Adderall

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For the generic compound, see Amphetamine.
Adderall
an image of the amphetamine skeletal formula
A 3d image of the amphetamine compound
Combination of
amphetamine aspartate monohydrate (25%) stimulant
amphetamine sulfate (25%) stimulant
dextroamphetamine saccharate (25%) stimulant
dextroamphetamine sulfate (25%) stimulant
Clinical data
Trade names Adderall, Adderall XR
AHFS/Drugs.com monograph
MedlinePlus a601234
Licence data US FDA:link
Pregnancy cat.
Legal status
Moderate
Routes Oral, insufflation, rectal, sublingual
Identifiers
CAS number 300-62-9 YesY 51-64-9
ATC code N06BA02 N06BA01
PubChem CID 3007
DrugBank DB00182
ChemSpider 13852819 YesY
KEGG D03740 YesY
ChEBI CHEBI:2679 YesY
ChEMBL CHEMBL405 YesY
 YesY (what is this?)  (verify)

Adderall[note 1] is a psychostimulant drug of the phenethylamine class used in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. Adderall is also used as a performance and cognitive enhancer, and recreationally as an aphrodisiac and euphoriant. The medication is a mixture of various salts of the two amphetamine stereoisomers and inactive ingredients; by salt content, the active ingredients are 75% dextroamphetamine salts (the dextrorotary or "right-handed" enantiomer) and 25% levoamphetamine salts (the levorotary or "left-handed" enantiomer).[note 2][sources 1]

Adderall works by increasing the activity of the neurotransmitters norepinephrine and dopamine in the brain, which results from its interactions with trace amine associated receptor 1 (TAAR1) and vesicular monoamine transporter 2 (VMAT2). Adderall shares many chemical and pharmacological properties with the human trace amine neurotransmitters, especially phenethylamine and N-methylphenethylamine, the latter being an isomer of amphetamine that is produced within the human body.[sources 2]

Adderall is generally well-tolerated and effective in treating the symptoms of ADHD. The most common side effects are cardiovascular, such as irregular heartbeat (usually as a fast heartbeat), and psychological, such as euphoria or anxiety. Much larger doses of Adderall are likely to impair cognitive function and induce rapid muscle breakdown. Drug addiction is a serious risk of Adderall abuse, but only rarely arises from medical use. Very high doses can result in a psychosis (e.g., delusions and paranoia) which rarely occurs at therapeutic doses even during long-term use. Recreational doses are generally much larger than prescribed therapeutic doses, and carry a far greater risk of serious side effects.[sources 3]

Uses[edit]

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

Medical[edit]

Adderall tablets
A group of 20 mg Adderall tablets, some broken in half, with a lengthwise-folded US dollar bill along the bottom for size comparison
Adderall capsules
A pair of 20 mg Adderall XR capsules with a US penny to illustrate size
US Prevalence of drugs in 2013[17]
Grade level Amphetamine Adderall
8th-graders 2.60% 1.80%
10th-graders 5.90% 4.40%
12th-graders 7.90% 7.40%

Adderall is used to treat attention deficit hyperactivity disorder (ADHD) and narcolepsy.[18][19] Long-term amphetamine exposure in some animal species is known to produce abnormal dopamine system development or nerve damage,[20][21] but, in humans with ADHD, amphetamines appear to improve brain development and nerve growth.[22][23][24] Magnetic resonance imaging (MRI) studies suggest that long-term treatment with amphetamine decreases abnormalities in brain structure and function found in subjects with ADHD, and improves function in several parts of the brain, such as the right caudate nucleus of the basal ganglia.[22][23][24]

Reviews of clinical stimulant research have established the safety and effectiveness of long-term amphetamine use for ADHD.[25][26] Controlled trials spanning two years have demonstrated treatment effectiveness and safety.[26][27] One review highlighted a nine-month randomized controlled trial in children with ADHD that found an average increase of 4.5 IQ points and continued improvements in attention, disruptive behaviors, and hyperactivity.[27]

