Chemistry:Adderall

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Short description: Drug mixture used mainly to treat ADHD and narcolepsy
Amphetamine/dextroamphetamine
salt mixture (1:1)[note 1]
an image of the amphetamine skeletal formula
a 3d image of the dextroamphetamine compound found in Adderall
Top: racemic amphetamine skeleton
Bottom: (D)-amphetamine ball-and-stick model
Combination of
amphetamine aspartate monohydrate25% – stimulant
(12.5% levo; 12.5% dextro)
amphetamine sulfate25% – stimulant
(12.5% levo; 12.5% dextro)
dextroamphetamine saccharate25% – stimulant
(0% levo; 25% dextro)
dextroamphetamine sulfate25% – stimulant
(0% levo; 25% dextro)
Clinical data
Trade namesAdderall, Adderall XR, Mydayis
Other namesMixed amphetamine salts; MAS
AHFS/Drugs.comMonograph
MedlinePlusa601234
License data
Dependence
liability		Moderate[3][4] – high[5][6][7]
Routes of
administration		By mouth, insufflation, rectal, sublingual
Drug classCNS stimulant
ATC code
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
  (verify)

Adderall and Mydayis[8] are trade names[note 2] for a combination drug called mixed amphetamine salts containing four salts of amphetamine. The mixture is composed of equal parts racemic amphetamine and dextroamphetamine, which produces a (3:1) ratio between dextroamphetamine and levoamphetamine, the two enantiomers of amphetamine. Both enantiomers are stimulants, but differ enough to give Adderall an effects profile distinct from those of racemic amphetamine or dextroamphetamine,[1][2] which are marketed as Evekeo and Dexedrine/Zenzedi, respectively.[1][10][11] Adderall is used in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. It is also used illicitly as an athletic performance enhancer, cognitive enhancer, appetite suppressant, and recreationally as a euphoriant. It is a central nervous system (CNS) stimulant of the phenethylamine class.[1]

Adderall is generally well-tolerated and effective in treating symptoms of ADHD and narcolepsy. At therapeutic doses, Adderall causes emotional and cognitive effects such as euphoria, change in sex drive, increased wakefulness, and improved cognitive control. At these doses, it induces physical effects such as a faster reaction time, fatigue resistance, and increased muscle strength. In contrast, much larger doses of Adderall can impair cognitive control, cause rapid muscle breakdown, provoke panic attacks, or induce a psychosis (e.g., paranoia, delusions, hallucinations). The side effects of Adderall vary widely among individuals, but most commonly include insomnia, dry mouth, loss of appetite, and weight loss. The risk of developing an addiction or dependence is insignificant when Adderall is used as prescribed at fairly low daily doses, such as those used for treating ADHD; however, the routine use of Adderall in larger daily doses poses a significant risk of addiction or dependence due to the pronounced reinforcing effects that are present at high doses. Recreational doses of amphetamine are generally much larger than prescribed therapeutic doses, and carry a far greater risk of serious adverse effects.[sources 1]

The two amphetamine enantiomers that compose Adderall (levoamphetamine and dextroamphetamine) alleviate the symptoms of ADHD and narcolepsy by increasing the activity of the neurotransmitters norepinephrine and dopamine in the brain, which results in part from their interactions with human trace amine-associated receptor 1 (hTAAR1) and vesicular monoamine transporter 2 (VMAT2) in neurons. Dextroamphetamine is a more potent Central nervous system (CNS) stimulant than levoamphetamine, but levoamphetamine has slightly stronger cardiovascular and peripheral effects and a longer elimination half-life than dextroamphetamine. The levoamphetamine component of Adderall has been reported to improve the treatment response in some individuals relative to dextroamphetamine alone. Adderall's active ingredient, amphetamine, shares many chemical and pharmacological properties with the human trace amines, particularly phenethylamine and N-methylphenethylamine, the latter of which is a positional isomer of amphetamine.[sources 2] In 2021, Adderall was the seventeenth most commonly prescribed medication in the United States, with more than 30 million prescriptions.[31][32]

Uses

30 Adderall XR 10 mg capsules
30 capsules of 10 mg Adderall XR
Adderall 20 mg tablets
A group of 20 mg Adderall tablets, some broken in half, with a lengthwise-folded US dollar bill along the bottom (3.07 inches; 7.8 cm) for size comparison

Medical

Part of this section is transcluded from Amphetamine. (edit | history)

Adderall is commonly used to treat attention deficit hyperactivity disorder (ADHD) and narcolepsy (a sleep disorder).[33][13] {{#section-h:Amphetamine|Medical}}

Available forms

Adderall is available as immediate-release (IR) tablets or two different extended-release (XR) formulations.[13][34] The extended-release capsules are generally used in the morning.[35] A shorter, 12-hour extended-release formulation is available under the brand Adderall XR and is designed to provide a therapeutic effect and plasma concentrations identical to taking two doses four hours apart.[34] The longer extended-release formulation, approved for 16 hours, is available under the brand Mydayis. In the United States, the immediate and extended-release formulations of Adderall are both available as generic drugs.[36][37]

Enhancing performance

Part of this section is transcluded from Amphetamine. (edit | history)

{{#section-h:Amphetamine|Enhancing performance}}

Adderall has been banned in the National Football League (NFL), Major League Baseball (MLB), National Basketball Association (NBA), and the National Collegiate Athletics Association (NCAA).[38] In leagues such as the NFL, there is a very rigorous process required to obtain an exemption to this rule even when the athlete has been medically prescribed the drug by their physician.[38]

