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Adderall

Adderall is a brand-name pharmaceutical psychostimulant composed of mixed amphetamine salts, the actions of which are sympathomimetic. The drug is used primarily to treat attention-deficit hyperactivity disorder and narcolepsy, which are its only two approved indications for use in the United States. It is available in two formulations: immediate release and extended release (XR). The XR formulation, however, is not approved to treat narcolepsy.

Other Uses

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 approved indication. Other recognized uses include:

Idiopathic Central Nervous System Hypersomnia established by recognized diagnostic criteria
Drug-induced brain dysfunction
Epilepsy
Depression shown to be refractory to other therapeutic modalities
Senile apathetic behavior.

These above uses are not necessarily licensed in any particular country; for example they are not FDA approved in the USA.

History

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 and this instant-release medication has since become available in a generic formulation of "mixed amphetamine salts". The active ingredients of Adderall include a combination of dextroamphetamine and racemic -amphetamine salts. In 2001, Shire Pharmaceuticals introduced an extended-release preparation of these ingredients in a variety of dosages under the brand name "Adderall XR" (extended release), on which Shire retains exclusive patent rights until the patent expires, expected in 2009.

Chemistry

Specifically, Adderall XR is composed of the following proportions of active ingredients:

1/4 dextroamphetamine saccharate
1/4 dextroamphetamine sulfate
1/4 (racemic dextro/levo-amphetamine) aspartate monohydrate
1/4 (racemic dextro/levo-amphetamine) sulfate

These four salts are metabolized at different rates and possess diverse half lives, therefore resulting in a less dramatic onset and termination of therapeutic action; as compared to single-salt amphetamine preparations.

The average elimination half-life in adults for dextroamphetamine and levoamphetamine is 10 hours and 13 hours respectively. Breakdown rates are affected by many factors including urinary and stomach pH, weight, gender, other medications being taken, and age.

Urinary and stomach pH levels can have the strongest effect on -amphetamine excretion and absorption. Co-administration of acidic substances (e.g. citric acid) causes an accelerated excretion of -amphetamine while co-administration of alkaline agents (e.g. antacids) causes a marked increase in both retention and absorption of amphetamines potentially resulting in dangerously high serum amphetamine levels.

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

Dosing and administration

Adderall is marketed as either an immediate-release tablet, Adderall, or an extended-release capsule, Adderall XR ("Extended Release"). Doses for both Adderall XR and Adderall are 5, 10, 15, 20, and 30 mg strengths with instant-release Adderall having two extra ones, 7.5 and 12.5 mg, and Adderall XR having a 25 mg dose.

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.

Manufacturer's claims of instant release have been disputed. A US patent granted for Adderall 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 -amphetamine was less effective in the first few hours.

Use as treatment for attention-deficit/hyperactivity disorder (ADHD)

Adderall has been commonly prescribed for many years as a treatment for children and adults with attention deficit/hyperactive disorder (ADHD), a disorder that prevents children and adults from being able to focus on tasks for extended periods of time, a particularly detrimental condition for school performance. After administration of Adderall students have been shown to give higher teacher ratings and perform better in mathematics within 1.5 hours of initial dose. Depending on dosage, these beneficial effects can also last several hours allowing improved performance throughout the day.

Other studies comparing Adderall with other similar medications have shown that Adderall is also more potent than Ritalin (methylphenidate) and has a longer period of efficaciousness. For many this means it is likely preferable as a medication for ADHD, and certainly a substitute for children who have adverse side effects to Ritalin, or for whom Ritalin has become ineffective.

There are also other reasons for taking Adderall aside from just alleviating the symptoms of ADHD. Untreated ADHD has been linked to an increased risk of psychoactive substance abuse later in life.Fortunately, the likelihood of a drug abuse disorder can be approximately halved by proper treatment during childhood. For many, these stimulant medications used to treat ADHD actually provide protection against developing other drug dependencies in this increased risk population. This contradicts the commonly held misconception that use of drugs like Adderall or Ritalin can cause increased drug dependency later in life.

However, specialists also stress the need for ADHD treatments not to solely rely on drugs like Adderall. They advise a comprehensive treatment plan that includes ADHD education, coaching and support groups; regular visits to your doctor; therapy or counseling regarding ADHD; involvement in recovery programs, and family and relationship counseling when appropriate.