Current models of ADHD suggest that it is associated with functional impairments in some of the brain's neurotransmitter systems;[5] these functional impairments involve impaired dopamine neurotransmission in the mesocorticolimbic projection and norepinephrine neurotransmission in the locus coeruleus and prefrontal cortex.[5] Psychostimulants like methylphenidate and amphetamine are effective in treating ADHD because they increase neurotransmitter activity in these systems.[11][5][28] Approximately 70% of those who use these stimulants see improvements in ADHD symptoms.[29][30] Children with ADHD who use stimulant medications generally have better relationships with peers and family members, perform better in school, are less distractible and impulsive, and have longer attention spans.[25][29] The Cochrane Collaboration's review[note 3] on the treatment of adult ADHD with amphetamines stated that while amphetamines improve short-term symptoms, they have higher discontinuation rates than non-stimulant medications due to their adverse side effects.[32]

A Cochrane Collaboration review on the treatment of ADHD in children with tic disorders such as Tourette syndrome indicated that stimulants in general do not make tics worse, but high doses of dextroamphetamine could exacerbate tics in some individuals.[33] Other Cochrane reviews on the use of amphetamine following stroke or acute brain injury indicated that it may improve recovery, but further research is needed to confirm this.[34][35][36]

Dosing and administration[edit]

Adderall is available as immediate release tablets or extended-release capsules.[37] The extended release capsule is generally used in the morning.[38] 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.[39]

Performance-enhancing[edit]

Therapeutic doses of amphetamine improve cortical network efficiency, resulting in higher performance on working memory tests in all individuals.[11][40] Amphetamine and other ADHD stimulants also improve task saliency (motivation to perform a task) and increase arousal (wakefulness), in turn promoting goal-directed behavior.[11][41][42] Stimulants such as amphetamine can improve performance on difficult and boring tasks[11][41] and are used by some students as a study and test-taking aid.[43] Based upon studies of self-reported illicit stimulant use, students primarily use stimulants such as amphetamine for performance enhancement rather than abusing them as recreational drugs.[44] However, high amphetamine doses that are above the therapeutic range can interfere with working memory and cognitive control.[11][41]

Amphetamine is used by some athletes for its psychological and performance-enhancing effects, such as increased stamina and alertness;[45][15] however, its use is prohibited at sporting events regulated by collegiate, national, and international anti-doping agencies.[46][47] In healthy people at oral therapeutic doses, amphetamine has been shown to increase physical strength, acceleration, stamina, and endurance, while reducing reaction time.[45][48][49] Amphetamine improves stamina, endurance, and reaction time primarily through reuptake inhibition and effluxion of dopamine in the central nervous system.[48][49][50] At therapeutic doses, the adverse effects of amphetamine do not impede athletic performance;[45][48][49] however, at much higher doses, amphetamine can induce effects that severely impair performance, such as rapid muscle breakdown and elevated body temperature.[9][10][48]

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).[51] 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 his physician.[51]

Recreational[edit]

Adderall is considered to have a high potential for misuse.[52][53] Adderall tablets can be crushed and snorted, or dissolved in water and injected.[54] Injection into the bloodstream can be dangerous because insoluble fillers within the tablets can block small blood vessels.[54]

Contraindications[edit]

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

According to the International Programme on Chemical Safety (IPCS) and United States Food and Drug Administration (USFDA),[note 4] amphetamine is contraindicated in people with a history of drug abuse, heart disease, severe agitation, or severe anxiety.[55][56] It is also contraindicated in people currently experiencing arteriosclerosis (hardening of the arteries), glaucoma (an eye condition), hyperthyroidism (excessive production of thyroid hormone), or hypertension (high blood pressure).[55][56] People who have experienced allergic reactions to other stimulants in the past or who are taking monoamine oxidase inhibitors (MAOIs) are advised not to take amphetamine.[55][56] These agencies also state that anyone with anorexia nervosa, bipolar disorder, depression, elevated blood pressure, liver or kidney problems, mania, psychosis, Raynaud's phenomenon, seizures, thyroid problems, tics, or Tourette syndrome should monitor their symptoms while taking amphetamine.[55][56] Evidence from human studies indicates that therapeutic amphetamine use does not cause developmental abnormalities in the fetus or newborns (i.e., it is not a human teratogen), but amphetamine abuse does pose risks to the fetus.[56] Amphetamine has also been shown to pass into breast milk, so the IPCS and USFDA advise mothers to avoid breastfeeding when using it.[55][56] Due to the potential for reversible growth impairments,[note 5] the USFDA advises monitoring the height and weight of children and adolescents prescribed amphetamines.[55]

