||This article's introduction section may not adequately summarize its contents. (December 2013)|
|amphetamine aspartate monohydrate||(25%) psychostimulant|
|amphetamine sulfate||(25%) psychostimulant|
|dextroamphetamine saccharate||(25%) psychostimulant|
|dextroamphetamine sulfate||(25%) psychostimulant|
|Licence data||US FDA:|
|Pregnancy cat.||C (US)|
|Legal status||Schedule I (CA) Schedule II (US)|
|Routes||Oral, insufflation, rectal, sublingual|
|ATC code||N06 N06|
|(what is this?)|
Adderall[note 1] is a psychostimulant pharmaceutical drug used in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. The medication is a mixture of amphetamine stereoisomer salts and inactive ingredients. Its active ingredients are 72.7% dextroamphetamine (the dextrorotary or "right-handed" enantiomer) and 27.3% levoamphetamine (the levorotary or "left-handed" enantiomer).[note 2] Adderall is available in immediate release and extended release formulations.
While concerns have been raised over side effects and rare, serious complications, Adderall is generally well-tolerated and effective. The most common side effects are cardiovascular, such as fast or irregular heartbeat, and psychological, such as anxiety.
- 1 Uses
- 2 Side effects
- 3 Overdose
- 4 Contraindications, interactions, and precautions
- 5 Mechanism of action
- 6 History
- 7 Commercial formulations
- 8 Legal status
- 9 Notes
- 10 References
Adderall is generally used for the treatment of ADHD and narcolepsy, the 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. 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 IMS Health.
In humans, literature reviews from 2013, including a meta-analysis and a systematic review, indicate that the long-term use of amphetamine at therapeutic doses for ADHD actually appears to produce beneficial changes in brain function and structure, such as an improvement in function of the right caudate nucleus. Moreover, according to Millichap on the use of ADHD stimulants, "[research] has confirmed the effectiveness and safety of the long-term use of [stimulant] medication." He emphasized one notable study, stating "a multicenter, placebo-controlled trial of amphetamine treatment for ADHD in Sweden found significant improvements in attention, hyperactivity, and disruptive behaviors and a mean change in IQ of +4.5 after more than 9 months of amphetamine [use];" however, he also noted that the population in the study had a remarkably high incidence of comorbid disorders associated with ADHD. Consequently, the author asserted that other long-term amphetamine trials in ADHD with less comorbidity could result in even greater functional improvements.
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, and summarized for parents. Amphetamines may improve ADHD symptoms in children over the age of six, but there is not enough evidence to be sure. Use for younger children and use for longer than a year in particular requires further study.
Dosing and administration
Adderall is available as immediate release form or extended-release form. The extended release capsule is generally used in the morning. Generic forms are available in some doses. 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.
Therapeutic doses of psychostimulants, including amphetamine, improve performance on working memory tests both in normal functioning individuals and those with ADHD. Moreover, these stimulants also increase arousal and, within the nucleus accumbens, improve task saliency. Thus, stimulants improve performance on effortful and tedious tasks as well. Consequently, amphetamine is used by some college and high-school students as a study and test-taking aid. Based upon studies of self-reported illicit stimulant use among college students, performance-enhancing use, as opposed to abuse as a recreational drug, is the primary reason that students use stimulants. In contrast, at doses much higher than those medically prescribed, stimulants can interfere with working memory and cognitive control.
Amphetamine is also used by some professional, collegiate and high school athletes for its strong stimulant effects. However, in competitive sports, this form of use is generally prohibited by anti-doping regulations. At moderate therapeutic doses, amphetamine has been shown to increase physical strength, acceleration, stamina, and endurance, while reducing reaction time. Like methylphenidate and bupropion, amphetamine increases stamina and endurance in humans primarily through reuptake inhibition and effluxion of dopamine in the central nervous system. Similar to cognition enhancement, very high amphetamine doses can induce side effects that impair athletic performance, such as rhabdomyolysis and hyperthermia.
Amphetamine is considered to have a high potential for misuse. 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. In 2012, the US National Institute on Drug Abuse (NIDA) published the following prevalence statistics for adolescent use of prescription amphetamine and Adderall within the past year:
The side effects of Adderall are many and varied, but the amount of the drug consumed is the primary factor in determining the likelihood and severity of side effects. Adderall is currently approved for long-term therapeutic use by the United States Food and Drug Administration (USFDA). Recreational use of Adderall generally involves far larger doses and is therefore significantly more dangerous, involving a much greater risk of serious side effects.