Generic equivalents/alternatives

Until recently, the closest generic equivalent to Adderall (which uses racemic mixed amphetamine salts) was dextroamphetamine sulfate also known as Dexedrine and available in a sustained release form called Dexedrine ER. As of 2008, mixed amphetamine salts are available as a generic formulation. It should be noted that Dexedrine is a single salt form of D-amphetamine, therefore Dexedrine and Dexedrine ER are not strict generic equivalents for Adderall and Adderall XR, though they may, in terms of physiological and psychological effects, be a de facto generic alternative. The savings between Adderall XR and generic Dexedrine ER are significant: 90 dextroamphetamine extended-release capsules cost $20 at a retail pharmacy in the United States, while the equivalent 90 Adderall XR capsules cost $270. The difference is because Adderall XR has been protected under patent in the United States. Until this patent expires, generic versions of Adderall XR will not become available. The generic formulation of Adderall, however, marketed as "mixed amphetamine salts" or "d-amphetamine salt combo," carry a significant savings over that of branded Adderall. On average, Adderall runs about $330 per 100 doses (or $3.30 per dose), whereas the generic mixed amphetamine salts are about one third as expensive - running about $120 per 100 doses (or a little more than $1 per dose).

Vyvanse is another alternative which is actually a prodrug (precursor) of dextroamphetamine. It behaves differently in the body than other formulations of amphetamines because in its parent form is not directly biologically active as an amphetamine (see Dextroamphetamine at "Formulations").

Mechanism of action

Adderall’s inclusion of levoamphetamine provides the pharmaceutical with a quicker onset and longer clinical effect compared to pharmaceuticals exclusively formulated of dextroamphetamine. Although it seems that where the human brain has a preference for dextroamphetamine over levoamphetamine, it has been reported that certain children have a better clinical response to levoamphetamine.

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 -amphetamine acts primarily on the dopaminergic (DA) systems, while -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 transporters 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 neither 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 while amphetamine also 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 causing more neurotransmitter to be released as well as prolonging its availability in the synapse by slowing its removal.

Side effects

In children

Decreased appetite
Difficulty falling asleep
Stomach ache
Emotional lability
Premature puberty
Kidney Failure

In adults

Dry mouth
Loss of appetite
Difficulty falling asleep
Weight loss

From overdose

These symptoms require immediate medical assistance:

Symptoms of tourettism
Seizures or abnormal EEGs
High blood pressure
Tachycardia
Swelling of hands/feet/ankles (for example, numbing of the fingertips)
Hyperactivity
Delusions
Hallucinations
Sweating
Vomiting
Intense Dehydration
Muscle Pain
Lower abdominal pain

Adderall abuse

Tolerance, extreme psychological dependence, and severe social disability can occur when amphetamines are abused. The manufacturer warns against exceeding the prescribed dosage, injecting the drug, or insufflation of the drug. 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.

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.

SSRIs (selective serotonin reuptake inhibitors, e.g., Fluoxetine, Citalopram, Paroxetine, etc.) — While rare, the possibility for serotonin syndrome exists with this combination. Use only when it is directed.
NRIs (norepinephrine reuptake inhibitors, e.g., Atomoxetine, Strattera, 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 (Zyban, Wellbutrin IR, ~SR, ~XL, etc.) — Both bupropion and amphetamine have noradrengic 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.
MAOIs (monoamine oxidase inhibitors, e.g., Phenelzine, Nardil, Selegiline, Emsam, Iproniazid, Iprozid, etc.) — Do not administer amphetamines for a minimum of two weeks after last use of MAOI type drug. Possible hypertensive crises, dangerously elevated amphetamine levels. 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.
Tricyclics and related compounds (tricyclic antidepressants, e.g., Imipramine, Tofranil, Janamine; as well as related compounds including Cyclobenzaprine) — See SNRIs and SSRIs. Possible potentiation of 5htp (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 amphetamines 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. Methadone, a opioid analgesic and anti-addictive. 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 Adderall (amphetamines in general) will lead to a elevated level of Adderall in the system and the drug will also remain longer in the body, this can lead to undesired or possibly serious side effects.

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.

Adderall is also reportedly widely used as a "study drug" at many American 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. Stories of students writing papers for an unusual number of continuous hours [e.g., 14 hours], or cramming all night for an exam with no loss of energy or concentrations 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. "In extreme cases, the drug can cause paranoia, hallucinations and heart attacks." William Frankenberger, psychology professor at University of Wisconsin at Eau Claire, led at a study at the university in 2004 that reported 14% of the campus had abused some form of ADHD drug, including Adderall.. 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.. Other forms of ADHD medication used as a performance enhancing drug include Ritalin, Concerta, and Dexedrine..

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.

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. 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 beyond the normal rate of the general population. In August 2005, Health Canada followed the committee report of three independent physicians and lifted the ban on Adderall XR. 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. 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. 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. 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.