Side effects[edit]

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

The 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.[9][10][15] Adderall is currently approved for long-term therapeutic use by the USFDA.[10] Recreational use of Adderall generally involves far larger doses and is therefore significantly more dangerous, involving a much greater risk of serious side effects.[15]

Physical

At normal therapeutic doses, the physical side effects of amphetamine vary widely by age and from person to person.[10] Cardiovascular side effects can include cardiac dysrhythmia (abnormal heart rhythm), hypertension (high blood pressure) or hypotension (low blood pressure) from a vasovagal response, and Raynaud's phenomenon (reduced blood flow to extremities).[10][15][57] Sexual side effects in males may include erectile dysfunction, frequent erections, or prolonged erections.[10] Abdominal side effects may include stomach pain, loss of appetite, nausea, and weight loss.[10] Other potential side effects include dry mouth, excessive grinding of the teeth, acne, profuse sweating, blurred vision, reduced seizure threshold, and tics (a type of movement disorder).[10][15][57] Dangerous physical side effects are rare at typical pharmaceutical doses.[15]

Amphetamine stimulates the medullary respiratory centers, producing faster and deeper breaths.[15] In a normal person at therapeutic doses, this effect is usually not noticeable, but when respiration is already compromised, it may be evident.[15] Amphetamine also induces contraction in the urinary bladder sphincter, the muscle which controls urination, which can result in difficulty urinating. This effect can be useful in treating bed wetting and loss of bladder control.[15] The effects of amphetamine on the gastrointestinal tract are unpredictable.[15] If intestinal activity is high, amphetamine may reduce gastrointestinal motility (the rate at which content moves through the digestive system);[15] however, amphetamine may increase motility when the smooth muscle of the tract is relaxed.[15] Amphetamine also has a slight analgesic effect and can enhance the pain relieving effects of opiates.[15]

USFDA commissioned studies from 2011 indicate that in children, young adults, and adults there is no association between serious adverse cardiovascular events (sudden death, heart attack, and stroke) and the medical use of amphetamine or other ADHD stimulants.[sources 4]

Psychological

Common psychological effects of therapeutic doses can include increased alertness, apprehension, concentration, decreased sense of fatigue, mood swings (elated mood followed by mildly depressed mood), increased initiative, insomnia or wakefulness, self-confidence, and sociability.[10][15] Less common side effects include anxiety, change in libido, grandiosity, irritability, repetitive or obsessive behaviors, and restlessness;[sources 5] these effects depend on the user's personality and current mental state.[15] Amphetamine psychosis (e.g., delusions and paranoia) can occur in heavy users.[9][10][12] Although very rare, this psychosis can also occur at therapeutic doses during long-term therapy.[9][10][13] According to the USFDA, "there is no systematic evidence" that stimulants produce aggressive behavior or hostility.[10]

Overdose[edit]

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

An amphetamine overdose can lead to many different symptoms, but is rarely fatal with appropriate care.[56][63] The severity of overdose symptoms vary positively with dosage and inversely with drug tolerance to amphetamine.[15][56] Tolerant individuals have been known to take as much as 5 grams of amphetamine, roughly 100 times the maximum daily therapeutic dose, in a day.[56] Symptoms of a moderate and extremely large overdose are listed below; fatal amphetamine poisoning usually also involves convulsions and coma.[9][15] Chronic overdose of amphetamine poses a high risk of developing an addiction, since high doses result in increased expression of the addiction gene ΔFosB. Consistent aerobic exercise appears to magnitude-dependently reduce this risk.[64]

Overdose symptoms by system
System Minor or moderate overdose[9][15][56] Severe overdose[sources 6]
Cardiovascular
Central nervous
system
Musculoskeletal
Respiratory
  • Rapid breathing
Urinary
Other

