Adderall

This article is about a common mixture of amphetamine salts. For general information about the drug and its racemate, see Amphetamine. For the 2023 EP by Slipknot, see Adderall (EP).

Amphetamine/dextroamphetamine
salt mixture (1:1) ^{[note 1]}

Top: racemic amphetamine skeleton Bottom: (D)-amphetamine ball-and-stick model
Combination of
amphetamine aspartate monohydrate	25% – stimulant (12.5% levo; 12.5% dextro)
amphetamine sulfate	25% – stimulant (12.5% levo; 12.5% dextro)
dextroamphetamine saccharate	25% – stimulant (0% levo; 25% dextro)
dextroamphetamine sulfate	25% – stimulant (0% levo; 25% dextro)
Clinical data
Trade names	Adderall, Adderall XR, Mydayis
Other names	Mixed amphetamine salts; MAS
AHFS/Drugs.com	Monograph
MedlinePlus	a601234
License data	US  DailyMed:  Adderall
Dependence liability	Moderate [3] [4] – high [5] [6] [7]
Routes of administration	By mouth, insufflation, rectal, sublingual
Drug class	CNS stimulant
ATC code	N06BA02 ( WHO ) N06BA01 ( WHO )
Legal status
Legal status	AU: S8 (Controlled drug) CA: Schedule I DE: Anlage III (Special prescription form required) NZ: Class B UK: Class B US: WARNING [8] Schedule II [9] UN: Psychotropic Schedule II
Pharmacokinetic data
Bioavailability	Oral: ~90% [10]
Identifiers
CAS Number	300-62-9  Y 51-64-9
PubChem CID	3007
IUPHAR/BPS	4804
DrugBank	DB00182  Y
ChemSpider	13852819  Y
UNII	CK833KGX7E
KEGG	D11624  Y
ChEBI	CHEBI:2679  Y
ChEMBL	ChEMBL405  Y
(verify)

Adderall and Mydayis ^[11] are trade names ^{[note 2]} for a combination drug 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. ^[13] 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] [14] [15]} 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]

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 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 and at fairly low daily doses, such as those used for treating ADHD. However, the routine use of Adderall in larger and 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 Adderall are generally much larger than prescribed therapeutic doses and also carry a far greater risk of serious adverse effects. ^{[sources 1]}

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 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. The active ingredient in Adderall, 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 2022, Adderall was the fourteenth most commonly prescribed medication in the United States, with more than 34 million prescriptions. ^{[35] [36]}

Uses

30 capsules of 10 mg Adderall XR

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

Adderall is commonly used to treat attention deficit hyperactivity disorder (ADHD) and narcolepsy (a sleep disorder). ^{[37] [17]}

ADHD

Long-term amphetamine exposure at sufficiently high doses in some animal species is known to produce abnormal dopamine system development or nerve damage, ^{[38] [39]} but, in humans with ADHD, long-term use of pharmaceutical amphetamines at therapeutic doses appears to improve brain development and nerve growth. ^{[40] [41] [42]} Reviews of 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. ^{[40] [41] [42]}

Reviews of clinical stimulant research have established the safety and effectiveness of long-term continuous amphetamine use for the treatment of ADHD. ^{[43] [44] [45]} Randomized controlled trials of continuous stimulant therapy for the treatment of ADHD spanning 2 years have demonstrated treatment effectiveness and safety. ^{[43] [44]} Two reviews have indicated that long-term continuous stimulant therapy for ADHD is effective for reducing the core symptoms of ADHD (i.e., hyperactivity, inattention, and impulsivity), enhancing quality of life and academic achievement, and producing improvements in a large number of functional outcomes ^{[note 3]} across 9 categories of outcomes related to academics, antisocial behavior, driving, non-medicinal drug use, obesity, occupation, self-esteem, service use (i.e., academic, occupational, health, financial, and legal services), and social function. ^{[43] [45]} One review highlighted a nine-month randomized controlled trial of amphetamine treatment for ADHD in children that found an average increase of 4.5  IQ points, continued increases in attention, and continued decreases in disruptive behaviors and hyperactivity. ^[44] Another review indicated that, based upon the longest follow-up studies conducted to date, lifetime stimulant therapy that begins during childhood is continuously effective for controlling ADHD symptoms and reduces the risk of developing a substance use disorder as an adult. ^[43]

Current models of ADHD suggest that it is associated with functional impairments in some of the brain's neurotransmitter systems; ^[46] these functional impairments involve impaired dopamine neurotransmission in the mesocorticolimbic projection and norepinephrine neurotransmission in the noradrenergic projections from the locus coeruleus to the prefrontal cortex. ^[46] Stimulants like methylphenidate and amphetamine are effective in treating ADHD because they increase neurotransmitter activity in these systems. ^{[18] [46] [47]} Approximately 80% of those who use these stimulants see improvements in ADHD symptoms. ^[48] 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. ^{[49] [50]} The Cochrane reviews ^{[note 4]} on the treatment of ADHD in children, adolescents, and adults with pharmaceutical amphetamines stated that short-term studies have demonstrated that these drugs decrease the severity of symptoms, but they have higher discontinuation rates than non-stimulant medications due to their adverse side effects. ^{[52] [53]} A Cochrane 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. ^[54]

