and phenylethylamine (PEA), which has actions similar to amphetamine itself, and is thought to be involved in feelings of lust, confidence, obsession, and sexuality. Some of the first antidepressants successfully marketed are in fact Monoamine-Oxidase inhibitors. However, MAO inhibition seen with amphetamine is not substantial enough in duration and quantity to entail the need for a tyramine-limited diet, unlike the more potent and long lived MAO-inhibiting antidepressants.

Amphetamine's ability to cause the inhibition of MAO results in the accumulation of monoamines: amphetamine directly stimulates the release of these neurochemicals, resulting in a potent elevation in monoamine neurotransmission. In sum, the effect of amphetamines is to increase neurotransmitter availability in the synapse, by both releasing more neurotransmitters, as well as prolonging their availability in the synapse by slowing their removal.

[edit] Adverse effects

Adderall has a high abuse potential. Because Adderall has a powerful effect of increasing blood pressure, it carries the same risk of sudden death, stroke, and heart attack in patients with pre-existing heart conditions, as does methylphenidate and other stimulants used to treat ADHD, as well as the same risk of seizures in patients with a history of seizures.^[1][27] Studies of long-term use of Adderall and methylphenidate in children have shown a temporary decrease in growth rate that does not affect final adult height.^[28] Stimulant medications also decrease appetite in some people, leading to weight loss, and this effect is more common with Adderall than methylphenidate^[28] or atomoxetine. Changes in vision have been reported with both Adderall and methylphenidate.^[1][27] "In extreme cases, the drug can cause paranoia, zombie-like psychosis, hallucinations and heart attacks."^[29]

[edit] Contraindications, interactions, and precautions

The following provides only general guidelines and is not comprehensive. Please refer to a more comprehensive list for further information regarding co-administration of amphetamine with other substances.

• MAOIs (monoamine oxidase inhibitors, e.g., phenelzine, selegiline, iproniazid, etc.) — Do not administer amphetamine for a minimum of two weeks after last use of MAOI type drug. High risk for hypertensive crisis. Preliminary trials of low dose amphetamine and MAOIs being administered together are in progress. However, this is to only be done under strict supervision of the prescribing parties.
• SSRIs (selective serotonin reuptake inhibitors, e.g., fluvoxamine, citalopram, paroxetine, etc.) — While a common combination, and although rare, the risk for serotonin syndrome exists. Use only when directed.
• NRIs (norepinephrine reuptake inhibitors, e.g., atomoxetine, etc.) — NRI medications and amphetamine both enhance noradrenergic activity. Possible augmentation/potentiation of effects. Use only when directed.
• SNRIs (selective serotonin-norepinephrine reuptake inhibitors) — See SSRIs and NRIs.
• Bupropion  — Both bupropion and amphetamine have noradrenergic and dopaminergic activity. Possible augmentation/potentiation of effects. Bupropion has pro-convulsant properties that may be enhanced or cumulatively potentiated by amphetamine. Use only when directed.
• Tricyclics and related compounds (tricyclic antidepressant  — See SNRIs and SSRIs. Possible potentiation of serotonin, dopamine and norepinephrine related drug effects. The combination of tricyclic and amphetamine compounds / other direct acting sympathomimetics has been associated with increased sympathetic action. Adjustments to dose may be required. Concurrent use not generally recommended due to interaction between direct acting sympathomimetics such as amphetamine and tricyclics. Indirect acting sympathomimetics may have decreased efficacy when combined with tricyclics (tricyclic blockade may inhibit the action of some indirect acting sympathomimetics).
• CYP2D6 (liver enzyme) inhibitors, e.g., most SSRIs such as fluoxetine, citalopram, paroxetine, etc. Some anti-psychotics such as thioridazine, haloperidol, and, levomepromazine. The stimulant cocaine. The opioid agonist methadone. There are additional drugs that inhibit CYP2D6, it is important to find out if any medication or drug that is being taken is a CYP2D6 inhibitor. Taking a CYP2D6 inhibiting drug along with amphetamine will lead to an elevated level of amphetamine in the system and the drug will also remain longer in the body, this can lead to undesired or possibly serious side effects.

