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Combination of
Dextroamphetamine Psychostimulant
Dextro/levo-amphetamine Psychostimulant
CAS number 51-64-9 300-62-9
ATC code N06BA02 N06BA01
PubChem 5826
DrugBank DB01576
Therapeutic considerations
Licence data

US Daily Med:link

Pregnancy cat.


Legal status

Schedule II(US)

Dependence Liability High
Routes Oral

Adderall is a brand-name pharmaceutical psychostimulant composed of mixed amphetamine salts, which is thought to work by increasing the amount of norepinephrine and dopamine in the brain.[1] Adderall is widely reported to increase alertness, concentration and overall cognitive performance while decreasing user fatigue. It is available in two formulations: immediate release and extended release (XR). 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.[3] Adderall is a Schedule II drug under the Controlled Substance Act for the United States; however, it is not a narcotic.[4]


[edit] 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[5] and this instant-release medication has since become available in a generic formulation of "mixed amphetamine salts"[6]. The active ingredients of Adderall XR include a combination of dextroamphetamine and racemic DL-amphetamine salts.[6] 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.[7]

However, due to issues with Shire's inability to evergreen[clarification needed] the patent for Adderall, the drug has gone generic.[citation needed] The generic formulation of the amphetamine salts extended release capsule is produced by Barr Pharmaceuticals. The dosage forms appear identical and the pricing is only reduced by approximately 25% between the brand and Barr generic.[citation needed]

[edit] Chemistry

Basic Amphetamine Structure
Note: Adderall contains an amine functional group.

Specifically, Adderall XR is composed of the following proportions of active ingredients[8]:

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.[6]

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. 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); however, there is a lack of empirical evidence for this claim.[citation needed]

Urinary and stomach pH levels can have the strongest effect on DL-amphetamine excretion and absorption. Co-administration of acidic substances (e.g. citric acid) causes an accelerated excretion of DL-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.[citation needed]

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

[edit] Dosing and administration

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.[9] Adderall XR is available in 5, 10, 15, 20, 25, and 30 mg doses.[10]

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.[citation needed]

Manufacturer's claims of instant release have been disputed. A US patent granted for Adderall[11] 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.[12]

[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). One study found that within 1.5 hours of receiving a dose of Adderall, students with ADHD performed better on mathematics tests and behaved better and more attentively in class.[13] Depending on dosage, the beneficial effects of stimulant medications can last several hours, allowing improved performance throughout the day.[14] Compared to the similar medication Ritalin (methylphenidate), studies have suggested that Adderall is generally more potent and has a longer period of efficacy, especially at lower doses. For those who experience adverse side effects to Ritalin or for whom Ritalin has become ineffective, Adderall is often recommended as a substitute.[15][16]

Untreated ADHD has been linked to an increased risk of substance abuse later in life,[17] but medical treatment for ADHD during childhood may reduce the chance of developing a substance abuse disorder later in life.[18] The most effective treatments for ADHD, however, generally involve both psychopharmacological and psychosocial components.[citation needed]

[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. Other recognized uses include[19]:

  • Idiopathic Central Nervous System Hypersomnia established by recognized diagnostic criteria
  • Drug-induced brain dysfunction
  • Epilepsy
  • Senile apathetic behavior
  • Psychiatric differential diagnosis of depression
  • Obesity[20]

[edit] 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.[21] 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 approximately $420.[22] 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).[21]

Vyvanse is another alternative which is actually a prodrug (designed to enter and exit the body efficiently) 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"). Vyvanse costs about $500 for 100 doses.[21]

[edit] Mechanism of action

With respect to central stimulant actions, the S(+) isomer (i.e., dextroamphetamine) is several times more potent than its R(-)enantiomer (i.e., levamphetamine); 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 levamphetamine 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 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.[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

Stimulant medications, including Adderall and methylphenidate (Ritalin), have a high abuse potential. Adderall carries the same risk of sudden death, stroke, and heart attack in patients with pre-existing heart conditions as methylphenidate and other stimulants used to treat ADHD, as well as the same risk of seizures in patients with a history of seizures.[3][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 Strattera. Changes in vision have been reported with both Adderall and methylphenidate.[3][27]

[edit] Adderall Prolonged Use

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.[8]

[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.

  • 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 5ht (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.

[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.[20]

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.[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. "In extreme cases, the drug can cause paranoia, hallucinations and heart attacks."[29] 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.[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.