At normal therapeutic doses, the physical side effects of Adderall vary widely by age and among individuals. Cardiovascular side effects can include irregular heartbeat (usually increased heart rate), hypertension (high blood pressure) or hypotension (low blood pressure) from a vasovagal response, and Raynaud's phenomenon (secondary). Sexual side effects in males may include erectile dysfunction, frequent erections, or prolonged erections. Other potential side effects include abdominal pain, acne, blurred vision, bruxism, diaphoresis, dry mouth, loss of appetite, nausea, reduced seizure threshold, tics, and weight loss. Dangerous physical side effects are quite rare in typical pharmaceutical doses.
Amphetamine stimulates the medullary respiratory centers, which increases the rate of respiration and produces deeper breaths. In a normal individual at therapeutic doses, amphetamine does not noticeably increase the rate of respiration or produce deeper breaths, but when respiration is already compromised, it may stimulate respiration. Amphetamine also induces contraction in the urinary bladder sphincter, which can result in difficulty urinating; however, this effect also makes amphetamine useful in treating enuresis and incontinence. In contrast, the effects of amphetamine on the gastrointestinal tract are unpredictable. Amphetamine may reduce gastrointestinal motility if intestinal activity is high, or increase motility if the smooth muscle of the tract are relaxed. Amphetamine also has a slight analgesic effect and can further enhance the analgesia of opiates.
Recent studies by the USFDA 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 medical use of amphetamine or other ADHD stimulants.
Common psychological effects of therapeutic doses can include alertness, apprehension, concentration, decreased sense of fatigue, mood swings (elevated mood or elation and euphoria followed by mild dysphoria), increased initiative, insomnia or wakefulness, self-confidence, and sociability. Less common or rare psychological effects that depend on the user's personality and current mental state include anxiety, change in libido, grandiosity, irritability, repetitive or obsessive behaviors, and restlessness. When heavily abused, amphetamine psychosis can occur. Although very rare, this psychosis can also occur at therapeutic doses during long-term therapy as a side effect. According to the USFDA, "there is no systematic evidence that stimulants cause aggressive behavior or hostility."
An amphetamine overdose is rarely fatal with appropriate care, but can lead to a number of different symptoms. A moderate overdose of Adderall may induce symptoms including: arrhythmia, confusion, dysuria, hypertension or hypotension, hyperthermia, hyperreflexia, myalgia, severe agitation, tachypnea, tremor, urinary hesitancy, and urinary retention. An extremely large overdose may produce symptoms such as adrenergic storm, amphetamine psychosis, anuria, cardiogenic shock, cerebral hemorrhage, circulatory collapse, hyperpyrexia, pulmonary hypertension, renal failure, rhabdomyolysis, serotonin syndrome, and stereotypy.[note 3] Fatal amphetamine poisoning usually also involves convulsions and coma.
Dependence, addiction and withdrawal
While addiction is a serious risk with heavy recreational amphetamine use, it is unlikely to arise from typical medical use. Tolerance is developed rapidly in amphetamine abuse; therefore, periods of extended use require increasing amounts of the drug in order to achieve the same effect. According to a Cochrane Collaboration review on withdrawal in highly dependent amphetamine and methamphetamine abusers, "when chronic heavy users abruptly discontinue amphetamine use, many report a time-limited withdrawal syndrome that occurs within 24 hours of their last dose." This review noted that withdrawal symptoms in chronic, high-dose users are frequent, occurring in up to 87.6% of cases, and persist for 3–4 weeks with a marked "crash" phase occurring during the first week. Amphetamine withdrawal symptoms can include fatigue, dysphoric mood, increased appetite, vivid or lucid dreams, hypersomnia or insomnia, increased movement or decreased movement, anxiety, and drug craving. The review suggested that withdrawal symptoms are associated with the degree of dependence, suggesting that therapeutic use would result in far milder discontinuation symptoms. The USFDA does not indicate the presence of withdrawal symptoms following discontinuation of amphetamine use after an extended period at therapeutic doses.
