Amphetamine mixed salts (medication)

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"Adderall" redirects here. For amphetamine base, see amphetamine.
amphetamine mixed salts
Combination of
amphetamine aspartate psychostimulant
amphetamine sulfate psychostimulant
dextroamphetamine saccharate psychostimulant
dextroamphetamine sulfate psychostimulant
Clinical data
Trade names Adderall
Adderall ER
Adderall XR
AHFS/Drugs.com monograph
MedlinePlus a601234
Licence data US Daily Med:link
Pregnancy cat. C (US)
Legal status Schedule I (CA) Schedule II (US)
Dependence liability High
Routes (Medical) Oral, (Recreational) Oral, Insufflated, Intravenous
Identifiers
CAS number 51-64-9 YesY 300-62-9
ATC code N06BA02 N06BA01
PubChem CID 44149306
DrugBank DB01576
ChemSpider 13852819 YesY
KEGG D03740 YesY
ChEBI CHEBI:2679 YesY
ChEMBL CHEMBL405 YesY
 N (what is this?)  (verify)

Amphetamine mixed salts (also known as amphetamine and dextroamphetamine mixed salts, amphetamine salt combo, or simply amphetamine salts, and sold under the brand name Adderall) is a pharmaceutical drug used in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. The active ingredient contained in this medication is a mixture of the salts of amphetamine and dextroamphetamine, both of which act as stimulants. As of 2013, there is a single commercial formulation, which contains a 3:1 ratio of dextroamphetamine (the dextrorotary or "right-handed" enantiomer) to levoamphetamine (the levorotary or "left-handed" enantiomer[1]). Amphetamine mixed salts are available in immediate release and extended release formulations.

Medical use[edit source | edit]

Amphetamine mixed salts is generally used for the treatment of ADHD and narcolepsy. These are the only two conditions for which the United States Food and Drug Administration has approved its use.[2] However, it is sometimes prescribed off-label for other conditions such as depression. It has been used to treat obesity, but the American Society of Health-System Pharmacists does not recommend this use.[3] Nearly 14 million monthly prescriptions for the condition were written for Americans ages 20 to 39 in 2011, two and a half times the 5.6 million just four years before, according to the data company I.M.S. Health.[4]

Attention deficit hyperactivity disorder[edit source | edit]

The comparative effectiveness of treatment options for children with ADHD, including different amphetamine medications, has been studied by the US Agency for Health Care Research and Quality,[5] and summarized for parents.[6] Amphetamines may improve ADHD in symptoms in children over the age of six, but there is not enough evidence to be sure.[5] Use for younger children and use for longer than a year in particular requires further study.[5]

Amphetamine mixed salts have also been shown to reduce ADHD in adults, but research is limited.[7]


Dosing and administration[edit source | edit]

Amphetamine mixed salts is available as immediate release form or extended-release form.[8] The extended release capsule is generally used in the morning.[9] Generic forms are available in some doses.[6] The extended release formulation available under the brand Adderall XR is designed to provide therapeutic effect and plasma concentrations identical to taking two doses 4 hours apart.[10]

Side effects[edit source | edit]

Physical effects[edit source | edit]

Physical effects of amphetamine can include dilated pupils, vasoconstriction or vasodilation, tachycardia or bradycardia, hypertension or hypotension, blood shot eyes, flushing, erectile dysfunction, restlessness, dry mouth, bruxism, headache, tachypnea, fever, diaphoresis, diarrhea, constipation, blurred vision, dizziness, reduced seizure threshold, insomnia, numbness, palpitations, arrhythmias, tics, dry and/or itchy skin, acne, and pallor.[11][12] Effects of extremely high doses can include coma, rhabdomyolysis, adrenergic storm, hyperthermia and stereotypy.[13][14] Dangerous physical side effects are exceedingly rare in typical pharmaceutical doses.