Recreational

Adderall has high potential for misuse as a recreational drug.[39][40][41] Adderall tablets can either be swallowed, crushed and snorted, or dissolved in water and injected.[42] Injection into the bloodstream can be dangerous because insoluble fillers within the tablets can block small blood vessels.[42]

Many postsecondary students have reported using Adderall for study purposes in different parts of the developed world.[41] Among these students, some of the risk factors for misusing ADHD stimulants recreationally include: possessing deviant personality characteristics (i.e., exhibiting delinquent or deviant behavior), inadequate accommodation of disability, basing one's self-worth on external validation, low self-efficacy, earning poor grades, and having an untreated mental health disorder.[41]

Contraindications

This section is an excerpt from Amphetamine § Contraindications[ edit ]

Adverse effects

Part of this section is transcluded from Amphetamine. (edit | history)

The adverse side effects of Adderall are many and varied, but the amount of substance consumed is the primary factor in determining the likelihood and severity of side effects.[16][27] Adderall is currently approved for long-term therapeutic use by the USFDA.[16] Recreational use of Adderall generally involves far larger doses and is therefore significantly more dangerous, involving a much greater risk of serious adverse drug effects than dosages used for therapeutic purposes.[27] {{#section-h:Amphetamine|Adverse effects}}

Overdose

This section is an excerpt from Amphetamine § Overdose[ edit ]

Interactions

  • Monoamine oxidase inhibitors (MAOIs) taken with amphetamine may result in a hypertensive crisis if taken within two weeks after last use of an MAOI type drug.[43]
  • Inhibitors of enzymes that directly metabolize amphetamine (particularly CYP2D6 and FMO3) will prolong the elimination of amphetamine and increase drug effects.[43][44][45]
  • Serotonergic drugs (such as most antidepressants) co-administered with amphetamine increases the risk of serotonin syndrome.[45]
  • Stimulants and antidepressants (sedatives and depressants) may increase (decrease) the drug effects of amphetamine, and vice versa.[43]
  • Gastrointestinal and urinary pH affect the absorption and elimination of amphetamine, respectively. Gastrointestinal alkalinizing agents increase the absorption of amphetamine. Urinary alkalinizing agents increase concentration of non-ionized species, decreasing urinary excretion.[43]
  • Proton-pump inhibitors (PPIs) modify the absorption of Adderall XR and Mydayis.[43][45]
  • Zinc supplementation may reduce the minimum effective dose of amphetamine when it is used for the treatment of ADHD.[note 3][49]

Pharmacology

Pharmacodynamics of amphetamine in a dopamine neuron
v · d · e
A pharmacodynamic model of amphetamine and TAAR1
via AADC
The image above contains clickable links
Amphetamine enters the presynaptic neuron across the neuronal membrane or through DAT.[24] Once inside, it binds to TAAR1 or enters synaptic vesicles through VMAT2.[24][25] When amphetamine enters synaptic vesicles through VMAT2, it collapses the vesicular pH gradient, which in turn causes dopamine to be released into the cytosol (light tan-colored area) through VMAT2.[25][50] When amphetamine binds to TAAR1, it reduces the firing rate of the dopamine neuron via potassium channels and activates protein kinase A (PKA) and protein kinase C (PKC), which subsequently phosphorylate DAT.[24][51][52] PKA-phosphorylation causes DAT to withdraw into the presynaptic neuron (internalize) and cease transport.[24] PKC-phosphorylated DAT may either operate in reverse or, like PKA-phosphorylated DAT, internalize and cease transport.[24] Amphetamine is also known to increase intracellular calcium, an effect which is associated with DAT phosphorylation through a CAMKIIα-dependent pathway, in turn producing dopamine efflux.[53][54]

Mechanism of action

Amphetamine, the active ingredient of Adderall, works primarily by increasing the activity of the neurotransmitters dopamine and norepinephrine in the brain.[23][55] It also triggers the release of several other hormones (e.g., epinephrine) and neurotransmitters (e.g., serotonin and histamine) as well as the synthesis of certain neuropeptides (e.g., cocaine and amphetamine regulated transcript (CART) peptides).[25][56] Both active ingredients of Adderall, dextroamphetamine and levoamphetamine, bind to the same biological targets,[27][28] but their binding affinities (that is, potency) differ somewhat.[27][28] Dextroamphetamine and levoamphetamine are both potent full agonists (activating compounds) of trace amine-associated receptor 1 (TAAR1) and interact with vesicular monoamine transporter 2 (VMAT2), with dextroamphetamine being the more potent agonist of TAAR1.[28] Consequently, dextroamphetamine produces more CNS stimulation than levoamphetamine;[28][57] however, levoamphetamine has slightly greater cardiovascular and peripheral effects.[27] It has been reported that certain children have a better clinical response to levoamphetamine.[29][30]

In the absence of amphetamine, VMAT2 will normally move monoamines (e.g., dopamine, histamine, serotonin, norepinephrine, etc.) from the intracellular fluid of a monoamine neuron into its synaptic vesicles, which store neurotransmitters for later release (via exocytosis) into the synaptic cleft.[25] When amphetamine enters a neuron and interacts with VMAT2, the transporter reverses its direction of transport, thereby releasing stored monoamines inside synaptic vesicles back into the neuron's intracellular fluid.[25] Meanwhile, when amphetamine activates TAAR1, the receptor causes the neuron's cell membrane-bound monoamine transporters (i.e., the dopamine transporter, norepinephrine transporter, or serotonin transporter) to either stop transporting monoamines altogether (via transporter internalization) or transport monoamines out of the neuron;[24] in other words, the reversed membrane transporter will push dopamine, norepinephrine, and serotonin out of the neuron's intracellular fluid and into the synaptic cleft.[24] In summary, by interacting with both VMAT2 and TAAR1, amphetamine releases neurotransmitters from synaptic vesicles (the effect from VMAT2) into the intracellular fluid where they subsequently exit the neuron through the membrane-bound, reversed monoamine transporters (the effect from TAAR1).[24][25]