Abuse of Adderall can result in a stimulant psychosis that may present with a variety of symptoms (e.g., paranoia, hallucinations, delusions). A Cochrane Collaboration review on treatment for amphetamine, dextroamphetamine, and methamphetamine abuse-induced psychosis states that about 5–15% of users fail to recover completely. The same review asserts that, based upon at least one trial, antipsychotic medications effectively resolve the symptoms of acute amphetamine psychosis. Psychosis very rarely arises from therapeutic use.
Studies conducted on rodents and primates consistently observe long-term dopaminergic neurotoxicity with sufficiently high doses of amphetamine. The most widely accepted mechanism for neurotoxicity from high-dose amphetamine use in humans is indirect damage to dopamine terminals via autoxidation of dopamine, rather than direct toxicity from amphetamine. Nonetheless, in part due to clinical research ethics, there is no evidence that Adderall or racemic amphetamine is directly or even indirectly neurotoxic in humans, even at high doses. On the other hand, there is in vitro evidence that amphetamine is neurogenerative and neuroprotective from increasing the activity of the psychostimulant protein cocaine and amphetamine regulated transcript.
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
Mechanism of action
Pharmacodynamics of amphetamine enantiomers in a dopamine neuron
Adderall's active ingredients dextroamphetamine and levoamphetamine have identical pharmacodynamics, but their binding affinities to their biomolecular targets vary. Dextroamphetamine is a more potent agonist of the trace amine-associated receptor 1 (TAAR1) than levoamphetamine. Consequently, dextroamphetamine produces roughly two times more CNS stimulation than levoamphetamine; however, levoamphetamine has slightly greater cardiovascular and peripheral effects. Levoamphetamine provides Adderall with a quicker onset and longer-lasting effects than dextroamphetamine alone. It has been reported that certain children have a better clinical response to levoamphetamine.
Adderall is available as an instant-release (IR) and an extended-release (XR) drug. As of December 2013, ten different companies have produced generic Adderall IR at one point, while Teva Pharmaceutical Industries, Actavis, and Barr Pharmaceuticals currently manufacture generic Adderall XR. Shire plc, the company that held the original patent for Adderall and Adderall XR, still manufactures brand name Adderall XR, but not Adderall IR.
Richwood Pharmaceuticals, which later merged with Shire plc, introduced the current Adderall brand in 1996 as an instant-release tablet. 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.
The first generic version of Adderall IR was introduced to market in 2002. Later on, 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 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.
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.
- amphetamine aspartate monohydrate (racemic - i.e. 50% dextroamphetamine and 50% levoamphetamine)
- amphetamine sulfate (racemic)
- dextroamphetamine sulfate
- dextroamphetamine saccharate
Adderall is available in immediate release and extended release formulations. The immediate release formulation is indicated for use in ADHD and narcolepsy. The extended release formulation is only approved for the treatment of ADHD.
- In Canada, amphetamines are in Schedule I of the Controlled Drugs and Substances Act, and can only be obtained by prescription.
- In Japan, the use, production, and import of any medicine containing amphetamine are prohibited.
- In South Korea, amphetamines are prohibited.
- In Thailand, Amphetamines are classified as Type 1 Narcotics.
- In the United Kingdom, amphetamines are regarded as Class B drugs. The maximum penalty for unauthorized possession is five years in prison and an unlimited fine. The maximum penalty for illegal supply is 14 years in prison and an unlimited fine.
- In the United States, amphetamine is a Schedule II prescription drug, classified as a CNS (central nervous system) stimulant.
- Internationally (United Nations), amphetamine is in Schedule II of the Convention on Psychotropic Substances
- The US nonproprietary name of Adderall is dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine sulfate and amphetamine aspartate.
- Enantiomers are molecules that are "mirror images" of one another; they are structurally identical but of the opposite orientation, like left and right hands. The compound "amphetamine" (racemic amphetamine) refers to equal parts of the enantiomers, i.e. 50% levoamphetamine and 50% dextroamphetamine.
- "National Drug Code Amphetamine Search Results". National Drug Code Directory. United States Food and Drug Administration. Archived from the original on 7 February 2014. Retrieved 16 December 2013.
- "Adderall". Drugs.com. Retrieved 20 May 2013.
- "Adderall". The American Society of Health-System Pharmacists. Retrieved 24 May 2013.