Addiction

Addiction glossary[67][68]
addiction – a state characterized by compulsive engagement in rewarding behavior or compulsive drug use, despite adverse consequences
reinforcing stimuli – stimuli that increase the probability of repeating behaviors paired with them
rewarding stimuli – stimuli that the brain interprets as intrinsically positive or as something to be approached
addictive drug – a drug that is both rewarding and reinforcing
addictive behavior – a behavior that is both rewarding and reinforcing
sensitization – an amplified response to a stimulus resulting from repeated exposure to it
drug tolerance – the diminishing effect of a drug resulting from repeated administration at a given dose
drug sensitization or reverse tolerance – the escalating effect of a drug resulting from repeated administration at a given dose
drug dependence – an adaptive state associated with a withdrawal syndrome upon cessation of repeated drug intake
physical dependence – dependence that involves physical–somatic withdrawal symptoms (e.g., fatigue)
psychological dependence – dependence that involves emotional–motivational withdrawal symptoms (e.g., dysphoria and anhedonia)
(edit | history)

Addiction is a serious risk with heavy recreational amphetamine use, but is unlikely to arise from typical medical use at therapeutic doses.[9][14][15] Tolerance develops rapidly in amphetamine abuse, so periods of extended use require increasingly larger doses of the drug in order to achieve the same effect.[69][70]

Biomolecular mechanisms

Current models of addiction from chronic drug use involve alterations in gene expression in certain parts of the brain, particularly the nucleus accumbens.[71][72][73] The most important transcription factors[note 6] that produce these alterations are ΔFosB, cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), and nuclear factor kappa B (NFκB).[72] ΔFosB is the most significant factor in drug addiction, since its overexpression in the nucleus accumbens is necessary and sufficient for many of the associated neural adaptations that occur;[72] it has been implicated in addictions to alcohol, cannabinoids, cocaine, nicotine, opiates, phencyclidine, and substituted amphetamines.[72][75][76] ΔJunD is the transcription factor which directly opposes ΔFosB.[72] Increases in nucleus accumbens ΔJunD expression using viral vectors can reduce or, with a large increase, even block many of the neural and behavioral alterations seen in chronic drug abuse (i.e., the alterations mediated by ΔFosB).[72] ΔFosB also plays an important role in regulating behavioral responses to natural rewards, such as palatable food, sex, and exercise.[72][75][77] Since natural rewards induce expression of ΔFosB just like drugs of abuse do, chronic acquisition of these rewards can result in a similar pathological state of addiction.[75][72] Consequently, ΔFosB is the key transcription factor involved in amphetamine addiction and amphetamine-induced sex addictions, a phenomenon known as dopamine dysregulation syndrome which has been observed in some patients taking dopaminergic medications.[75][77][78]

The effects of amphetamine on gene regulation are both dose- and route-dependent.[73] Most of the research on gene regulation and addiction is based upon animal studies with intravenous amphetamine administration at very high doses.[73] The few studies that have used equivalent (weight-adjusted) human therapeutic doses and oral administration show that these changes, if they occur, are relatively minor.[73]

Pharmacological treatments

A Cochrane Collaboration review on amphetamine and methamphetamine addiction and abuse indicates that the current evidence on effective treatments is extremely limited.[79] The review indicated that fluoxetine[note 7] and imipramine[note 8] have some limited benefits in treating abuse and addiction, but concluded that there is currently no effective pharmacological treatment for amphetamine addiction or abuse.[79] A corroborating review indicated that amphetamine addiction is mediated through increased activation of dopamine receptors and co-localized NMDA receptors in the mesolimbic dopamine pathway (a pathway in the brain that connects the ventral tegmental area to the nucleus accumbens).[80] This review also noted that magnesium ions and serotonin inhibit NMDA receptors and that the magnesium ions do so by blocking the receptor's calcium channels.[80] It also suggested that, based upon animal testing, pathological (addiction-inducing) amphetamine use significantly reduces the level of intracellular magnesium throughout the brain.[80] Supplemental magnesium,[note 9] like fluoxetine treatment, has been shown to reduce amphetamine self-administration (doses given to oneself) in both humans and lab animals.[79][80]

Behavioral treatments

Cognitive behavioral therapy is currently the most effective clinical treatment for psychostimulant addiction.[81] Additionally, research on the neurobiological effects of physical exercise suggests that consistent aerobic exercise, especially endurance exercise (e.g., marathon running), prevents the development of drug addiction and is an effective adjunct (supplemental) treatment for amphetamine addiction.[64][75] Exercise leads to better treatment outcomes when used as an adjunct treatment, particularly for psychostimulant addictions.[64] In particular, aerobic exercise decreases psychostimulant self-administration, reduces the reinstatement (i.e., relapse) of drug-seeking, and induces opposite effects on striatal dopamine receptor D2 (DRD2) signaling (increased DRD2 density) to those induced by pathological stimulant use (decreased DRD2 density).[75]