[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.[31] 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.[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.[37] 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.[38] 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. [39]

[edit] See also

[edit] References

  1. ^ Adderall XR Prescribing Information
  2. ^ Adderall Prescribing Information
  3. ^ a b c Adderall XR Prescribing Information
  4. ^ [1] Schedule II drugs
  5. ^ Press Release: Barr and Shire Sign Three Agreements, August 14, 2006, Accessed May 1, 2008.
  6. ^ a b c Adderall (Amphetamine Mixed Salts) drug description - FDA approved labeling for prescription drugs and medications at RxList
  7. ^ Shire Pharmaceuticals Group plc (2001-11-01). "Shire's Adderall XR Receives Patent Protection". Shire Pharmaceuticals Group plc. Shire Pharmaceuticals Group plc. Retrieved on 2009-01-04. "Shire Pharmaceuticals Group plc announces that a formulation and composition patent relating to ADDERALL XR has been issued by the US Patent and Trademark Office, expiring in 2018." 
  8. ^ a b Shire US Inc., "Prescribing Information" sheet (PDF) for Adderall XR, November, 2008. Accessed January 22, 2009
  9. ^ Drug Information for Adderall Oral - WebMD
  10. ^ Drug Information for Adderall XR Oral - WebMD
  11. ^ US6,384,020 (PDF version) (2002-05-07) Flanner, Henry H., et al., A pharmaceutical composition comprising lactitol and one or more amphetamine salts in a rapid release formulation. 
  12. ^
  13. ^ Swanson, et al., Analog Classroom Assessment of Adderall(R) in Children With ADHD, Journal of the American Academy of Child & Adolescent Psychiatry. 37(5):519-526, May 1998. "Subjective (teacher ratings of deportment and attention) and objective (scores on math tests) measures were obtained. … Rapid improvements on teacher ratings and math performance were observed by 1.5 hours after administration, and these effects dissipated by the end of the day."
  14. ^ Biederman, et al., A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study of SLI381 (Adderall XR) in Children With Attention-Deficit/Hyperactivity Disorder, PEDIATRICS Vol. 110 No. 2 August 2002, pp. 258-266
  15. ^ Pelham, et al., A Comparison of Ritalin and Adderall: Efficacy and Time-course in Children With Attention-deficit/Hyperactivity Disorder, PEDIATRICS Vol. 103 No. 4 April 1999, p. e43
  16. ^ Pliszka, et al., A Double-Blind, Placebo-Controlled Study of Adderall and Methylphenidate in the Treatment of Attention-Deficit/Hyperactivity Disorder, Journal of the American Academy of Child & Adolescent Psychiatry. 39(5):619-626, May 2000.
  17. ^ Biederman, et al., Is ADHD a Risk Factor for Psychoactive Substance Use Disorders? Finding From a Four-Year Prospective Follow-Up Study, FOCUS 1:196-204 (2003)
  18. ^ Wilens, et al., Does Stimulant Therapy of Attention-Deficit/Hyperactivity Disorder Beget Later Substance Abuse? A Meta-analytic Review of the Literature, PEDIATRICS Vol. 111 No. 1 January 2003, pp. 179-185
  19. ^ Narcotic Prescription Changes for Chronic Pain
  20. ^ a b Madelyn Fernstrom, Ph.D., CNS (2006-10-26). "Quick-fix diet drugs: Effective or harmful?". Today. Retrieved on 2008-08-18. "There are about a half dozen drugs regularly used as off label treatments for obesity. These include: ... Adderall ..." 
  21. ^ a b c Brand and Generic Prices for Adderall
  22. ^ Product Information - Adderall Xr
  23. ^ [2] Foye's principles of medicinal chemistry
  24. ^ [3] The American Psychiatric Publishing textbook of psychopharmacology
  25. ^ Glaser, et al. (2005). "Differential Effects of Amphetamine Isomers on Dopamine in the Rat Striatum and Nucleus Accumbens Core". Psychopharmacology 178: 250–258 (Pages: 255,256). doi:10.1007/s00213-004-2012-6. 
  26. ^ Arnold (2000). "Methylphenidate vs Amphetamine: Comparative Review". Journal of Attention Disorders 3 (4): 200–211. doi:10.1177/108705470000300403. 
  27. ^ a b Ritalin SR Prescribing Information
  28. ^ a b Pliszka, S. R., Matthews, T. L., Braslow, K. J., & Watson, M. A. (2006). Comparative effects of methylphenidate and mixed salts amphetamine on height and weight in children with attention-deficit/hyperactivity disorder. Journal of the American Academy of Child & Adolescent Psychiatry, 45(5), 520-526.
  29. ^ a b c d Megan Twohey (2006-03-25). "Pills become an addictive study aid". Milwaukee Journal Sentinel. Journal Sentinel Inc.. Retrieved on 2008-09-08. "At colleges, students take a deadly risk by abusing ADHD drug" 
  30. ^ Monson, PharmD, Kristi and Schoenstadt, MD, Arthur. "Alternatives to Adderall." 10 April 2008.
  31. ^ Public Health Advisory for Adderall and Adderall XR
  32. ^ Ibid.
  33. ^ Sudden Death in 12 Kids on ADHD Drug Adderall
  34. ^ Report of the Adderall XR New Drug Committee
  35. ^ Canada Reverses Ban On ADHD Medication - Rosack 40 (19): 2 - Psychiatr News
  36. ^ Resources for Information about ADD/ADHD and Related Disorders
  37. ^ Patient Information Sheet for Adderall
  38. ^ Dire Warning Not Urged for ADHD Drugs -
  39. ^ British Health Agency Discourages Ritalin Use
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