Amphetamine mixed salts (medication)
|Licence data||US Daily Med:|
|Pregnancy cat.||C (US)|
|Legal status||Schedule I (CA) Schedule II (US)|
|Routes||(Medical) Oral, (Recreational) Oral, Insufflated, Intravenous|
|ATC code||N06 N06|
| (what is this?)
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). Amphetamine mixed salts are available in immediate release and extended release formulations.
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. 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.
Attention deficit hyperactivity disorder
Amphetamine mixed salts has shown to significantly reduce symptoms associated with ADHD and reportedly presents minimal side-effects. Compared to alternate medication methylphenidate, some studies have suggested that amphetamine mixed salts is slightly more potent and has a longer period of efficacy, especially at lower doses. For patients who experience adverse side effects or do not find methylphenidate effective, amphetamine mixed salts is often recommended as a substitute.
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.
Dosing and administration
Amphetamine mixed salts is available as immediate release form or extended-release form.
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.
Side effects of amphetamine salts include dry mouth, insomnia, tired feeling, drowsiness, dizziness, nervousness, headache and weight loss, diarrhea, as well as changes in heartbeat and blood pressure.
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.
Studies on rats show long-term neurological and behavioral changes resulting from prenatal and early postnatal exposure to amphetamines. Warnings from the Patient Medication Guide for Adderall include emergence of new psychotic or manic symptoms, aggression and blurred vision. 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.
Contraindications, interactions, and precautions
- 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. (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
Amphetamine mixed salts is in FDA pregnancy category C. Drugs assigned category C have been demonstrated to have adverse effect on fetus in animal studies, but no adequate studies on human are available.
Prolonged high doses of amphetamines followed by an abrupt cessation can result in extreme fatigue, insomnia, irritability, weight gain, mental depression, urination problems (sometimes mistaken for a urinary tract infection), and bloody stools. Chronic abuse of amphetamines can result in the manifestation of amphetamine psychosis; occasionally this psychosis can occur at therapeutic doses during chronic therapy as a treatment emergent side effect.
In the Unites States, a formula of amphetamine mixed salts was approved by the U.S. Food and Drug Administration (FDA) on January 19, 1960 under the name Obetrol. between 1965 and 1973, this formula was offered in 10 mg and 20 mg strength through Obetrol Pharmaceuticals division of an American pharmaceutical company Rexar under the trade name Obetrol. Its indication was for exogenous obesity.
The formulation for the 1965-1973 Obetrol 10 mg strength:
- Methamphetamine saccharate 2.5 mg
- Methamphetamine hydrochloride 2.5 mg
- Amphetamine sulfate 2.5 mg
- Dextroamphetamine sulfate 2.5 mg
Obetrol was withdrawn from the market in 1973 under DESI statute.
Rexar reformulated and continued to sell the unapproved formulation of Obetrol. This formulation was sold as Adderall by Richwood after it acquired Rexar resulting in FDA warning in 1994. Richwood submitted this formulation as NDA 11-522 and gained approval.
- amphetamine aspartate monohydrate (racemic)
- amphetamine sulfate (racemic)
- dextroamphetamine sulfate
- dextroamphetamine saccharate
Amphetamine mixed salts are available in immediate release and extended release formulations. The immediate release formulation is indicated for use in ADHD and narcolepsy,. The extended release formulation only approved for the treatment of ADHD.
Mechanism of action
|This section requires expansion. (May 2013)|
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. Dextroamphetamine (the dextrorotary enantiomer) and levoamphetamine (the levorotary enantiomer) have different pharmacological properties. 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. The overall greater potency of dextroamphetamine to central actions suggests that this form may have a higher potential for abuse.
Levoamphetamine provides mixed amphetamine salts quicker onset and longer-lasting effects than dextroamphetamine alone. It has been reported that certain children have a better clinical response to levoamphetamine.
"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."
Urinary and stomach pH levels influence amphetamine excretion and absorption. An acidic stomach and GI pH will decrease the absorption of amphetamine salts. 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.