Withdrawal

According to another Cochrane Collaboration review on withdrawal in highly addicted 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."[82] This review noted that withdrawal symptoms in chronic, high-dose users are frequent, occurring in up to 87.6% of cases, and persist for three to four weeks with a marked "crash" phase occurring during the first week.[82] Amphetamine withdrawal symptoms can include anxiety, drug craving, depressed mood, fatigue, increased appetite, increased movement or decreased movement, lack of motivation, sleeplessness or sleepiness, and lucid dreams.[82] The review indicated that withdrawal symptoms are associated with the degree of dependence, suggesting that therapeutic use would result in far milder discontinuation symptoms.[82] Manufacturer prescribing information does not indicate the presence of withdrawal symptoms following discontinuation of amphetamine use after an extended period at therapeutic doses.[83][84][85]

Psychosis

The main section for this topic is on the page Stimulant psychosis, in the section Substituted amphetamines.

Abuse of amphetamine can result in a stimulant psychosis that may present with a variety of symptoms (e.g., paranoia and delusions).[12] 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.[12][86] According to the same review, there is at least one trial that shows antipsychotic medications effectively resolve the symptoms of acute amphetamine psychosis.[12] Psychosis very rarely arises from therapeutic use.[13][55]

Toxicity

In rodents and primates, sufficiently high doses of amphetamine cause dopaminergic neurotoxicity, or damage to dopamine neurons, which is characterized as reduced transporter and receptor function.[87] There is no evidence that amphetamine is directly neurotoxic in humans.[88][89] High-dose amphetamine can cause indirect neurotoxicity as a result of increased oxidative stress from reactive oxygen species and autoxidation of dopamine.[20][90][91]

Interactions[edit]

Pharmacology[edit]

Pharmacodynamics of amphetamine enantiomers in a dopamine neuron

A pharmacodynamic model of amphetamine and TAAR1
via AADC
Amphetamine enters the presynaptic neuron across the neuronal membrane or through DAT. Once inside, it binds to TAAR1 or enters synaptic vesicles through VMAT2. When amphetamine enters the synaptic vesicles through VMAT2, dopamine is released into the cytosol (yellow-orange area). When amphetamine binds to TAAR1, it reduces dopamine receptor firing rate via potassium channels and triggers protein kinase A (PKA) and protein kinase C (PKC) signaling, resulting in DAT phosphorylation. PKA-phosphorylation causes DAT to withdraw into the presynaptic neuron (internalize) and cease transport. PKC-phosphorylated DAT may either operate in reverse or, like PKA-phosphorylated DAT, internalize and cease transport. Amphetamine is also known to increase intracellular calcium, a known effect of TAAR1 activation, which is associated with DAT phosphorylation through a CAMK-dependent pathway, in turn producing dopamine efflux.
The main section for this topic is on the page Amphetamine, in the section Pharmacology.

Mechanism of action[edit]

For a more complete and detailed description of amphetamine pharmacodynamics, see the pharmacodynamics section in the Amphetamine article.

Amphetamine, the active ingredient of Adderall, works primarily by increasing the activity of the neurotransmitters dopamine and norepinephrine in the brain and more specifically, in the nucleus accumbens, prefrontal cortex, and locus coeruleus regions.[5][28] It also triggers the release of several other neurotransmitters (e.g., serotonin, histamine, and epinephrine, among others) from neurons and also the synthesis of neuropeptides (e.g., cocaine and amphetamine regulated transcript (CART) peptides).[7][94] Both active ingredients of Adderall, dextroamphetamine and levoamphetamine, bind to the same biological targets,[15][95] but their binding affinities (that is potency) differ somewhat.[15][95] 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.[95] Consequently, dextroamphetamine produces roughly two times more CNS stimulation than levoamphetamine;[95][96] however, levoamphetamine has slightly greater cardiovascular and peripheral effects.[15] Levoamphetamine provides Adderall with a quicker onset and longer-lasting effects than dextroamphetamine alone.[97] It has been reported that certain children have a better clinical response to levoamphetamine.[98]

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 are essentially chemical storage units inside a neuron.[7] 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.[7] 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 molecules altogether (via internalization) or even transport them in reverse;[6] 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.[6] 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).[6][7]

Related endogenous compounds[edit]

For more details on related compounds, see Trace amines.