Pharmacokinetics

This section is transcluded from Amphetamine#Pharmacokinetics. (edit | history)

{{#section-h:Amphetamine|Pharmacokinetics}}

Pharmacomicrobiomics

This section is an excerpt from Amphetamine § Pharmacomicrobiomics[ edit ]

Related endogenous compounds

This section is transcluded from Amphetamine#Related endogenous compounds. (edit | history)

{{#section-h:Amphetamine|Related endogenous compounds}}

History

The pharmaceutical company Rexar reformulated their popular weight loss drug Obetrol following its mandatory withdrawal from the market in 1973 under the Kefauver Harris Amendment to the Federal Food, Drug, and Cosmetic Act due to the results of the Drug Efficacy Study Implementation (DESI) program (which indicated a lack of efficacy). The new formulation simply replaced the two methamphetamine components with dextroamphetamine and amphetamine components of the same weight (the other two original dextroamphetamine and amphetamine components were preserved), preserved the Obetrol branding, and despite it lacking FDA approval, it still made it onto the market and was marketed and sold by Rexar for many years.

In 1994, Richwood Pharmaceuticals acquired Rexar and began promoting Obetrol as a treatment for ADHD (and later narcolepsy as well), now marketed under the new brand name of Adderall, a contraction of the phrase "A.D.D. for All" intended to convey that "it was meant to be kind of an inclusive thing" for marketing purposes.[58] The FDA cited the company for numerous significant CGMP violations related to Obetrol discovered during routine inspections following the acquisition (including issuing a formal warning letter for the violations), then later issued a second formal warning letter to Richwood Pharmaceuticals specifically due to violations of "the new drug and misbranding provisions of the FD&C Act". Following extended discussions with Richwood Pharmaceuticals regarding the resolution of a large number of issues related to the company's numerous violations of FDA regulations, the FDA formally approved the first Obetrol labeling/sNDA revisions in 1996, including a name change to Adderall and a restoration of its status as an approved drug product.[59][60] In 1997 Richwood Pharmaceuticals was acquired by Shire Pharmaceuticals in a $186 million transaction.[58]

Richwood Pharmaceuticals, which later merged with Shire plc, introduced the current Adderall brand in 1996 as an instant-release tablet.[61] In 2006, Shire agreed to sell rights to the Adderall name for the instant-release form of the medication to Duramed Pharmaceuticals.[62] DuraMed Pharmaceuticals was acquired by Teva Pharmaceuticals in 2008 during their acquisition of Barr Pharmaceuticals, including Barr's Duramed division.[63]

The first generic version of Adderall IR was introduced to market in 2002.[9] Later on, Barr and Shire reached a settlement agreement permitting Barr to offer a generic form of the extended-release drug beginning in April 2009.[9][64]

Commercial formulation

Chemically, Adderall is a mixture of four amphetamine salts; specifically, it is composed of equal parts (by mass) of amphetamine aspartate monohydrate, amphetamine sulfate, dextroamphetamine sulfate, and dextroamphetamine saccharate.[34] This drug mixture has slightly stronger CNS effects than racemic amphetamine due to the higher proportion of dextroamphetamine.[24][27] Adderall is produced as both an immediate-release (IR) and extended-release (XR) formulation.[9][13][34] (As of December 2013), ten different companies produced generic Adderall IR, while Teva Pharmaceutical Industries, Actavis, and Barr Pharmaceuticals manufactured generic Adderall XR.[9] (As of 2013), Shire plc, the company that held the original patent for Adderall and Adderall XR, still manufactured brand name Adderall XR, but not Adderall IR.[9]

Comparison to other formulations

Adderall is one of several formulations of pharmaceutical amphetamine, including singular or mixed enantiomers and as an enantiomer prodrug. The table below compares these medications (based on U.S.-approved forms):

Amphetamine base in marketed amphetamine medications
drug formula molecular mass
[note 4] 		amphetamine base
[note 5] 		amphetamine base
in equal doses 		doses with
equal base
content
[note 6]
(g/mol) (percent) (30 mg dose)
total base total dextro- levo- dextro- levo-
dextroamphetamine sulfate[66][67] (C9H13N)2•H2SO4
368.49
270.41
73.38%
73.38%
—
22.0 mg
—
30.0 mg
amphetamine sulfate[68] (C9H13N)2•H2SO4
368.49
270.41
73.38%
36.69%
36.69%
11.0 mg
11.0 mg
30.0 mg
Adderall
62.57%
47.49%
15.08%
14.2 mg
4.5 mg
35.2 mg
25% dextroamphetamine sulfate[66][67] (C9H13N)2•H2SO4
368.49
270.41
73.38%
73.38%
—
25% amphetamine sulfate[68] (C9H13N)2•H2SO4
368.49
270.41
73.38%
36.69%
36.69%
25% dextroamphetamine saccharate[69] (C9H13N)2•C6H10O8
480.55
270.41
56.27%
56.27%
—
25% amphetamine aspartate monohydrate[70] (C9H13N)•C4H7NO4•H2O
286.32
135.21
47.22%
23.61%
23.61%
lisdexamfetamine dimesylate[71] C15H25N3O•(CH4O3S)2
455.49
135.21
29.68%
29.68%
—
8.9 mg
—
74.2 mg
amphetamine base suspension[note 7][72] C9H13N
135.21
135.21
100%
76.19%
23.81%
22.9 mg
7.1 mg
22.0 mg