Detection of use
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
||This section needs additional citations for verification. (November 2012)|
Amphetamines are considered to have a high potential for misuse and a high liability for dependence and listed as Schedule II in the US Schedule II in the UN and Schedule I in Canada (CSA)
Survey results published in 2006 found that amphetamine salts like Adderall were used three times more on college campuses than methylphenidate (commonly known as Ritalin). White and Hispanic students used amphetamine salts far more often than black and Asian students.
Amphetamine mixed salts are a drug of abuse along with other forms of amphetamines Amphetamine salts can be crushed, and snorted or dissolved in water and injected. Injection into the bloodstream can be dangerous because insoluble fillers within the tablets can block small blood vessels.
Prescription amphetamines such as amphetamine mixed salts are often obtained by those with a prescription and diverted and sold to those who do not have a prescription.
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 DuraMed Pharmaceuticals was acquired by Teva Pharmaceuticals in 2008 when Teva completed its acquisition of Barr Pharmaceuticals (including Barr's Duramed division). 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. Shire was unable to extend patents by evergreening and generic version of Adderall XR became available in 2009. In 2009, Barr and Shire reached a settlement agreement permitting Barr to offer a generic form of the drug beginning April 1, 2009.
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 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 dexamphetamine (the main isomeric-amphetamine component of Adderall) had a longer duration of action, however D-amphetamine was less effective in the first few hours.
- United Nations: Schedule II of CSA
- Canada: Prescription only, Schedule I
- New Zealand: International travelers with valid prescriptions must declare them, the drugs will be taken, and the patient must go to a dispensary daily to receive their medications.
- South Korea: prohibited 
- Thailand: Amphetamines are classified as Type 1 Narcotics.
- United States: Prescription only, Schedule II controlled substance.
- Enantiomers are molecules that are "mirror images" of one another; they are structurally identical but of the opposite orientation, like left and right hands
- "Adderall". Drugs.com. Retrieved 20 May 2013.
- "Adderall". The American Society of Health-System Pharmacists. Retrieved 24 May 2013.
- Biederman J, Lopez FA, Boellner SW, Chandler MC (August 2002). "A randomized, double-blind, placebo-controlled, parallel-group study of SLI381 (Adderall XR) in children with attention-deficit/hyperactivity disorder". Pediatrics 110 (2 Pt 1): 258–66. doi:10.1542/peds.110.2.258. PMID 12165576.
- "Adderall vs Ritalin – Benefits, Problems". Health and Life. August 21, 2009.[unreliable source?]
- Pelham WE, Aronoff HR, Midlam JK, Shapiro CJ, Gnagy EM, Chronis AM, Onyango AN, Forehand G, Nguyen A, Waxmonsky J (April 1999). "A comparison of ritalin and adderall: efficacy and time-course in children with attention-deficit/hyperactivity disorder". Pediatrics 103 (4): e43. doi:10.1542/peds.103.4.e43. PMID 10103335.
- Pliszka SR, Browne RG, Olvera RL, Wynne SK (May 2000). "A double-blind, placebo-controlled study of Adderall and methylphenidate in the treatment of attention-deficit/hyperactivity disorder". J Am Acad Child Adolesc Psychiatry 39 (5): 619–26. doi:10.1097/00004583-200005000-00016. PMID 10802980.
- Schwartz A (2013-02-13). "Drowned in a Stream of Prescriptions". New York Times.
- "ADDERALL (CII)" (PDF). Food and Drug Administration. February 2007. Retrieved 2009-06-23.
- "Medication Guide Adderall XR". US Food and Drug Administration (FDA). Retrieved 19 May 2013.
- Pliszka SR, Matthews TL, Braslow KJ, Watson MA (May 2006). "Comparative effects of methylphenidate and mixed salts amphetamine on height and weight in children with attention-deficit/hyperactivity disorder". J Am Acad Child Adolesc Psychiatry 45 (5): 520–6. doi:10.1097/01.chi.0000205702.48324.fd. PMID 16670648.
- "Adderall XR prescribing information". Shire US. March 2009. Retrieved 2009-06-23.
- Barkley RA (2010). Taking Charge of Adult ADHD. New York: The Guilford Press. p. 122. ISBN 1-60623-710-1.