Recent studies by the FDA indicate that, in children, young adults, and adults, there is no association between serious adverse cardiovascular events (sudden death, myocardial infarction, and stroke) and the use of amphetamines or other ADHD stimulants.[15][16][17]

Chronic[edit source | edit]

A study on comparative effects between amphetamine mixed salts and methylphenidate in children who have been treated for a year or more have shown a temporary decrease in growth rate that does not affect final adult height. Change in weight was reported as slightly greater for amphetamine mixed salts and authors concluded that the result may be clinically insignificant.[18]

Most longterm users of amphetamines will experience severe, time-limited withdrawal symptoms within 24 hours of their last dose.[19] Symptoms can include dysphoric mood, irritability, anxiety, agitation, vivid or unpleasant dreams, hypersomnia or fatigue, cravings and more.[19] Thoughts of suicide have been reported.[19] This initial "crash" can last up to a week, followed generally by about two weeks of less acute withdrawal symptoms.[19] Antidepressant drugs have been studied to ease amphetamine withdrawal, but more research on their effects is needed.[19]

Contraindications, interactions, and precautions[edit source | edit]

  • MAOIs (monoamine oxidase inhibitors, e.g., phenelzine, selegiline, iproniazid, etc.) —There is a high risk of a hypertensive crisis if amphetamine is administered within two weeks after last use of an MAOI type drug. Preliminary trials of low-dose amphetamine and MAOIs being administered together are in progress. However, this is to be done only 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. Bupropion is a potent CYP2D6 inhibitor. Bupropion has pro-convulsant properties that may be enhanced or cumulatively potentiated by amphetamine.[20] (Use only when directed)
  • Monoaminergic tricyclic antidepressant  — See NRIs, SNRIs, and SSRIs. Possible potentiation of serotonin-, dopamine-, and/or norepinephrine-related drug effects. The combination of monoaminergic tricyclics and amphetamine compounds has been associated with increased sympathomimetic effects. The exceptions to this class (i.e. non-monoaminergic tricyclic antidepressants) include the glutamatergic tricyclic tianeptine and sigmaergic tricyclic opipramol.
  • CYP2D6 (liver enzyme) inhibitors, e.g., Bupropion and most SSRIs such as fluoxetine, citalopram, paroxetine, etc. Some anti-psychotics such as thioridazine, haloperidol, and levomepromazine, as well as cocaine, the opioid agonist methadone, and others. It is important to determine if any medication or drug taken is a CYP2D6 inhibitor. Taking a CYP2D6-inhibiting drug along with amphetamine will lead to an elevated level of amphetamine in the system, resulting in the drug's remaining in the body for a longer period, which can lead to undesirable and possibly serious side effects.
  • Individuals with pre-existing cardiac conditions or mental illnesses.
  • Individuals with a history of drug abuse

Pregnancy[edit source | edit]

Amphetamine mixed salts is in FDA pregnancy category C.[2] Drugs assigned category C have been demonstrated to have adverse effect on fetus in animal studies, but no adequate studies on human are available.[21] Studies on rats show long-term neurological and behavioral changes resulting from prenatal and early postnatal exposure to amphetamines.[22][23]

Psychosis[edit source | edit]

Main article: Stimulant psychosis

Abuse of amphetamines can result in a stimulant psychosis which may present with a variety of symptoms (e.g. paranoia, hallucinations, delusions). A Cochrane Collaboration review on treatment for amphetamine, dextroamphetamine, and methamphetamine induced psychosis[24] states that about 5-15% of users fail to recover completely.[25] The same review asserts that, based upon at least one trial, antipsychotic medications effectively resolve the symptoms of acute amphetamine psychosis.[24] An amphetamine psychosis may also develop occasionally as a treatment-emergent side effect.[26]

Mechanism of action[edit source | edit]

Main article: Amphetamine#Pharmacology
Main article: Dextroamphetamine mechanism of action

Amphetamine's pharmacological activity is due mainly to the release of dopamine and norepinephrine. It can also increase serotonin release, although it is disputed whether this is pharmacologically significant at therapeutic doses.[27][28][29] Dextroamphetamine (the dextrorotary enantiomer) and levoamphetamine (the levorotary enantiomer) have different pharmacological properties.[30] Dextroamphetamine is several times more potent in the central nervous system than levoamphetamine, but the two isomers have comparable activity in the peripheral nervous system.[31] The overall greater potency of dextroamphetamine to central actions suggests that this form may have a higher potential for abuse.[32]

Levoamphetamine provides mixed amphetamine salts quicker onset and longer-lasting effects than dextroamphetamine alone.[33] It has been reported that certain children have a better clinical response to levoamphetamine.[34]

