Adderall

Adderall is the brand name of a fixed-dose combination medication used for the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy.<ref name="Adderall FDA label" /> It is also used as an athletic performance enhancer, cognitive enhancer, appetite suppressant, and recreationally as a euphoriant. Such uses are illegal in many countries. It is a central nervous system (CNS) stimulant of the phenethylamine class.<ref name="Amphetamine Formulations Review">Template:Cite journal</ref><ref name="Unique Dopamine Pharmacology">Template:Cite journal</ref> It contains the amphetamines dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate, and amphetamine sulfate.<ref name="Adderall FDA label" /> It is taken by mouth.<ref name="Adderall FDA label" />

In 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 psychosis (e.g., paranoia, delusions, hallucinations). The side effects vary widely among individuals but most commonly include insomnia, dry mouth, loss of appetite and weight loss. The routine use of Adderall at higher-than-prescribed doses poses a significant risk of addiction or dependence due to the pronounced reinforcing effects that are present at high doses. Recreational doses of Adderall are generally much larger than prescribed therapeutic doses and also carry a far greater risk of serious adverse effects.<ref group="sources"><ref name="Libido" /><ref name="Adderall FDA label" /><ref name="Malenka_2009" /><ref name="Ergogenics" /><ref name="FDA" /><ref name="Cochrane" /><ref name="Stimulant Misuse" /><ref name="NHMH_3e-Addiction doses" /><ref name="Addiction risk" /><ref>Template:Cite book</ref><ref>Template:Cite journal</ref></ref>

The two amphetamine enantiomers that compose Adderall, such as Adderall tablets/capsules (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 CNS stimulant than levoamphetamine, but levoamphetamine has slightly stronger cardiovascular and peripheral effects and a longer elimination half-life than dextroamphetamine. The active ingredient in Adderall, amphetamine, shares many chemical and pharmacological properties with the human trace amines, particularly phenethylamine and Template:Nowrap, the latter of which is a positional isomer of amphetamine.<ref group="sources"><ref name="Malenka_2009_03b" /><ref name="Miller" /><ref name="E Weihe" /><ref>Template:Cite journal</ref><ref name="Westfall" /><ref name="TAAR1 stereoselective" /><ref name="Child Psychiatry" /><ref name="Arnold" /></ref> In 2023, Adderall was the fifteenth most commonly prescribed medication in the United States, with more than 32Template:Nbspmillion prescriptions.<ref name="Top300Drugs">Template:Cite web</ref><ref>Template:Cite web</ref> Template:TOC limit

Uses

Medical

Adderall is indicated for the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy.<ref name="Adderall FDA label">Template:Cite web</ref><ref name="Amphetamine Formulations Review" />

Attention Deficit Hyperactivity Disorder

{{#lsth:Amphetamine|ADHD}}

Narcolepsy

{{#lsth:Amphetamine|Narcolepsy}}

Available forms

Adderall is available as immediate-release (IR) tablets and extended-release (XR) capsules.<ref name="Adderall FDA label" /><ref name="Adderall XR FDA label" /> Mydayis is available as an extended-release formulation.<ref name="Mydayis FDA label" /> Adderall XR is approved to treat attention deficit hyperactivity disorder for up to 12 hours in individuals 6 years and older and uses a double-bead formulation. The capsule can be swallowed like a tablet, or it can be opened and the beads sprinkled over applesauce for comparable absorption.<ref name="Adderall XR FDA label" /> Upon ingestion, half of the beads provide immediate administration of medication, while the other half are enveloped in a coating that must dissolve, delaying absorption of its contents. It is designed to provide a therapeutic effect and plasma concentrations identical to taking two doses of Adderall IR four hours apart.<ref name="Adderall XR FDA label" /> Mydayis uses a longer-lasting triple-bead formulation and is approved to treat attention deficit hyperactivity disorder for up to 16 hours in individuals aged 13 years of age and older.<ref name="Mydayis FDA label" /> In the United States, the immediate and extended-release formulations of Adderall are available as generic medications.<ref>Template:Cite web</ref><ref>Template:Cite web</ref> Generic formulations of Mydayis became available in the US in October 2023.<ref>Template:Cite web</ref>

Enhancing performance

Adderall is banned by the National Football League (NFL), Major League Baseball (MLB), the National Basketball Association (NBA), the National Collegiate Athletic Association (NCAA), and the National Hockey League (NHL).<ref name="Leon">Template:Cite web</ref> In leagues such as the National Football League, 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.<ref name="Leon" />

Recreational

Adderall has a high potential for misuse as a recreational drug.<ref>Template:Cite web</ref><ref>Template:Cite web</ref><ref name="Abelman 68">Template:Cite journal</ref> Adderall tablets can either be swallowed, crushed and snorted, or dissolved in water and injected.<ref name="NIDA">Template:Cite web</ref> Injection into the bloodstream can be dangerous because insoluble fillers within the tablets can block small blood vessels.<ref name="NIDA" />