[edit] Prolonged use

Prolonged high doses of amphetamines followed by an abrupt cessation can result in extreme fatigue and mental depression. Chronic abuse of amphetamines can result in the manifestation of amphetamine psychosis.^[1]

[edit] Performance-enhancing use

Due to side effects including appetite suppression and weight loss, Adderall has also been used as an off-label drug for obesity.^[19]

Adderall is also reportedly widely used as a "study drug" at many universities. Adderall is reported to help focus energy and concentration to a much higher level than normal. It enables the user to focus and stay awake.^[29] Stories of students writing papers continuously for an unusually long time, or "cramming" all night for an exam with no loss of energy or concentration are common. However, the user reportedly can suffer from drastic side effects the following day if Adderall was used to avoid a normal sleep pattern^{[citation needed]}. William Frankenberger, psychology professor at University of Wisconsin at Eau Claire, led a study at the university in 2004 that reported 14% of the campus had abused some form of ADHD drug, including Adderall.^[29] College campuses known to be highly competitive or have a high rate of binge drinking had up to 25% of students who misused an ADHD medication within one year, a survey of students at 119 colleges across the country concluded.^[29] Other forms of ADHD medication used as a performance enhancing drug include methylphenidate preparations, such as Ritalin and Concerta.^[30]

The Nevada State Athletic Commission has banned athletes in the state from using Adderall. Tim Credeur was removed from a UFC fight on the finale of The Ultimate Fighter 7 because of a positive drug test due to his use of it. New Orleans Saints kicker Garrett Hartley served a four-game suspension when the 2009 NFL regular season began, because he tested positive for the banned stimulant. The Arizona Cardinals tight end Ben Patrick received a four-game suspension as a result of using Adderall.^[31]

[edit] Government warnings

On February 9, 2005, Health Canada suspended all sales of Adderall XR after data collected by manufacturer Shire Pharmaceuticals linked the drug to 12 sudden deaths in American children.^[32] Further research found data suggesting use of Adderall resulted in an increased risk of cardiac defect. Given the more than 37,000,000 prescriptions for Adderall filled during the four years, the U.S. Food and Drug Administration could find no increased risk of sudden death among Adderall users.^[32][33] In August 2005, Health Canada followed the committee report of three independent physicians and lifted the ban on Adderall XR.^[34][35] Given that persons with ADHD are more likely to engage in risky or dangerous behavior, it has been suggested that stimulant medications for persons with ADHD may actually result in lower incidence of premature death.^[36] The use of Adderall is generally not advised in those persons with pre-existing cardiac or mental illnesses. It is also not advised in persons who have a history of drug abuse.^[2] Although FDA safety advisors voted 8 to 7 to issue a black box warning, the FDA's pediatric advisory committee refused to give the drug its most severe black box warning in March 2006.^[37] A Black Box Warning regarding amphetamine abuse potential is in place, however. In September 2008, Britain's National Institute for Health and Clinical Excellence urged physicians not to prescribe Adderall or similar drugs to children under 5, and to exhaustively consider other approaches to behavioral modification before prescribing such drugs to children 5 and up.^[38]

[edit] International availability and legal status

• South Korea: Adderall, and all other amphetamine-based medications (such as Vyvanse and Dexedrine), are considered "banned narcotics" in South Korea. They cannot be obtained at a South Korean pharmacy, and are illegal to import. Concerta and other methylphenidate-based medications, however, are available.^{[citation needed]}
• Taiwan: Adderall and Dexedrine are classified as schedule II controlled drugs, and are not available in Taiwan. Methylphenidate-based medications are available. Vyvanse is not currently classified, and is not available in Taiwan.

[edit] References