Pharmacokinetics[edit source | edit]

"The mean elimination half-life for d-amphetamine is 10 hours in adults; 11 hours in adolescents aged 13–17 years and weighing less than or equal to 75 kg/165 lbs; and 9 hours in children aged 6 to 12 years. For the l-amphetamine, the mean elimination half-life in adults is 13 hours; 13 to 14 hours in adolescents; and 11 hours in children aged 6 to 12 years. On a mg/kg body weight basis children have a higher clearance than adolescents or adults."[10]

Urinary and stomach pH levels influence amphetamine excretion and absorption.[35] An acidic stomach and GI pH will decrease the absorption of amphetamine salts.[36] Plasma half life of amphetamine sulfate, a constituent of amphetamine mixed salts is dependent on pH of urinary system. For each unit of pH increase, plasma half life of amphetamine sulfate is increased by 7 hours.[37]

Detection of use[edit source | edit]

Techniques such as immunoassay may cross-react with a number of sympathomimetics drugs, so chromatographic methods specific for amphetamine should be employed to prevent false-positive results. Chiral techniques may be employed to help distinguish the source of the drug, whether obtained legally (by prescription) or illegally or possibly as a result of formation from a prodrug such as lisdexamfetamine or selegiline. Chiral separation can be used to differentiate amphetamine mixed salts use from use of another prescription form of amphetamine or from use of illicit amphetamine[38][39][40]

Performance-enhancing use[edit source | edit]

Therapeutic doses of psychostimulants, such as methylphenidate and amphetamine, improve performance on working memory tasks both in individuals with ADHD and in normal subjects; it is important to recognize, however, that stimulants act not only on working memory function, but also on general levels of arousal and, within the nucleus accumbens, improve the saliency of tasks. Thus, stimulants improve performance on effortful but tedious tasks as well.[41] Consequently, Adderall, an amphetamine mixture, is used by some college and high-school students as a study and test-taking aid.[42] In contrast, at abused (much higher) doses, stimulants can interfere with working memory and cognitive control.[41]

In addition, amphetamine is also used by some professional,[43] collegiate[44] and high school[44] athletes for its strong stimulant effects; in competitive sports, this form of use is prohibited by anti-doping regulations. At low to moderate therapeutic doses (10–40 mg), amphetamine has been shown to increase physical strength, stamina, and endurance in numerous studies.[45][46][47] Like methylphenidate and bupropion, amphetamine increases endurance in humans primarily through reuptake inhibition and effluxion of dopamine in the central nervous system.[45]

Furthermore, phenethylamine and its monomethylated derivatives, i.e. amphetamine and amphetamine isomers, all have comparable and notable antinociceptive properties, which manifest as increased pain tolerance.[48]

Recreational use[edit source | edit]

Amphetamine is considered to have a high potential for misuse and a high liability for dependence and listed as Schedule II in the US,[49][50] Schedule II in the UN Convention of Psychotropic Substances and Schedule I in Canada (CSA).[51] Amphetamine mixed salts is a drug of abuse.[52] Amphetamine salts can be crushed, and snorted or dissolved in water and injected.[53] Injection into the bloodstream can be dangerous because insoluble fillers within the tablets can block small blood vessels.[53]

Recreational use of amphetamines is exceedingly dangerous, especially when used at very high doses. Research has shown that amphetamine binges in lab animals cause neurotoxicity in dopaminergic pathways, resulting in permanent but not irreversible cognitive impairments.[54] Moreover, extremely high doses of amphetamine can induce rapid muscle breakdown, repetitive or stereotyped behaviors, catecholaminergic/adrenergic storm, and coma.[55] An amphetamine overdose is rarely fatal with appropriate care.[56]

History[edit source | edit]

Adderall is available as an instant-release (IR) and 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 does continue to manufacture the extended-release version of Adderall ("Adderall XR"). Richwood Pharmaceuticals (later merged with Shire) 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[57] DuraMed Pharmaceuticals was acquired by Teva Pharmaceuticals in 2008 when Teva completed its acquisition of Barr Pharmaceuticals (including Barr's Duramed division).[58] Therefore, following its acquisition of Duramed, Teva 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.)