Many postsecondary students have reported using Adderall for study purposes in different parts of the developed world.<ref name="Abelman 68" /> Among these students, some of the risk factors for misusing ADHD stimulants recreationally include: 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.<ref name="Abelman 68" />

Adverse effects

Template:Transcluded section 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.<ref name="FDA" /><ref name="Westfall" /> Adderall is currently approved for long-term therapeutic use by the USFDA.<ref name="FDA" /> 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.<ref name="Westfall" /> Template:Trim

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.<ref name="Adderall XR FDA label" />
• Inhibitors of enzymes that directly metabolize amphetamine (particularly CYP2D6 and FMO3) will prolong the elimination of amphetamine and increase drug effects.<ref name="Adderall XR FDA label" /><ref name="FMO" /><ref name="Mydayis FDA label" />
• Serotonergic drugs (such as most antidepressants) co-administered with amphetamine increases the risk of serotonin syndrome.<ref name="Mydayis FDA label" />
• Stimulants and antidepressants (sedatives and depressants) may increase (decrease) the drug effects of amphetamine, and vice versa.<ref name="Adderall XR FDA label" />
• Gastrointestinal and urinary pH affect the absorption and elimination of amphetamine, respectively. Gastrointestinal alkalinizing agents increase the absorption of amphetamine. Urinary alkalinizing agents increase the concentration of non-ionized species, decreasing urinary excretion.<ref name="Adderall XR FDA label" />
• Proton-pump inhibitors (PPIs) modify the absorption of Adderall XR and Mydayis.<ref name="Adderall XR FDA label" /><ref name="Mydayis FDA label" />
• Zinc supplementation may reduce the minimum effective dose of amphetamine when it is used for the treatment of ADHD.<ref group="note">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.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref name="Primary 2002 amph-zinc study">Template:Cite journal</ref> The human serotonin transporter and norepinephrine transporter do not contain zinc binding sites.<ref name="Primary 2002 amph-zinc study" /></ref><ref>Template:Cite journal</ref>
• Norepinephrine reuptake inhibitors (NRIs) like atomoxetine prevent norepinephrine release induced by amphetamines and have been found to reduce the stimulant, euphoriant, and sympathomimetic effects of dextroamphetamine in humans.<ref>Template:Cite journal</ref><ref>Template:Cite book</ref><ref>Template:Cite journal</ref>

Pharmacology

Mechanism of action

Template:Nowrap

Compound	Template:Abbrlink	Template:Abbrlink	Template:Abbrlink	Template:Reference column heading
Phenethylamine	10.9	39.5	>10000	<ref>Template:Cite journal</ref><ref name="Forsyth2012" /><ref name="Blough2008" />
Dextroamphetamine	6.6–7.2	5.8–24.8	698–1765	<ref name="RothmanBaumannDersch2001">Template:Cite journal</ref><ref>Template:Cite journal</ref>
Levoamphetamine	9.5	27.7	Template:Abbr	<ref name="Forsyth2012">Template:Cite journal</ref><ref name="Blough2008">Template:Cite book</ref>
Dextromethamphetamine	12.3–13.8	8.5–24.5	736–1291.7	<ref name="RothmanBaumannDersch2001" /><ref>Template:Cite journal</ref>
Levomethamphetamine	28.5	416	4640	<ref name="RothmanBaumannDersch2001" />
Notes: The smaller the value, the more strongly the drug releases the neurotransmitter. See also Monoamine releasing agent § Activity profiles for a larger table with more compounds. Refs: <ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Template:Amphetamine pharmacodynamics Amphetamine, the active ingredient of Adderall, works primarily by increasing the activity of the neurotransmitters dopamine and norepinephrine in the brain.<ref name="Malenka_2009_03b">Template:Cite book</ref><ref name="cognition enhancers" /> 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).<ref name="E Weihe" /><ref>Template:Cite web</ref> Both active ingredients of Adderall, dextroamphetamine and levoamphetamine, bind to the same biological targets,<ref name="Westfall"/><ref name="TAAR1 stereoselective" /> but their binding affinities (that is, potency) differ somewhat.<ref name="Westfall"/><ref name="TAAR1 stereoselective" /> 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.<ref name="TAAR1 stereoselective" /> Consequently, dextroamphetamine produces more Template:Abbr stimulation than levoamphetamine;<ref name="TAAR1 stereoselective">Template:Cite journal</ref><ref>Template:Cite journal</ref> however, levoamphetamine has slightly greater cardiovascular and peripheral effects.<ref name="Westfall" /> It has been reported that certain children have a better clinical response to levoamphetamine.<ref name="Child Psychiatry">Template:Cite book</ref><ref name="Arnold">Template:Cite journal</ref>