Society and culture

Legal status

  • In Canada, amphetamines are in Schedule I of the Controlled Drugs and Substances Act, and can only be obtained by prescription.[73]
  • In Japan, the use, production, and import of any medicine containing amphetamines is prohibited.[74]
  • In South Korea, amphetamines are prohibited.[75]
  • In Taiwan, amphetamines including Adderall are Schedule 2 drugs with a minimum five years prison term for possession.[76] Only Ritalin can be legally prescribed for treatment of ADHD [citation needed].
  • In Thailand, amphetamines are classified as Type 1 Narcotics.[77]
  • 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.[78]
  • In the United States, amphetamine is a Schedule II prescription drug, classified as a central nervous system (CNS) stimulant.[79]
  • Internationally, amphetamine is in Schedule II of the Convention on Psychotropic Substances.[80][81]

Shortages

In February 2023, news organizations began reporting on shortages of Adderall in the United States that have lasted for over five months.[82][83] The Food and Drug Administration first reported the shortage in October 2022.[84] In May 2023, 7 months into the shortage, the Food and Drug Administration commissioner Robert Califf stated that "a number of generic drugs are in shortage at any given time because there's not enough profit". He points out that Adderall is a special case because it is a controlled substance and the amount available for prescription is controlled by the Drug Enforcement Administration. He also faults a "tremendous increase in prescribing" due to virtual prescribing and general overprescribing and overdiagnosing, adding that "if only the people that needed these drugs got them, there probably wouldn't be a [stimulant medication] shortage".[85][86]

Notes

  1. ↑ Salts of racemic amphetamine and dextroamphetamine are mixed in a (1:1) ratio to produce this drug. Because the racemate is composed of equal parts dextroamphetamine and levoamphetamine, this drug can also be described as a mixture of the D and (L)-enantiomers of amphetamine in a (3:1) ratio, although none of the components of the mixture are levoamphetamine salts.[1][2]
  2. ↑ The trade name Adderall is used primarily throughout this article because the four-salt composition of the drug makes its nonproprietary name (dextroamphetamine sulfate 25%, dextroamphetamine saccharate 25%, amphetamine sulfate 25%, and amphetamine aspartate 25%) excessively lengthy.[9] Mydayis is a relatively new trade name that is not commonly used to refer generally to the mixture.[8]
  3. ↑ The human dopamine transporter contains a high affinity extracellular zinc binding site which, upon zinc binding, inhibits dopamine reuptake and amplifies amphetamine-induced dopamine efflux in vitro.[46][47][48] The human serotonin transporter and norepinephrine transporter do not contain zinc binding sites.[48]
  4. ↑ For uniformity, molecular masses were calculated using the Lenntech Molecular Weight Calculator[65] and were within 0.01g/mol of published pharmaceutical values.
  5. ↑ Amphetamine base percentage = molecular massbase / molecular masstotal. Amphetamine base percentage for Adderall = sum of component percentages / 4.
  6. ↑ dose = (1 / amphetamine base percentage) × scaling factor = (molecular masstotal / molecular massbase) × scaling factor. The values in this column were scaled to a 30 mg dose of dextroamphetamine sulfate. Due to pharmacological differences between these medications (e.g., differences in the release, absorption, conversion, concentration, differing effects of enantiomers, half-life, etc.), the listed values should not be considered equipotent doses.
  7. ↑ This product (Dyanavel XR) is an oral suspension (i.e., a drug that is suspended in a liquid and taken by mouth) that contains 2.5 mg/mL of amphetamine base.[72] The amphetamine base contains dextro- to levo-amphetamine in a ratio of 3.2:1,[72] which is approximately the ratio in Adderall. The product uses an ion exchange resin to achieve extended release of the amphetamine base.[72]
Image legend

Reference notes

  1. ↑ [12][13][14][15][16][17][18][19][20][21][22]
  2. ↑ [23][24][25][26][27][28][29][30]