- "FDA Asks Attention-Deficit Hyperactivity Disorder (ADHD) Drug Manufacturers to Develop Patient Medication Guides". Press Release. U.S. Food and Drug Administration. February 21, 2007.
- "ADDERALL (CII)". NDA 11-522/S-040. U.S. Food and Drug Administration.
- "ADHD Medications and Risk of Stroke In Young and Middle-Aged Adults". Retrieved 11 June 2013.
- "ADHD Medications and Risk of Serious Coronary Heart Disease in Young and Middle-Aged Adults". Retrieved 11 June 2013.
- "Attention Deficit Hyperactivity Disorder Medications and Risk of Serious Cardiovascular Disease in Children and Youth". Retrieved 11 June 2013.
- Stahl SM, Pradko JF, Haight BR, Modell JG, Rockett CB, Learned-Coughlin S (2004). "A Review of the Neuropharmacology of Bupropion, a Dual Norepinephrine and Dopamine Reuptake Inhibitor". Prim Care Companion J Clin Psychiatry 6 (4): 159–166. doi:10.4088/PCC.v06n0403. PMC 514842. PMID 15361919.
- "FDA Pregnancy Categories" (PDF). University of Washington Drug Information Center.
- Berman SM, Kuczenski R, McCracken JT, London ED (February 2009). "Potential adverse effects of amphetamine treatment on brain and behavior: a review". Mol. Psychiatry 14 (2): 123–42. doi:10.1038/mp.2008.90. PMC 2670101. PMID 18698321.
- "Adverse events reported with immediate-release mixed amphetamine salt products". Center for Drug Evaluation and Resarch (CDER) – United Stated Food and Drug Administration (FDA). 2006-02-01. Retrieved 2013-05-20.
- Physicians' Desk Reference (20 ed.). Medical Economics. 1966. p. 811.; Physicians' Desk Reference (25 ed.). Medical Economics. 1973. p. 1027.
- "REGULATORY NEWS: Richwood's Adderall". Health News Daily. 22 Feb 1996. Retrieved 29 May 2013.
- Kleijn J, Wiskerke J, Cremers TI, Schoffelmeer AN, Westerink BH, Pattij T (June 2012). "Effects of amphetamine on dopamine release in the rat nucleus accumbens shell region depend on cannabinoid CB1 receptor activation". Neurochem. Int. 60 (8): 791–8. doi:10.1016/j.neuint.2012.03.002. PMID 22426202.
- Kuczenski R, Segal DS (May 1997). "Effects of methylphenidate on extracellular dopamine, serotonin, and norepinephrine: comparison with amphetamine". J. Neurochem. 68 (5): 2032–7. doi:10.1046/j.1471-4159.1997.68052032.x. PMID 9109529.
- Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, Partilla JS (January 2001). "Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin". Synapse 39 (1): 32–41. doi:10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3. PMID 11071707.
- Heal DJ, Smith SL, Findling RL (2012). "ADHD: Current and Future Therapeutics". In Tannock R, Clare S. Behavioral Neuroscience of Attention Deficit Hyperactivity Disorder and Its Treatment. Current Topics in Behavioral Neurosciences. Berlin: Springer. ISBN 3-642-24611-7.
- Lemke TL, Williams DH, Foye WO (2002). "Hallucinogens, stimulants, and related drugs of abuse". Foye's principles of medicinal chemistry (5th, illustrated ed.). Hagerstwon, MD: Lippincott Williams & Wilkins. p. 445. ISBN 0-683-30737-1.
- Nemeroff CB, Schatzberg AF (2004). The American Psychiatric Publishing textbook of psychopharmacology. Washington, DC: American Psychiatric Pub. ISBN 1-58562-060-2.
- Glaser PE, Thomas TC, Joyce BM, Castellanos FX, Gerhardt GA (March 2005). "Differential effects of amphetamine isomers on dopamine release in the rat striatum and nucleus accumbens core". Psychopharmacology (Berl.) 178 (2–3): 250–8. doi:10.1007/s00213-004-2012-6. PMID 15719230.
- Arnold LE (2000). "Methyiphenidate vs. Amphetamine: Comparative review". Journal of Attention Disorders 3 (4): 200–11. doi:10.1177/108705470000300403.