Amphetamine has a very similar structure and function to the endogenous trace amines, which are naturally occurring neurotransmitter molecules produced in the human body and brain.[6][8] Among this group, the most closely related compounds are phenethylamine, the parent compound of amphetamine, and N-methylphenethylamine, an isomer of amphetamine (i.e., it has an identical molecular formula).[6][8][99] In humans, phenethylamine is produced directly from L-phenylalanine by the aromatic amino acid decarboxylase (AADC) enzyme, which converts L-DOPA into dopamine as well.[8][99] In turn, N‑methylphenethylamine is metabolized from phenethylamine by phenylethanolamine N-methyltransferase, the same enzyme that metabolizes norepinephrine into epinephrine.[8][99] Like amphetamine, both phenethylamine and N‑methylphenethylamine regulate monoamine neurotransmission via TAAR1;[6][99] unlike amphetamine, both of these substances are broken down by monoamine oxidase B, and therefore have a shorter half-life than amphetamine.[8][99]

History, society, and culture[edit]

Richwood Pharmaceuticals, which later merged with Shire plc, introduced the current Adderall brand in 1996 as an instant-release tablet.[100] In 2006, Shire agreed to sell rights to the Adderall name for this instant-release medication to Duramed Pharmaceuticals[101] DuraMed Pharmaceuticals was acquired by Teva Pharmaceuticals in 2008 when during their acquisition of Barr Pharmaceuticals, including Barr's Duramed division.[102]

The first generic version of Adderall IR was introduced to market in 2002.[2] Later on, Barr and Shire reached a settlement agreement permitting Barr to offer a generic form of the drug beginning in April 2009.[2][103]

Commercial formulation[edit]

Chemically, Adderall is a mixture of several amphetamine salts; specifically, it is composed of equal parts (by mass) of amphetamine aspartate monohydrate, amphetamine sulfate, dextroamphetamine sulfate, and dextroamphetamine saccharate.[39] This drug mixture has slightly stronger CNS effects than racemic amphetamine due to the higher proportion of dextroamphetamine.[6][15] Adderall is produced as both an immediate release (IR) and extended release (XR) formulation.[2][37][104] 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.[2] Shire plc, the company that held the original patent for Adderall and Adderall XR, still manufactures brand name Adderall XR, but not Adderall IR.[2]

Past formulations[edit]

Rexar, a pharmaceutical company, reformulated another drug, branded as Obetrol, 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 13 February 1996.[105]

Legal status[edit]

  • In Canada, amphetamines are in Schedule I of the Controlled Drugs and Substances Act, and can only be obtained by prescription.[106]
  • In Japan, the use, production, and import of any medicine containing amphetamine are prohibited.[107]
  • In South Korea, amphetamines are prohibited.[108]
  • In Thailand, Amphetamines are classified as Type 1 Narcotics.[109]
  • 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.[110]
  • In the United States, amphetamine is a Schedule II prescription drug, classified as a CNS stimulant.[111]
  • Internationally (United Nations), amphetamine is in Schedule II of the Convention on Psychotropic Substances.[112][113]

Notes[edit]

  1. ^ The US nonproprietary name of Adderall is dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine sulfate and amphetamine aspartate.[1][2] It is sometimes referred to as amphetamine mixed salts and other variants thereof.
  2. ^ 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.
  3. ^ Cochrane Collaboration reviews are high quality meta-analytic systematic reviews of randomized controlled trials.[31]
  4. ^ The statements supported by the USFDA come from prescribing information, which is the copyrighted intellectual property of the manufacturer and approved by the USFDA.
  5. ^ In individuals who experience sub-normal height and weight gains, a rebound to normal levels is expected to occur if stimulant therapy is briefly interrupted.[26][27][57] The average reduction in final adult height from continuous stimulant therapy over a 3 year period is 2 cm.[57]
  6. ^ Transcription factors are proteins that increase or decrease the expression of specific genes.[74]
  7. ^ During short-term treatment, fluoxetine may decrease drug craving.[79]
  8. ^ During "medium-term treatment," imipramine may extend the duration of adherence to addiction treatment.[79]
  9. ^ The review indicated that magnesium L-aspartate and magnesium chloride produce significant changes in addictive behavior;[80] other forms of magnesium were not mentioned.