References

  1. ↑ 1.0 1.1 1.2 1.3 "Amphetamine, past and present--a pharmacological and clinical perspective". Journal of Psychopharmacology 27 (6): 479–496. June 2013. doi:10.1177/0269881113482532. PMID 23539642. 
  2. ↑ 2.0 2.1 "Adderall produces increased striatal dopamine release and a prolonged time course compared to amphetamine isomers". Psychopharmacology 191 (3): 669–677. April 2007. doi:10.1007/s00213-006-0550-9. PMID 17031708. 
  3. ↑ "Understanding the risk of using medications for attention deficit hyperactivity disorder with respect to physical growth and cardiovascular function". Child and Adolescent Psychiatric Clinics of North America 17 (2): 459–74, xi. April 2008. doi:10.1016/j.chc.2007.11.010. PMID 18295156. 
  4. ↑ "European guidelines on managing adverse effects of medication for ADHD". European Child & Adolescent Psychiatry 20 (1): 17–37. January 2011. doi:10.1007/s00787-010-0140-6. PMID 21042924. 
  5. ↑ "Evaluation of risks associated with short- and long-term psychostimulant therapy for treatment of ADHD in children". Expert Opinion on Drug Safety 3 (2): 93–100. March 2004. doi:10.1517/14740338.3.2.93. PMID 15006715. 
  6. ↑ "The potential for misuse and abuse of medications in ADHD: a review". Postgraduate Medicine 126 (5): 64–81. September 2014. doi:10.3810/pgm.2014.09.2801. PMID 25295651. 
  7. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named Stahl's Essential Psychopharmacology
  8. ↑ 8.0 8.1 "Shire launches new ADHD drug Mydayis as it weighs a neuroscience exit". Fierce Pharma (Questex LLC). 28 August 2017. https://www.fiercepharma.com/marketing/shire-launches-new-adhd-drug-mydayis-as-it-weighs-a-neuroscience-exit. 
  9. ↑ 9.0 9.1 9.2 9.3 9.4 9.5 "National Drug Code Amphetamine Search Results". United States Food and Drug Administration. http://www.accessdata.fda.gov/scripts/cder/ndc/results.cfm?beginrow=1&numberperpage=160&searchfield=amphetamine&searchtype=ActiveIngredient&OrderBy=ProprietaryName. 
  10. ↑ "Pharmacology". Arbor Pharmaceuticals, LLC. https://www.evekeo.com/hcp/evekeo-pharmacology. 
  11. ↑ "Prescribing Information & Medication Guide". Arbor Pharmaceuticals LLC. https://zenzedi.com/docs/PIandMedicationGuide.pdf. 
  12. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named Libido
  13. ↑ 13.0 13.1 13.2 13.3 "Adderall- dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate, and amphetamine sulfate tablet". Teva Pharmaceuticals USA, Inc.. 8 November 2019. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f22635fe-821d-4cde-aa12-419f8b53db81. 
  14. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named Malenka_2009
  15. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named Ergogenics
  16. ↑ 16.0 16.1 16.2 Cite error: Invalid <ref> tag; no text was provided for refs named FDA
  17. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named Cochrane
  18. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named Stimulant Misuse
  19. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named NHMH_3e-Addiction doses
  20. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named Addiction risk
  21. ↑ Encyclopedia of Psychopharmacology. Berlin, Germany; London, England: Springer. 2010. p. 78. ISBN 9783540686989. 
  22. ↑ "Monoamine transporters and psychostimulant addiction". Biochemical Pharmacology 75 (1): 196–217. January 2008. doi:10.1016/j.bcp.2007.08.003. PMID 17825265. 
  23. ↑ 23.0 23.1 "Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin". Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York, USA: McGraw-Hill Medical. 2009. pp. 154–157. ISBN 9780071481274. 
  24. ↑ 24.0 24.1 24.2 24.3 24.4 24.5 24.6 24.7 24.8 24.9 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. PMID 21073468. 
  25. ↑ 25.0 25.1 25.2 25.3 25.4 25.5 25.6 "VMAT2: a dynamic regulator of brain monoaminergic neuronal function interacting with drugs of abuse". Ann. N. Y. Acad. Sci. 1216 (1): 86–98. January 2011. doi:10.1111/j.1749-6632.2010.05906.x. PMID 21272013. Bibcode: 2011NYASA1216...86E. "VMAT2 is the CNS vesicular transporter for not only the biogenic amines DA, NE, EPI, 5-HT, and HIS, but likely also for the trace amines TYR, PEA, and thyronamine (THYR) ... [Trace aminergic] neurons in mammalian CNS would be identifiable as neurons expressing VMAT2 for storage, and the biosynthetic enzyme aromatic amino acid decarboxylase (AADC).". 
  26. ↑ Broadley KJ (March 2010). "The vascular effects of trace amines and amphetamines". Pharmacology & Therapeutics 125 (3): 363–375. doi:10.1016/j.pharmthera.2009.11.005. PMID 19948186. 
  27. ↑ 27.0 27.1 27.2 27.3 27.4 27.5 27.6 Cite error: Invalid <ref> tag; no text was provided for refs named Westfall
  28. ↑ 28.0 28.1 28.2 28.3 28.4 "Trace amine-associated receptor 1 is a stereoselective binding site for compounds in the amphetamine class". Bioorg. Med. Chem. 19 (23): 7044–7048. December 2011. doi:10.1016/j.bmc.2011.10.007. PMID 22037049. 
  29. ↑ 29.0 29.1 Explorations in Child Psychiatry. Springer Science & Business Media. 11 November 2013. pp. 93–94. ISBN 9781468421279. https://books.google.com/books?id=Ob7eBwAAQBAJ. Retrieved 28 April 2015. 
  30. ↑ 30.0 30.1 Arnold LE (2000). "Methyiphenidate vs. Amphetamine: Comparative review". Journal of Attention Disorders 3 (4): 200–211. doi:10.1177/108705470000300403. 
  31. ↑ "The Top 300 of 2021". https://clincalc.com/DrugStats/Top300Drugs.aspx. 