Narcolepsy

Narcolepsy is a chronic sleep-wake disorder that is associated with excessive daytime sleepiness, cataplexy, and sleep paralysis. ^[55] Patients with narcolepsy are diagnosed as either type 1 or type 2, with only the former presenting cataplexy symptoms. ^[56] Type 1 narcolepsy results from the loss of approximately 70,000 orexin-releasing neurons in the lateral hypothalamus, leading to significantly reduced cerebrospinal orexin levels; ^{[57] [58]} this reduction is a diagnostic biomarker for type 1 narcolepsy. ^[56] Lateral hypothalamic orexin neurons innervate every component of the ascending reticular activating system (ARAS), which includes noradrenergic, dopaminergic, histaminergic, and serotonergic nuclei that promote wakefulness. ^{[58] [59]}

Amphetamine’s therapeutic mode of action in narcolepsy primarily involves increasing monoamine neurotransmitter activity in the ARAS. ^{[57] [60] [61]} This includes noradrenergic neurons in the locus coeruleus, dopaminergic neurons in the ventral tegmental area, histaminergic neurons in the tuberomammillary nucleus, and serotonergic neurons in the dorsal raphe nucleus. ^{[59] [61]} Dextroamphetamine, the more dopaminergic enantiomer of amphetamine, is particularly effective at promoting wakefulness because dopamine release has the greatest influence on cortical activation and cognitive arousal, relative to other monoamines. ^[57] In contrast, levoamphetamine may have a greater effect on cataplexy, a symptom more sensitive to the effects of norepinephrine and serotonin. ^[57] Noradrenergic and serotonergic nuclei in the ARAS are involved in the regulation of the REM sleep cycle and function as "REM-off" cells, with amphetamine's effect on norepinephrine and serotonin contributing to the suppression of REM sleep and a possible reduction of cataplexy at high doses. ^{[57] [56] [59]}

The American Academy of Sleep Medicine (AASM) 2021 clinical practice guideline conditionally recommends dextroamphetamine for the treatment of both type 1 and type 2 narcolepsy. ^[62] Treatment with pharmaceutical amphetamines is generally less preferred relative to other stimulants (e.g., modafinil) and is considered a third-line treatment option. ^{[63] [64] [65]} Medical reviews indicate that amphetamine is safe and effective for the treatment of narcolepsy. ^{[57] [63] [62]} Amphetamine appears to be most effective at improving symptoms associated with hypersomnolence, with three reviews finding clinically significant reductions in daytime sleepiness in patients with narcolepsy. ^{[57] [63] [62]} Additionally, these reviews suggest that amphetamine may dose-dependently improve cataplexy symptoms. ^{[57] [63] [62]} However, the quality of evidence for these findings is low and is consequently reflected in the AASM's conditional recommendation for dextroamphetamine as a treatment option for narcolepsy. ^[62]

Available forms

Adderall is available as immediate-release (IR) tablets and extended-release (XR) capsules. ^{[17] [66]} Mydayis is only available as an extended-release formulation. ^[67] Adderall XR is approved to treat ADHD 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. ^[66] 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. ^[66] Mydayis uses a longer-lasting triple-bead formulation and is approved to treat ADHD for up to 16 hours in individuals 13 years and older. ^[67] In the United States, the immediate and extended-release formulations of Adderall are both available as generic drugs. ^{[68] [69]} Generic formulations of Mydayis became available in the US in October 2023. ^[70]

Enhancing performance

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

Cognitive performance

In 2015, a systematic review and a meta-analysis of high quality clinical trials found that, when used at low (therapeutic) doses, amphetamine produces modest yet unambiguous improvements in cognition, including working memory, long-term episodic memory, inhibitory control, and some aspects of attention, in normal healthy adults; ^{[71] [72]} these cognition-enhancing effects of amphetamine are known to be partially mediated through the indirect activation of both dopamine D₁ receptor and α₂-adrenergic receptor in the prefrontal cortex. ^{[18] [71]} A systematic review from 2014 found that low doses of amphetamine also improve memory consolidation, in turn leading to improved recall of information. ^[73] Therapeutic doses of amphetamine also enhance cortical network efficiency, an effect which mediates improvements in working memory in all individuals. ^{[18] [74]} Amphetamine and other ADHD stimulants also improve task saliency (motivation to perform a task) and increase arousal (wakefulness), in turn promoting goal-directed behavior. ^{[18] [75] [76]} Stimulants such as amphetamine can improve performance on difficult and boring tasks and are used by some students as a study and test-taking aid. ^{[18] [76] [77]} Based upon studies of self-reported illicit stimulant use, 5–35% of college students use diverted ADHD stimulants, which are primarily used for enhancement of academic performance rather than as recreational drugs. ^{[78] [79] [80]} However, high amphetamine doses that are above the therapeutic range can interfere with working memory and other aspects of cognitive control. ^{[18] [76]}