- Washington N (1991). Antacids and anti-reflux agents. Boca Raton: CRC Press. p. 175. ISBN 0-8493-5444-7.
- Venable SJ, Aschenbrenner DS (2009). Drug therapy in nursing. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins. p. 359. ISBN 0-7817-6587-0.
- Nobles S (2002). Delmar's drug reference for health care professionals. Albany, N.Y: Delmar. p. 10. ISBN 0-7668-2523-X.
- Cody JT, Valtier S, Nelson SL (October 2004). "Amphetamine excretion profile following multidose administration of mixed salt amphetamine preparation". J Anal Toxicol 28 (7): 563–74. doi:10.1093/jat/28.7.563. PMID 15516315.
- Paul BD, Jemionek J, Lesser D, Jacobs A, Searles DA (September 2004). "Enantiomeric Separation and Quantitation of (±)-Amphetamine, (±)-Methamphetamine, (±)-MDA, (±)-MDMA, and (±)-MDEA in Urine Specimens by GC-EI-MS after Derivatization with (R)-(−)- or (S)-(+)-α-Methoxy-α-(trifluoromethy)phenylacetyl Chloride (MTPA)". J Anal Toxicol 28 (6): 449–55. doi:10.1093/jat/28.6.449. PMID 15516295.
- Baselt R (2011). Disposition of Toxic Drugs and Chemicals in Man (9th ed.). Seal Beach, CA: Biomedical Publications. pp. 85–8.
- "Commonly Abused Prescription Drugs Chart". National Institute on Drug Abuse. Retrieved 2012-05-07.
- "Stimulant ADHD Medications - Methylphenidate and Amphetamines". National Institute on Drug Abuse,. Retrieved 2012-05-07.
- Teter CJ, McCabe SE, LaGrange K, Cranford JA, Boyd CJ (October 2006). "Illicit use of specific prescription stimulants among college students: prevalence, motives, and routes of administration". Pharmacotherapy 26 (10): 1501–10. doi:10.1592/phco.26.10.1501. PMC 1794223. PMID 16999660.
- "NCAA Banned Drugs and Medical Exceptions Policy". Retrieved 27 June 2011.
- "Amphetamines" (PDF). Drug Fact Sheet. U.S. Drug Enforcement Administration.
- "National Institute on Drug Abuse. 2009. Stimulant ADHD Medications - Methylphenidate and Amphetamines". National Institute on Drug Abuse. Retrieved 27 February 2013.
- "Barr and Shire Sign Three Agreements" (Press release). Barr Pharmaceuticals. 2006-08-14. Retrieved 2009-06-23.
- "Teva Completes Acquisition of Barr". Drugs.com. Retrieved 2011-10-31.
- "Shire’s Adderall XRTM receives patent protection" (PDF) (Press release). Shire Pharmaceuticals. 2001-11-28. Retrieved 2009-06-23.[dead link]
- Foley, Stephen (2006-08-16). "Shire in deal with Barr to delay launch of rival to its ADHD drug". London: The Independent. Retrieved 2006-06-23.
- "Teva sells 1st generic of Adderall XL in US". Forbes Magazine. Associated Press. 2009-04-02. Archived from the original on 9 April 2009. Retrieved 2009-04-22.[dead link]
- US patent 6384020, Flanner HH, Chang R-K, Pinkett JE, Wassink SE, White LR, "A pharmaceutical composition comprising lactitol and one or more amphetamine salts in a rapid-release formulation", issued 2002-05-07, assigned to Shire Lab Inc.
- Buck ML (March 2002). "Amphetamines in the Treatment of Attention-Deficit/Hyperactivity Disorder". Pediatric Pharmacotherapy 8 (3).
- 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.
- The Minister and Attorney General. "Controlled Drugs and Substances Act". Justice Laws Website. Government of Canada.
- "Thailand Law". Government of Thailand. Retrieved 2013-05-23.
- 21 U.S.C. § 829
- "Lists of: Scheduling Actions, Controlled Substances, Regulated Chemicals". DEA Listing of Controlled Substances.
- "Issuance of Multiple Prescriptions for Schedule II Controlled Substances". Retrieved 2012-12-16.