  32. ↑ "Dextroamphetamine; Dextroamphetamine Saccharate; Amphetamine; Amphetamine Aspartate - Drug Usage Statistics". https://clincalc.com/DrugStats/Drugs/DextroamphetamineDextroamphetamineSaccharateAmphetamineAmphetamineAspartate. 
  33. ↑ "Amphetamine, past and present – a pharmacological and clinical perspective". Journal of Psychopharmacology 27 (6): 479–496. June 2013. doi:10.1177/0269881113482532. PMID 23539642. "The intravenous use of d-amphetamine and other stimulants still pose major safety risks to the individuals indulging in this practice. Some of this intravenous abuse is derived from the diversion of ampoules of d-amphetamine, which are still occasionally prescribed in the UK for the control of severe narcolepsy and other disorders of excessive sedation. ... For these reasons, observations of dependence and abuse of prescription d-amphetamine are rare in clinical practice, and this stimulant can even be prescribed to people with a history of drug abuse provided certain controls, such as daily pick-ups of prescriptions, are put in place (Jasinski and Krishnan, 2009b).". 
  34. ↑ 34.0 34.1 34.2 34.3 "Adderall XR Prescribing Information". Shire US Inc. December 2013. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021303s026lbl.pdf. 
  35. ↑ Truven Health Analytics. "Amphetamine/Dextroamphetamine (By mouth)". Micromedex Consumer Medication Information. https://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0008973/?report=details. 
  36. ↑ "Generic Adderall Availability" (in en). https://www.drugs.com/availability/generic-adderall.html. 
  37. ↑ "Generic Adderall XR Availability" (in en). https://www.drugs.com/availability/generic-adderall-xr.html. 
  38. ↑ 38.0 38.1 "Do pro sports leagues have an Adderall problem?". USA TODAY. https://www.usatoday.com/story/sports/nfl/2012/11/27/adderall-in-pro-sports/1730431/. 
  39. ↑ "Commonly Abused Prescription Drugs Chart". National Institute on Drug Abuse. http://www.drugabuse.gov/drugs-abuse/commonly-abused-drugs/commonly-abused-prescription-drugs-chart. 
  40. ↑ "Stimulant ADHD Medications – Methylphenidate and Amphetamines". National Institute on Drug Abuse. http://www.drugabuse.gov/publications/infofacts/stimulant-adhd-medications-methylphenidate-amphetamines. 
  41. ↑ 41.0 41.1 41.2 "Mitigating risks of students use of study drugs through understanding motivations for use and applying harm reduction theory: a literature review". Harm Reduction Journal 14 (1): 68. 6 October 2017. doi:10.1186/s12954-017-0194-6. ISSN 1477-7517. PMID 28985738. 
  42. ↑ 42.0 42.1 "National Institute on Drug Abuse. 2009. Stimulant ADHD Medications – Methylphenidate and Amphetamines". National Institute on Drug Abuse. http://www.drugabuse.gov/publications/drugfacts/stimulant-adhd-medications-methylphenidate-amphetamines. 
  43. ↑ 43.0 43.1 43.2 43.3 43.4 "Adderall XR Prescribing Information". December 2013. pp. 8–10. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021303s026lbl.pdf. 
  44. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named FMO
  45. ↑ 45.0 45.1 45.2 "Mydayis Prescribing Information". Shire US Inc.. June 2017. pp. 1–21. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/022063s000lbl.pdf. 
  46. ↑ "SPECT and PET of the dopamine transporter in attention-deficit/hyperactivity disorder". Expert Rev. Neurother. 8 (4): 611–625. April 2008. doi:10.1586/14737175.8.4.611. PMID 18416663. "Zinc binds at ... extracellular sites of the DAT [103], serving as a DAT inhibitor. In this context, controlled double-blind studies in children are of interest, which showed positive effects of zinc [supplementation] on symptoms of ADHD [105,106]. It should be stated that at this time [supplementation] with zinc is not integrated in any ADHD treatment algorithm.". 
  47. ↑ "How addictive drugs disrupt presynaptic dopamine neurotransmission". Neuron 69 (4): 628–649. February 2011. doi:10.1016/j.neuron.2011.02.010. PMID 21338876. "They did not confirm the predicted straightforward relationship between uptake and release, but rather that some compounds including AMPH were better releasers than substrates for uptake. Zinc, moreover, stimulates efflux of intracellular [3H]DA despite its concomitant inhibition of uptake (Scholze et al., 2002).". 
  48. ↑ 48.0 48.1 "The role of zinc ions in reverse transport mediated by monoamine transporters". J. Biol. Chem. 277 (24): 21505–21513. June 2002. doi:10.1074/jbc.M112265200. PMID 11940571. "The human dopamine transporter (hDAT) contains an endogenous high affinity Zn2+ binding site with three coordinating residues on its extracellular face (His193, His375, and Glu396). ... Although Zn2+ inhibited uptake, Zn2+ facilitated [3H]MPP+ release induced by amphetamine, MPP+, or K+-induced depolarization specifically at hDAT but not at the human serotonin and the norepinephrine transporter (hNET). ... Surprisingly, this amphetamine-elicited efflux was markedly enhanced, rather than inhibited, by the addition of 10 μM Zn2+ to the superfusion buffer (Fig. 2 A, open squares). We stress that Zn2+ per se did not affect basal efflux (Fig. 2 A). ... In many brain regions, Zn2+ is stored in synaptic vesicles and co-released together with glutamate; under basal conditions, the extracellular levels of Zn2+ are low (~10 nM; see Refs. 39, 40). Upon neuronal stimulation, however, Zn2+ is co-released with the neurotransmitters and, consequently, the free Zn2+ concentration may transiently reach values that range from 10–20 μM (10) up to 300 μM (11). The concentrations of Zn2+ shown in this study, required for the stimulation of dopamine release (as well as inhibition of uptake), covered this physiologically relevant range, with maximum stimulation occurring at 3–30 μM. It is therefore conceivable that the action of Zn2+ on hDAT does not merely reflect a biochemical peculiarity but that it is physiologically relevant. ... Thus, when Zn2+ is co-released with glutamate, it may greatly augment the efflux of dopamine.". 