In the absence of amphetamine, Template:Abbr 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.<ref name="E Weihe">Template:Cite journal</ref> 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.<ref name="E Weihe" /> Meanwhile, when amphetamine activates Template:Abbr, 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;<ref name="Miller" /> 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.<ref name="Miller" /> 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).<ref name="Miller" /><ref name="E Weihe" />

History

The pharmaceutical company Rexar reformulated their 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 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.<ref name="Schwarz2013">Template:Cite news</ref> 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.<ref name="FDA Review">Template:Cite web</ref><ref>Template:Cite news</ref> In 1997 Richwood Pharmaceuticals was acquired by Shire Pharmaceuticals in a $186 million transaction.<ref name="Schwarz2013" />

Richwood Pharmaceuticals, which later merged with Shire,<ref name="Schwarz2013" /> introduced the Adderall brand in 1996 as an instant-release tablet.<ref name="FDA Review" /> In 2006, Shire agreed to sell rights to the Adderall name for the instant-release form of the medication to Duramed Pharmaceuticals.<ref>Template:Cite web</ref> DuraMed Pharmaceuticals was acquired by Teva Pharmaceuticals in 2008 during their acquisition of Barr Pharmaceuticals, including Barr's Duramed division.<ref>Template:Cite web</ref>

The first generic version of Adderall IR was introduced to the market in 2002.<ref name="NDCD">Template:Cite web</ref> 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.<ref name="NDCD" /><ref>Template:Cite news</ref>

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.<ref name="Adderall XR FDA label" /> This drug mixture has slightly stronger Template:Abbr effects than racemic amphetamine due to the higher proportion of dextroamphetamine.<ref name="Miller">Template:Cite journal</ref><ref name="Westfall" /> Adderall is produced as both an immediate-release (IR) and extended-release (XR) formulation.<ref name="NDCD" /><ref name="Adderall FDA label" /><ref name="Adderall XR FDA label" /> Template:As of, ten different companies produced generic Adderall IR, while Teva Pharmaceutical Industries, Actavis, and Barr Pharmaceuticals manufactured generic Adderall XR.<ref name="NDCD" /> Template:As of, Shire plc, the company that held the original patent for Adderall and Adderall XR, still manufactured brand name Adderall XR, but not Adderall IR.<ref name="NDCD" />

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 US-approved forms): Template:Amphetamine base in marketed amphetamine medications

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.<ref>Template:Cite web</ref>
• In Japan, the use, production, and import of any medicine containing amphetamines is prohibited.<ref>Template:Cite web</ref>
• In South Korea, amphetamines are prohibited.<ref>Template:Cite web</ref>
• In Taiwan, amphetamines including Adderall are Schedule 2 drugs with a minimum five-year prison term for possession.<ref>Template:Cite web</ref> On the contrary, Ritalin can be legally prescribed as a form of treatment of ADHD.<ref>Template:Cite web</ref>
• In Thailand, amphetamines are classified as Type 1 Narcotics.<ref>Template:Cite web</ref>
• 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.<ref>Template:Cite web</ref>
• In the United States, amphetamine is a Schedule II prescription drug, classified as a central nervous system (CNS) stimulant.<ref name=":USAS2" />
• Internationally, amphetamine is in Schedule II of the Convention on Psychotropic Substances.<ref>Template:Cite book</ref><ref>Template:Cite web</ref>

Names

A similar combination is also sold under the brand name Mydayis.<ref name="Mydayis FDA label" /><ref name="Mydayis Launch">Template:Cite web</ref> Mydayis contains the amphetamines dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine aspartate monohydrate, and amphetamine sulfate capsule.<ref name="Mydayis FDA label" />

Shortages

In February 2023, news organizations began reporting on shortages of Adderall in the United States that have lasted for over five months.<ref>Template:Cite news</ref><ref>Template:Cite news</ref> The US Food and Drug Administration (FDA) first reported the shortage in October 2022.<ref>Template:Cite news</ref> In May 2023, seven months into the shortage, the FDA commissioner 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".<ref>Template:Cite news</ref><ref>Template:Cite news</ref> The shortage has continued into 2025.<ref>Template:Cite web</ref><ref>Template:Cite news</ref><ref>Template:Cite webTemplate:Dead linkTemplate:Cbignore</ref> It has led to the creation and expansion of businesses that outsource the search for Adderall. One company charges $50 per U.S. customer to hire workers in the Philippines or another country to make phone calls to all the pharmacies located near the customer and check whether they have any Adderall. Celebrity endorsements have contributed to the increased demand for Adderall.<ref>Template:Cite web</ref>

Notes

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