- Schwartz A (2013-02-13). "Drowned in a Stream of Prescriptions". New York Times.
- Hart H, Radua J, Nakao T, Mataix-Cols D, Rubia K (February 2013). "Meta-analysis of functional magnetic resonance imaging studies of inhibition and attention in attention-deficit/hyperactivity disorder: exploring task-specific, stimulant medication, and age effects". JAMA Psychiatry 70 (2): 185–198. doi:10.1001/jamapsychiatry.2013.277. PMID 23247506.
- Spencer TJ, Brown A, Seidman LJ, Valera EM, Makris N, Lomedico A, Faraone SV, Biederman J (September 2013). "Effect of psychostimulants on brain structure and function in ADHD: a qualitative literature review of magnetic resonance imaging-based neuroimaging studies". J. Clin. Psychiatry 74 (9): 902–917. doi:10.4088/JCP.12r08287. PMC 3801446. PMID 24107764.
- Millichap JG (2010). "Chapter 3: Medications for ADHD". In Millichap JG. Attention Deficit Hyperactivity Disorder Handbook: A Physician's Guide to ADHD (2nd ed.). New York: Springer. p. 111–113. ISBN 9781441913968.
- Millichap JG (2010). Millichap JG, ed. Attention Deficit Hyperactivity Disorder Handbook: A Physician's Guide to ADHD (2nd ed.). New York: Springer. pp. 122–123. ISBN 9781441913968.
- Charach A, Dashti B, Carson P, Booker L, Lim CG, Lillie E, Yeung E, Ma J, Raina P, Schachar R (October 2011). "Attention Deficit Hyperactivity Disorder: Effectiveness of Treatment in At-Risk Preschoolers; Long-Term Effectiveness in All Ages; and Variability in Prevalence, Diagnosis, and Treatment". AHRQ Comparative Effectiveness Reviews (Agency for Healthcare Research and Quality) 44. PMID 22191110.
- John M. Eisenberg Center for Clinical Decisions and Communications Science (June 2012). "Treatment Options for ADHD in Children and Teens: A Review of Research for Parents and Caregivers". Comparative Effectiveness Review Summary Guides for Consumers. Agency for Healthcare Research and Quality. Retrieved 20 June 2013.
- "ADDERALL (CII)" (PDF). Food and Drug Administration. February 2007. Retrieved 2009-06-23.
- "Amphetamine/Dextroamphetamine (by mouth)". Micromedex consumer medication information. Truven Health Analytics. Retrieved 20 June 2013.
- "Medication Guide Adderall XR". US Food and Drug Administration (FDA). Retrieved 19 May 2013.
- Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 13: Higher Cognitive Function and Behavioral Control". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. p. 318. ISBN 9780071481274. "Therapeutic (relatively low) doses of psychostimulants, such as methylphenidate and amphetamine, improve performance on working memory tasks both in individuals with ADHD and in normal subjects. Positron emission tomography (PET) demonstrates that methylphenidate decreases regional cerebral blood flow in the dorsolateral prefrontal cortex and posterior parietal cortex while improving performance of a spacial working memory task. This suggests that cortical networks that normally process spatial working memory become more efficient in response to the drug. Both methylphenidate and amphetamines act by triggering the release of dopamine, norepinephrine, and serotonin, actions mediated via the plasma membrane transporters of these neurotransmitters and via the shared vesicular monoamine transporter (Chapter 6). Based on animal studies with micro-iontophoretic application of selective D1 dopamine receptor agonists (such as the partial agonist SKF38393 or the full agonist SKF81297) and antagonist (such as SCH23390), and clinical evidence in humans with ADHD, it is now believed that dopamine and norepinephrine, but not serotonin, produce the beneficial effects of stimulants on working memory. At abused (relatively high) doses, stimulants can interfere with working memory and cognitive control, as will be discussed below. 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, probably acting at different sites in the brain through indirect stimulation of dopamine and norepinephrine receptors."
- Twohey M (26 March 2006). "Pills become an addictive study aid". JS Online. Archived from the original on 15 August 2007. Retrieved 2 December 2007.
- 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): 1501–1510. doi:10.1592/phco.26.10.1501. PMC 1794223. PMID 16999660.