Reference notes[edit]

References[edit]

  1. ^ a b Heal DJ, Smith SL, Gosden J, Nutt DJ (June 2013). "Amphetamine, past and present – a pharmacological and clinical perspective". J. Psychopharmacol. 27 (6): 479–496. doi:10.1177/0269881113482532. PMC 3666194. PMID 23539642. Mixed enantiomers/mixed salts amphetamine (3:1 d:l isomers) 
  2. ^ a b c d e f "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. 
  3. ^ a b Montgomery KA (June 2008). "Sexual desire disorders". Psychiatry (Edgmont) 5 (6): 50–55. PMC 2695750. PMID 19727285. 
  4. ^ Wilens TE, Adler LA, Adams J, Sgambati S, Rotrosen J, Sawtelle R, Utzinger L, Fusillo S (January 2008). "Misuse and diversion of stimulants prescribed for ADHD: a systematic review of the literature". J. Am. Acad. Child Adolesc. Psychiatry 47 (1): 21–31. doi:10.1097/chi.0b013e31815a56f1. PMID 18174822. Stimulant misuse appears to occur both for performance enhancement and their euphorogenic effects, the latter being related to the intrinsic properties of the stimulants (e.g., IR versus ER profile) ...

    Although useful in the treatment of ADHD, stimulants are controlled II substances with a history of preclinical and human studies showing potential abuse liability.
     
  5. ^ a b c d e Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York, USA: McGraw-Hill Medical. pp. 154–157. ISBN 9780071481274. 
  6. ^ a b c d e f g h 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. 
  7. ^ a b c d e Eiden LE, Weihe E (January 2011). "VMAT2: a dynamic regulator of brain monoaminergic neuronal function interacting with drugs of abuse". Ann. N. Y. Acad. Sci. 1216: 86–98. doi:10.1111/j.1749-6632.2010.05906.x. PMID 21272013. 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). 
  8. ^ a b c d e f Broadley KJ (March 2010). "The vascular effects of trace amines and amphetamines". Pharmacol. Ther. 125 (3): 363–375. doi:10.1016/j.pharmthera.2009.11.005. PMID 19948186. Fig. 2. Synthetic and metabolic pathways for endogenous and exogenously administered trace amines and sympathomimetic amines ...
    Trace amines are metabolized in the mammalian body via monoamine oxidase (MAO; EC 1.4.3.4) (Berry, 2004) (Fig. 2) ... It deaminates primary and secondary amines that are free in the neuronal cytoplasm but not those bound in storage vesicles of the sympathetic neurone ...
    Thus, MAO inhibitors potentiate the peripheral effects of indirectly acting sympathomimetic amines ... this potentiation occurs irrespective of whether the amine is a substrate for MAO. An α-methyl group on the side chain, as in amphetamine and ephedrine, renders the amine immune to deamination so that they are not metabolized in the gut. Similarly, β-PEA would not be deaminated in the gut as it is a selective substrate for MAO-B which is not found in the gut ...
    Brain levels of endogenous trace amines are several hundred-fold below those for the classical neurotransmitters noradrenaline, dopamine and serotonin but their rates of synthesis are equivalent to those of noradrenaline and dopamine and they have a very rapid turnover rate (Berry, 2004). Endogenous extracellular tissue levels of trace amines measured in the brain are in the low nanomolar range. These low concentrations arise because of their very short half-life ...
     