  49. ↑ "Biomarkers and attention-deficit/hyperactivity disorder: a systematic review and meta-analyses". J. Am. Acad. Child Adolesc. Psychiatry 51 (10): 1003–1019.e20. October 2012. doi:10.1016/j.jaac.2012.08.015. PMID 23021477. "Although we did not find a sufficient number of studies suitable for a meta-analysis of PEA and ADHD, three studies20,57,58 confirmed that urinary levels of PEA were significantly lower in patients with ADHD compared with controls. ... Administration of D-amphetamine and methylphenidate resulted in a markedly increased urinary excretion of PEA,20,60 suggesting that ADHD treatments normalize PEA levels. ... Similarly, urinary biogenic trace amine PEA levels could be a biomarker for the diagnosis of ADHD,20,57,58 for treatment efficacy,20,60 and associated with symptoms of inattentivenesss.59 ... With regard to zinc supplementation, a placebo controlled trial reported that doses up to 30 mg/day of zinc were safe for at least 8 weeks, but the clinical effect was equivocal except for the finding of a 37% reduction in amphetamine optimal dose with 30 mg per day of zinc.110". 
  50. ↑ "Striatal dopamine neurotransmission: regulation of release and uptake". Basal Ganglia 6 (3): 123–148. August 2016. doi:10.1016/j.baga.2016.02.001. PMID 27141430. "Despite the challenges in determining synaptic vesicle pH, the proton gradient across the vesicle membrane is of fundamental importance for its function. Exposure of isolated catecholamine vesicles to protonophores collapses the pH gradient and rapidly redistributes transmitter from inside to outside the vesicle. ... Amphetamine and its derivatives like methamphetamine are weak base compounds that are the only widely used class of drugs known to elicit transmitter release by a non-exocytic mechanism. As substrates for both DAT and VMAT, amphetamines can be taken up to the cytosol and then sequestered in vesicles, where they act to collapse the vesicular pH gradient.". 
  51. ↑ "Electrophysiological effects of trace amines on mesencephalic dopaminergic neurons". Front. Syst. Neurosci. 5: 56. July 2011. doi:10.3389/fnsys.2011.00056. PMID 21772817. "Three important new aspects of TAs action have recently emerged: (a) inhibition of firing due to increased release of dopamine; (b) reduction of D2 and GABAB receptor-mediated inhibitory responses (excitatory effects due to disinhibition); and (c) a direct TA1 receptor-mediated activation of GIRK channels which produce cell membrane hyperpolarization.". 
  52. ↑ "TAAR1". GenAtlas. University of Paris. 28 January 2012. http://genatlas.medecine.univ-paris5.fr/fiche.php?symbol=TAAR1. Retrieved 29 May 2014. " • tonically activates inwardly rectifying K(+) channels, which reduces the basal firing frequency of dopamine (DA) neurons of the ventral tegmental area (VTA)" 
  53. ↑ "Amphetamine modulates excitatory neurotransmission through endocytosis of the glutamate transporter EAAT3 in dopamine neurons". Neuron 83 (2): 404–416. July 2014. doi:10.1016/j.neuron.2014.05.043. PMID 25033183. "AMPH also increases intracellular calcium (Gnegy et al., 2004) that is associated with calmodulin/CamKII activation (Wei et al., 2007) and modulation and trafficking of the DAT (Fog et al., 2006; Sakrikar et al., 2012). ... For example, AMPH increases extracellular glutamate in various brain regions including the striatum, VTA and NAc (Del Arco et al., 1999; Kim et al., 1981; Mora and Porras, 1993; Xue et al., 1996), but it has not been established whether this change can be explained by increased synaptic release or by reduced clearance of glutamate. ... DHK-sensitive, EAAT2 uptake was not altered by AMPH (Figure 1A). The remaining glutamate transport in these midbrain cultures is likely mediated by EAAT3 and this component was significantly decreased by AMPH". 
  54. ↑ "Mechanisms of dopamine transporter regulation in normal and disease states". Trends Pharmacol. Sci. 34 (9): 489–496. September 2013. doi:10.1016/j.tips.2013.07.005. PMID 23968642. "AMPH and METH also stimulate DA efflux, which is thought to be a crucial element in their addictive properties [80], although the mechanisms do not appear to be identical for each drug [81]. These processes are PKCβ– and CaMK–dependent [72, 82], and PKCβ knock-out mice display decreased AMPH-induced efflux that correlates with reduced AMPH-induced locomotion [72].". 
  55. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named cognition enhancers
  56. ↑ "Amphetamine: Biomolecular Interactions and Pathways". National Center for Biotechnology Information. https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=3007#x301. 