- Liddle DG, Connor DJ (June 2013). "Nutritional supplements and ergogenic AIDS". Prim. Care 40 (2): 487–505. doi:10.1016/j.pop.2013.02.009. PMID 23668655. "Amphetamines and caffeine are stimulants that increase alertness, improve focus, decrease reaction time, and delay fatigue, allowing for an increased intensity and duration of training...
Physiologic and performance effects
• Amphetamines increase dopamine/norepinephrine release and inhibit their reuptake, leading to central nervous system (CNS) stimulation
• Amphetamines seem to enhance athletic performance in anaerobic conditions 39 40
• Improved reaction time
• Increased muscle strength and delayed muscle fatigue
• Increased acceleration
• Increased alertness and attention to task"
- Bracken NM (January 2012). "National Study of Substance Use Trends Among NCAA College Student-Athletes". NCAA Publications. National Collegiate Athletic Association. Retrieved 8 October 2013.
- Roelands B, de Koning J, Foster C, Hettinga F, Meeusen R (May 2013). "Neurophysiological determinants of theoretical concepts and mechanisms involved in pacing". Sports Med. 43 (5): 301–311. doi:10.1007/s40279-013-0030-4. PMID 23456493.
- "Adderall XR Prescribing Information". United States Food and Drug Administration. December 2013. p. 11. Retrieved 30 December 2013.
- "Adderall XR Prescribing Information". United States Food and Drug Administration. December 2013. pp. 4–8. Retrieved 30 December 2013.
- "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.
- "National Institute on Drug Abuse. 2009. Stimulant ADHD Medications - Methylphenidate and Amphetamines". National Institute on Drug Abuse. Retrieved 27 February 2013.
- "Prescription Drugs". National Institute on Drug Abuse. Retrieved 3 November 2013.
- Westfall DP, Westfall TC (2010). "Miscellaneous Sympathomimetic Agonists". In Brunton LL, Chabner BA, Knollmann BC. Goodman & Gilman's Pharmacological Basis of Therapeutics (12th ed.). New York: McGraw-Hill. ISBN 9780071624428.
- Vitiello B (April 2008). "Understanding the risk of using medications for attention deficit hyperactivity disorder with respect to physical growth and cardiovascular function". Child Adolesc. Psychiatr. Clin. N. Am. 17 (2): 459–474. doi:10.1016/j.chc.2007.11.010. PMC 2408826. PMID 18295156.
- "FDA Drug Safety Communication: Safety Review Update of Medications used to treat Attention-Deficit/Hyperactivity Disorder (ADHD) in children and young adults". United States Food and Drug Administration. 20 December 2011. Retrieved 4 November 2013.
- Cooper WO, Habel LA, Sox CM, Chan KA, Arbogast PG, Cheetham TC, Murray KT, Quinn VP, Stein CM, Callahan ST, Fireman BH, Fish FA, Kirshner HS, O'Duffy A, Connell FA, Ray WA (November 2011). "ADHD drugs and serious cardiovascular events in children and young adults". N. Engl. J. Med. 365 (20): 1896–1904. doi:10.1056/NEJMoa1110212. PMID 22043968.
- "FDA Drug Safety Communication: Safety Review Update of Medications used to treat Attention-Deficit/Hyperactivity Disorder (ADHD) in adults". United States Food and Drug Administration. 15 December 2011. Retrieved 4 November 2013.
- Habel LA, Cooper WO, Sox CM, Chan KA, Fireman BH, Arbogast PG, Cheetham TC, Quinn VP, Dublin S, Boudreau DM, Andrade SE, Pawloski PA, Raebel MA, Smith DH, Achacoso N, Uratsu C, Go AS, Sidney S, Nguyen-Huynh MN, Ray WA, Selby JV (December 2011). "ADHD medications and risk of serious cardiovascular events in young and middle-aged adults". JAMA 306 (24): 2673–2683. doi:10.1001/jama.2011.1830. PMC 3350308. PMID 22161946.
- Montgomery KA (June 2008). "Sexual desire disorders". Psychiatry (Edgmont) 5 (6): 50–55. PMC 2695750. PMID 19727285.
- O'Connor PG (February 2012). "Amphetamines". Merck Manual for Health Care Professionals. Merck. Retrieved 8 May 2012.