In 2001, Shire 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.[59] Shire was unable to extend patents by evergreening and generic version of Adderall XR became available in 2009.[60] In 2009, Barr and Shire reached a settlement agreement permitting Barr to offer a generic form of the drug beginning April 1, 2009.[61]

Patent disputes[edit source | edit]

Manufacturer's claims of instant release have been disputed. A US patent granted for Adderall[62] was a pharmaceutical composition patent listing a rapid immediate-release oral dosage form. No claim of increased or smooth drug delivery was made. A study by James and colleague as published in the November 2001 issue of the Journal of the American Academy of Child and Adolescent Psychiatry, placebo-controlled crossover study conducted among 35 children ages 5–12 indicated that patients behaved similarly to those having taken other immediate-release amphetamines. The authors found that sustained-release dextro-amphetamine (the main isomeric-amphetamine component of Adderall) had a longer duration of action; however, D-amphetamine was less effective in the first few hours.[63]

Commercial formulations[edit source | edit]

Historical[edit source | edit]

Rexar, a pharmaceutical company, reformulated another drug, branded as Obetrol, to exclude methamphetamine and continued to sell this new formulation under the same brand name. This new unapproved formulation was later rebranded and sold as Adderall by Richwood after it acquired Rexar resulting in FDA warning in 1994. Richwood submitted this formulation as NDA 11-522 and Adderall gained FDA approval for the treatment of attention-deficit/hyperactivity disorder therapy on February 13, 1996.[64]

Current[edit source | edit]

Amphetamine mixed salts is a psychostimulant medication used primarily for the treatment of ADHD and narcolepsy.[3]

It is a mixture of amphetamine salts consisting of equal amounts by mass of:[10]

This mixture acts as a dopamine releasing agent, dopamine reuptake inhibitor, norepinephrine releasing agent, norepinephrine reuptake inhibitor and can be mildly serotonergic.[22]

Amphetamine mixed salts are available in immediate release and extended release formulations. The immediate release formulation is indicated for use in ADHD and narcolepsy,.[8] The extended release formulation only approved for the treatment of ADHD.[22]

Legal status[edit source | edit]

References[edit source | edit]

  1. ^ Enantiomers are molecules that are "mirror images" of one another; they are structurally identical but of the opposite orientation, like left and right hands
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  64. ^ "REGULATORY NEWS: Richwood's Adderall". Health News Daily. 22 Feb 1996. Retrieved 29 May 2013. 
  65. ^ United Nations Office on Drugs and Crime (2007). Preventing Amphetamine-type Stimulant Use Among Young People: A Policy and Programming Guide. New York: United Nations. ISBN 92-1-148223-2. 
  66. ^ The Minister and Attorney General. "Controlled Drugs and Substances Act". Justice Laws Website. Government of Canada. 
  67. ^ kouseikyoku.mhlw.go.jp
  68. ^ Dr. P. "Moving to Korea brings medical, social changes". Tne Korean Times. 
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  70. ^ 21 U.S.C. § 829
  71. ^ "Lists of: Scheduling Actions, Controlled Substances, Regulated Chemicals". DEA Listing of Controlled Substances. 
  72. ^ "Issuance of Multiple Prescriptions for Schedule II Controlled Substances". Retrieved 2012-12-16. 
Phenethylamines
Amphetamines
Phenylisopropylamines
Phentermines
Cathinones
Phenylisobutylamines
Phenylalkylpyrrolidines
Catecholamines
(and close relatives)
Miscellaneous
Psychostimulants, agents used for ADHD, and nootropics (N06B)
Centrally acting sympathomimetics
Xanthine derivatives
Glutamate receptor
Eugeroics / Benzhydryl compounds
Histamine H3 receptor antagonists
GABAA α5 inverse agonists
Dopamine D1 receptor agonists
α7 nicotinic agonists / PAMs
Prolyl endopeptidase inhibitors
Alpha-adrenergic agonists
Plants
Antioxidants
Other psychostimulants and nootropics

M: PSO/PSI

dsrd (o, p, m, p, a, d, s), sysi/epon, spvo

proc (eval/thrp), drug (N5A/5B/5C/6A/6B/6D)
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