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  64. ^ a b c Lynch WJ, Peterson AB, Sanchez V, Abel J, Smith MA (September 2013). "Exercise as a novel treatment for drug addiction: a neurobiological and stage-dependent hypothesis". Neurosci Biobehav Rev 37 (8): 1622–44. doi:10.1016/j.neubiorev.2013.06.011. PMC 3788047. PMID 23806439. these data show that exercise can affect dopaminergic signaling at many different levels, which may underlie its ability to modify vulnerability during drug use initiation. Exercise also produces neuroadaptations that may influence an individual's vulnerability to initiate drug use. Consistent with this idea, chronic moderate levels of forced treadmill running blocks not only subsequent methamphetamine-induced conditioned place preference, but also stimulant-induced increases in dopamine release in the NAc (Chen et al., 2008) and striatum (Marques et al., 2008). ... [These] findings indicate the efficacy of exercise at reducing drug intake in drug-dependent individuals ... wheel running [reduces] methamphetamine self-administration under extended access conditions (Engelmann et al., 2013) ... These findings suggest that exercise may "magnitude"-dependently prevent the development of an addicted phenotype possibly by blocking/reversing behavioral and neuro-adaptive changes that develop during and following extended access to the drug. ... Exercise has been proposed as a treatment for drug addiction that may reduce drug craving and risk of relapse. Although few clinical studies have investigated the efficacy of exercise for preventing relapse, the few studies that have been conducted generally report a reduction in drug craving and better treatment outcomes (see Table 4). ... Taken together, these data suggest that the potential benefits of exercise during relapse, particularly for relapse to psychostimulants, may be mediated via chromatin remodeling and possibly lead to greater treatment outcomes. 
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  67. ^ Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and Addictive Disorders". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 364–375. ISBN 9780071481274. 
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  74. ^ Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 4: Signal Transduction in the Brain". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York, USA: McGraw-Hill Medical. p. 94. ISBN 9780071481274. All living cells depend on the regulation of gene expression by extracellular signals for their development, homeostasis, and adaptation to the environment. Indeed, many signal transduction pathways function primarily to modify transcription factors that alter the expression of specific genes. Thus, neurotransmitters, growth factors, and drugs change patterns of gene expression in cells and in turn affect many aspects of nervous system functioning, including the formation of long-term memories. Many drugs that require prolonged administration, such as antidepressants and antipsychotics, trigger changes in gene expression that are thought to be therapeutic adaptations to the initial action of the drug. 
  75. ^ a b c d e f Olsen CM (December 2011). "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology 61 (7): 1109–1122. doi:10.1016/j.neuropharm.2011.03.010. PMC 3139704. PMID 21459101. Similar to environmental enrichment, studies have found that exercise reduces self-administration and relapse to drugs of abuse (Cosgrove et al., 2002; Zlebnik et al., 2010). There is also some evidence that these preclinical findings translate to human populations, as exercise reduces withdrawal symptoms and relapse in abstinent smokers (Daniel et al., 2006; Prochaska et al., 2008), and one drug recovery program has seen success in participants that train for and compete in a marathon as part of the program (Butler, 2005). ... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some patients taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al., 2006; Aiken, 2007; Lader, 2008). 
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  78. ^ Pitchers KK, Vialou V, Nestler EJ, Laviolette SR, Lehman MN, Coolen LM (February 2013). "Natural and drug rewards act on common neural plasticity mechanisms with ΔFosB as a key mediator". J. Neurosci. 33 (8): 3434–3442. doi:10.1523/JNEUROSCI.4881-12.2013. PMC 3865508. PMID 23426671. Drugs of abuse induce neuroplasticity in the natural reward pathway, specifically the nucleus accumbens (NAc), thereby causing development and expression of addictive behavior. ... Together, these findings demonstrate that drugs of abuse and natural reward behaviors act on common molecular and cellular mechanisms of plasticity that control vulnerability to drug addiction, and that this increased vulnerability is mediated by ΔFosB and its downstream transcriptional targets. ... Sexual behavior is highly rewarding (Tenk et al., 2009), and sexual experience causes sensitized drug-related behaviors, including cross-sensitization to amphetamine (Amph)-induced locomotor activity (Bradley and Meisel, 2001; Pitchers et al., 2010a) and enhanced Amph reward (Pitchers et al., 2010a). Moreover, sexual experience induces neural plasticity in the NAc similar to that induced by psychostimulant exposure, including increased dendritic spine density (Meisel and Mullins, 2006; Pitchers et al., 2010a), altered glutamate receptor trafficking, and decreased synaptic strength in prefrontal cortex-responding NAc shell neurons (Pitchers et al., 2012). Finally, periods of abstinence from sexual experience were found to be critical for enhanced Amph reward, NAc spinogenesis (Pitchers et al., 2010a), and glutamate receptor trafficking (Pitchers et al., 2012). These findings suggest that natural and drug reward experiences share common mechanisms of neural plasticity 
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