- Shoptaw SJ, Kao U, Ling W (2009). "Treatment for amphetamine psychosis". In Shoptaw SJ, Ali R. Cochrane Database Syst. Rev. (1): 2–8. doi:10.1002/14651858.CD003026.pub3. PMID 19160215. "A minority of individuals who use amphetamines develop full-blown psychosis requiring care at emergency departments or psychiatric hospitals. In such cases, symptoms of amphetamine psychosis commonly include paranoid and persecutory delusions as well as auditory and visual hallucinations in the presence of extreme agitation. More common (about 18%) is for frequent amphetamine users to report psychotic symptoms that are sub-clinical and that do not require high-intensity intervention...
About 5-15% of the users who develop an amphetamine psychosis fail to recover completely (Hofmann 1983)...
Findings from one trial indicate use of antipsychotic medications effectively resolves symptoms of acute amphetamine psychosis."
- Spiller HA, Hays HL, Aleguas A (June 2013). "Overdose of drugs for attention-deficit hyperactivity disorder: clinical presentation, mechanisms of toxicity, and management". CNS Drugs 27 (7): 531–543. doi:10.1007/s40263-013-0084-8. PMID 23757186.
- Albertson TE (2011). "Amphetamines". In Olson KR, Anderson IB, Benowitz NL, Blanc PD, Kearney TE, Kim-Katz SY, Wu AHB. Poisoning & Drug Overdose (6th ed.). New York: McGraw-Hill Medical. pp. 77–79. ISBN 9780071668330.
- Oskie SM, Rhee JW (11 February 2011). "Amphetamine Poisoning". Emergency Central. Unbound Medicine. Retrieved 11 June 2013.
- Isbister GK, Buckley NA, Whyte IM (September 2007). "Serotonin toxicity: a practical approach to diagnosis and treatment". Med. J. Aust. 187 (6): 361–365. PMID 17874986.
- Stolerman IP (2010). Stolerman IP, ed. Encyclopedia of Psychopharmacology. Berlin; London: Springer. p. 78. ISBN 9783540686989. "Although [substituted amphetamines] are also used as recreational drugs, with important neurotoxic consequences when abused, addiction is not a high risk when therapeutic doses are used as directed."
- "Amphetamines: Drug Use and Abuse". Merck Manual Home Edition. Merck. February 2003. Archived from the original on 17 February 2007. Retrieved 28 February 2007.
- Shoptaw SJ, Kao U, Heinzerling K, Ling W (2009). "Treatment for amphetamine withdrawal". In Shoptaw SJ. Cochrane Database Syst. Rev. (2): CD003021. doi:10.1002/14651858.CD003021.pub2. PMID 19370579. "
The prevalence of this withdrawal syndrome is extremely common (Cantwell 1998; Gossop 1982) with 87.6% of 647 individuals with amphetamine dependence reporting six or more signs of amphetamine withdrawal listed in the DSM when the drug is not available (Schuckit 1999)...Withdrawal symptoms typically present within 24 hours of the last use of amphetamine, with a withdrawal syndrome involving two general phases that can last 3 weeks or more. The first phase of this syndrome is the initial “crash” that resolves within about a week (Gossop 1982;McGregor 2005)..."
- "Adderall IR Prescribing Information". United States Food and Drug Administration. March 2007. Retrieved 4 November 2013.
- "Dexedrine Medication Guide". United States Food and Drug Administration. May 2013. Retrieved 4 November 2013.
- "Adderall XR Prescribing Information". United States Food and Drug Administration. December 2013. Retrieved 30 December 2013.
- Hofmann FG (1983). A Handbook on Drug and Alcohol Abuse: The Biomedical Aspects (2nd ed.). New York: Oxford University Press. p. 329. ISBN 9780195030570.
- "Adderall XR Prescribing Information". United States Food and Drug Administration. December 2013. pp. 4–6. Retrieved 30 December 2013.