  57. ↑ "Comparative effects of d-amphetamine, l-amphetamine, and methylphenidate on mood in man". Psychopharmacology 53 (1): 1–12. June 1977. doi:10.1007/bf00426687. PMID 407607. 
  58. ↑ 58.0 58.1 "The Selling of Attention Deficit Disorder". The New York Times. 14 December 2013. ISSN 0362-4331. https://www.nytimes.com/2013/12/15/health/the-selling-of-attention-deficit-disorder.html. 
  59. ↑ "(Collection of internal FDA information pertaining to the topic of Obetrol/Adderall)". US Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/nda/96/11522S010_Adderall.pdf. 
  60. ↑ "REGULATORY NEWS: Richwood's Adderall". Health News Daily. 22 February 1996. http://www.elsevierbi.com/Publications/Health-News-Daily/1996/2/22/REGULATORY-NEWS-Richwoods-Adderall. 
  61. ↑ "APPROVAL LETTER". http://www.accessdata.fda.gov/drugsatfda_docs/nda/96/11522S010_Adderall.pdf. 
  62. ↑ "August 2006 News Archives: Barr and Shire Sign Three Agreements". GenericsWeb. http://www.genericsweb.com/news/generics_industry_news_archive/August2006.html. "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) ..." 
  63. ↑ "Teva Completes Acquisition of Barr". Drugs.com. https://www.drugs.com/news/teva-completes-acquisition-barr-15356.html. 
  64. ↑ "Teva sells 1st generic of Adderall XL in US". Forbes Magazine. Associated Press. 2 April 2009. https://www.forbes.com/feeds/ap/2009/04/02/ap6248888.html. 
  65. ↑ "Molecular Weight Calculator". Lenntech. http://www.lenntech.com/calculators/molecular/molecular-weight-calculator.htm. Retrieved 19 August 2015. 
  66. ↑ 66.0 66.1 "Dextroamphetamine Sulfate USP". Mallinckrodt Pharmaceuticals. March 2014. http://www2.mallinckrodt.com/WorkArea/DownloadAsset.aspx?id=2147491568. Retrieved 19 August 2015. 
  67. ↑ 67.0 67.1 "D-amphetamine sulfate". Tocris. 2015. http://www.tocris.com/dispprod.php?ItemId=5305#.VXpspvlViko. Retrieved 19 August 2015. 
  68. ↑ 68.0 68.1 "Amphetamine Sulfate USP". Mallinckrodt Pharmaceuticals. March 2014. http://www2.mallinckrodt.com/WorkArea/DownloadAsset.aspx?id=2147491599. Retrieved 19 August 2015. 
  69. ↑ "Dextroamphetamine Saccharate". Mallinckrodt Pharmaceuticals. March 2014. http://www2.mallinckrodt.com/WorkArea/DownloadAsset.aspx?id=2147491576. Retrieved 19 August 2015. 
  70. ↑ "Amphetamine Aspartate". Mallinckrodt Pharmaceuticals. March 2014. http://www2.mallinckrodt.com/WorkArea/DownloadAsset.aspx?id=2147491591. Retrieved 19 August 2015. 
  71. ↑ "Vyvanse Prescribing Information". Shire US Inc.. May 2017. pp. 17–21. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021977s045,208510s001lbl.pdf. Retrieved 10 July 2017. 
  72. ↑ 72.0 72.1 72.2 72.3 Cite error: Invalid <ref> tag; no text was provided for refs named Dyanavel
  73. ↑ "Controlled Drugs and Substances Act (S.C. 1996, c. 19)". 25 April 2017. http://laws-lois.justice.gc.ca/eng/acts/C-38.8/. 
  74. ↑ "Importing or Bringing Medication into Japan for Personal Use". Japan Ministry of Health, Labour and Welfare. http://www.mhlw.go.jp/english/topics/import/. 
  75. ↑ P. (25 May 2012). "Moving to Korea brings medical, social changes". The Korean Times. http://www.koreatimes.co.kr/www/news/nation/2012/10/319_111757.html. 
  76. ↑ "Caught in the Dragnet". 2 August 2002. http://www.taipeitimes.com/News/feat/archives/2002/08/11/0000159895/4. 
  77. ↑ "Thailand Law". Government of Thailand. http://narcotic.fda.moph.go.th/faq/upload/Thai%20Narcotic%20Act%202012.doc._37ef.pdf. 
  78. ↑ "Class A, B and C drugs". Home Office, Government of the United Kingdom. http://www.homeoffice.gov.uk/drugs/drugs-law/Class-a-b-c/. 
  79. ↑ Substance Abuse and Mental Health Services Administration. "Trends in Methamphetamine/Amphetamine Admissions to Treatment: 1993–2003". United States Department of Health and Human Services. http://www.oas.samhsa.gov/2k6/methTx/methTX.htm. 
  80. ↑ 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 978-92-1-148223-2. http://www.unodc.org/pdf/youthnet/ATS.pdf. Retrieved 7 February 2012. 
  81. ↑ International Narcotics Control Board. "List of psychotropic substances under international control". Vienna: United Nations. http://www.incb.org/pdf/e/list/green.pdf. 
  82. ↑ "The ADHD medication shortage is getting worse. What went wrong?—Neither drugmakers nor the DEA anticipated a sharp rise in ADHD diagnoses during the pandemic. Now an entire class of medications may be in short supply.". NBC. 6 February 2023. https://www.nbcnews.com/health/health-news/adderall-shortage-adhd-drugs-affected-will-end-rcna66766. 
  83. ↑ "Adderall shortage raises questions about widespread dependency on the drug". PBS Newshour. 25 November 2022. https://www.pbs.org/newshour/show/adderall-shortage-raises-questions-about-widespread-dependency-on-the-drug. 
  84. ↑ "Where's the Urgency on the Adderall Shortage?" (in en-us). Intelligencer. 27 March 2023. https://nymag.com/intelligencer/2023/03/wheres-the-urgency-on-the-adderall-shortage.html. 
  85. ↑ "'Exciting Time': FDA Commissioner Talks AI and Misinformation". WebMD. 31 May 2023. https://www.webmd.com/a-to-z-guides/news/20230530/fda-commissioner-talks-ai-and-misinformation. 
  86. ↑ "FDA Commissioner Blames Adderall Shortage on Stimulant Overuse, Telehealth, Generics". Anni Layne Rodgers via Additidemag. 2 June 2023. https://www.additudemag.com/adderall-shortage-stimulant-use-telehealth-califf/amp/. 

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