- Advokat C (2007). "Update on amphetamine neurotoxicity and its relevance to the treatment of ADHD". J. Atten. Disord. 11 (1): 8–16. doi:10.1177/1087054706295605. PMID 17606768. "There is substantial evidence that when [substituted amphetamines] are administered to nonhuman animals, in a manner that mimics patterns of abuse in humans (high doses over several days), they are neurotoxic to biogenic amine neurotransmitter systems in rodents and primates (Fuller, 1985; Gibb et al., 1999; O’Dell, Weihmuller, & Marshall, 1991; Ricaurte, Guillery, Seiden, Schuster, & Moore, 1982; Seiden & Sabol, 1996; Sonsalla, Jochnowitz, Zeevalk, Postveen, & Hall, 1996; Villemagne et al., 1998; Woolverton, Ricaurte, Forno, & Seiden, 1989)...somewhat surprisingly, the “effects of repeated therapeutic doses of amphetamine on DAT density in living human brain are unknown”"
- Sulzer D, Zecca L (February 2000). "Intraneuronal dopamine-quinone synthesis: a review". Neurotox. Res. 1 (3): 181–195. doi:10.1007/BF03033289. PMID 12835101.
- Miyazaki I, Asanuma M (June 2008). "Dopaminergic neuron-specific oxidative stress caused by dopamine itself". Acta Med. Okayama 62 (3): 141–150. PMID 18596830.
- 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): 123–142. doi:10.1038/mp.2008.90. PMC 2670101. PMID 18698321.
- Malenka RC, Nestler EJ, Hyman SE (2009). "15". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. p. 370. ISBN 9780071481274. "Unlike cocaine and amphetamine, methamphetamine is directly toxic to midbrain dopamine neurons."
- Biomolecular Interactions and Pathways. "Amphetamine". PubChem Compound. National Center for Biotechnology Information. Retrieved 13 October 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.
- Lewin AH, Miller GM, Gilmour B (December 2011). "Trace amine-associated receptor 1 is a stereoselective binding site for compounds in the amphetamine class". Bioorg. Med. Chem. 19 (23): 7044–7048. doi:10.1016/j.bmc.2011.10.007. PMC 3236098. PMID 22037049.
- Smith R C, Davis J M (June 1977). "Comparative effects of d-amphetamine, l-amphetamine, and methylphenidate on mood in man". Psychopharmacology 53 (1): 1–12. PMID 407607.
- 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.
- "APPROVAL LETTER". United States Food and Drug Administration. Retrieved 30 December 2013.
- "Barr and Shire Sign Three Agreements". August 2006 News Archives. GenericsWeb. Retrieved 30 December 2013. "WOODCLIFF LAKE, N.J., Aug. 14 /PRNewswire-FirstCall/ -- Barr Pharmaceuticals, Inc. today announced that its subsidiary Duramed Pharmaceuticals, Inc. and Shire plc have signed a Product Acquisition Agreement for ADDERALL(R) (immediate-release mixed amphetamine salts) tablets and a Product Development Agreement for six proprietary products, and that its subsidiary Barr Laboratories, Inc. (Barr) has signed a Settlement and License Agreement relating to the resolution of two pending patent cases involving Shire's ADDERALL XR(R) ..."
- "Teva Completes Acquisition of Barr". Drugs.com. Retrieved 2011-10-31.
- "Teva sells 1st generic of Adderall XL in US". Forbes Magazine. Associated Press. 2 April 2009. Archived from the original on 9 April 2009. Retrieved 22 April 2009.
- 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).
- "REGULATORY NEWS: Richwood's Adderall". Health News Daily. 22 Feb 1996. Retrieved 29 May 2013.
- Miller GM (January 2011). "The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity". J. Neurochem. 116 (2): 164–76. doi:10.1111/j.1471-4159.2010.07109.x. PMC 3005101. PMID 21073468.
- The Minister and Attorney General. "Controlled Drugs and Substances Act". Justice Laws Website. Government of Canada.
- "Importing or Bringing Medication into Japan for Personal Use". Japan Ministry of Health, Labour and Welfare.
- "Thailand Law". Government of Thailand. Retrieved 2013-05-23.
- "Class A, B and C drugs". Home Office, Government of the United Kingdom. Archived from the original on 4 August 2007. Retrieved 23 July 2007.
- Substance Abuse and Mental Health Services Administration. "Trends in Methamphetamine/Amphetamine Admissions to Treatment: 1993–2003". The Drug and Alcohol Services Information System (DASIS) Report. United States Department of Health and Human Services. Retrieved 28 February 2007.
- 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.
- International Narcotics Control Board. "List of psychotropic substances under international control" (PDF). Vienna: United Nations. Archived from the original on 5 December 2005. Retrieved 19 November 2005.