Physical performance

Amphetamine is used by some athletes for its psychological and athletic performance-enhancing effects, such as increased endurance and alertness; ^{[19] [31]} however, non-medical amphetamine use is prohibited at sporting events that are regulated by collegiate, national, and international anti-doping agencies. ^{[81] [82]} In healthy people at oral therapeutic doses, amphetamine has been shown to increase muscle strength, acceleration, athletic performance in anaerobic conditions, and endurance (i.e., it delays the onset of fatigue), while improving reaction time. ^{[19] [83] [84]} Amphetamine improves endurance and reaction time primarily through reuptake inhibition and release of dopamine in the central nervous system. ^{[83] [84] [85]} Amphetamine and other dopaminergic drugs also increase power output at fixed levels of perceived exertion by overriding a "safety switch", allowing the core temperature limit to increase in order to access a reserve capacity that is normally off-limits. ^{[84] [86] [87]} At therapeutic doses, the adverse effects of amphetamine do not impede athletic performance; ^{[19] [83]} however, at much higher doses, amphetamine can induce effects that severely impair performance, such as rapid muscle breakdown and elevated body temperature. ^{[20] [83]}

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). ^[88] 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. ^[88]

Recreational

See also: History and culture of substituted amphetamines

Adderall has a high potential for misuse as a recreational drug. ^{[89] [90] [91]} Adderall tablets can either be swallowed, crushed and snorted, or dissolved in water and injected. ^[92] Injection into the bloodstream can be dangerous because insoluble fillers within the tablets can block small blood vessels. ^[92]

Many postsecondary students have reported using Adderall for study purposes in different parts of the developed world. ^[91] 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. ^[91]

Contraindications

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

According to the International Programme on Chemical Safety (IPCS) and the U.S. Food and Drug Administration (FDA), ^{[note 5]} amphetamine is contraindicated in people with a history of drug abuse, ^{[note 6]} cardiovascular disease, severe agitation, or severe anxiety. ^{[95] [96] [97]} It is also contraindicated in individuals with advanced arteriosclerosis (hardening of the arteries), glaucoma (increased eye pressure), hyperthyroidism (excessive production of thyroid hormone), or moderate to severe hypertension. ^{[95] [96] [97]} These agencies indicate that people who have experienced allergic reactions to other stimulants or who are taking monoamine oxidase inhibitors (MAOIs) should not take amphetamine, ^{[95] [96] [97]} although safe concurrent use of amphetamine and monoamine oxidase inhibitors has been documented. ^{[98] [99]} These agencies also state that anyone with anorexia nervosa, bipolar disorder, depression, hypertension, liver or kidney problems, mania, psychosis, Raynaud's phenomenon, seizures, thyroid problems, tics, or Tourette syndrome should monitor their symptoms while taking amphetamine. ^{[96] [97]} 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. ^[97] Amphetamine has also been shown to pass into breast milk, so the IPCS and the FDA advise mothers to avoid breastfeeding when using it. ^{[96] [97]} Due to the potential for reversible growth impairments, ^{[note 7]} the FDA advises monitoring the height and weight of children and adolescents prescribed an amphetamine pharmaceutical. ^[96]

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. ^{[20] [31]} Adderall is currently approved for long-term therapeutic use by the USFDA. ^[20] 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. ^[31]

Physical

Cardiovascular side effects can include hypertension or hypotension from a vasovagal response, Raynaud's phenomenon (reduced blood flow to the hands and feet), and tachycardia (increased heart rate). ^{[20] [31] [103]} Sexual side effects in males may include erectile dysfunction, frequent erections, or prolonged erections. ^[20] Gastrointestinal side effects may include abdominal pain, constipation, diarrhea, and nausea. ^{[7] [20] [104]} Other potential physical side effects include appetite loss, blurred vision, dry mouth, excessive grinding of the teeth, nosebleed, profuse sweating, rhinitis medicamentosa (drug-induced nasal congestion), reduced seizure threshold, tics (a type of movement disorder), and weight loss. ^{[sources 3]} Dangerous physical side effects are rare at typical pharmaceutical doses. ^[31]

Amphetamine stimulates the medullary respiratory centers, producing faster and deeper breaths. ^[31] In a normal person at therapeutic doses, this effect is usually not noticeable, but when respiration is already compromised, it may be evident. ^[31] Amphetamine also induces contraction in the urinary bladder sphincter, the muscle which controls urination, which can result in difficulty urinating. ^[31] This effect can be useful in treating bed wetting and loss of bladder control. ^[31] The effects of amphetamine on the gastrointestinal tract are unpredictable. ^[31] If intestinal activity is high, amphetamine may reduce gastrointestinal motility (the rate at which content moves through the digestive system); ^[31] however, amphetamine may increase motility when the smooth muscle of the tract is relaxed. ^[31] Amphetamine also has a slight analgesic effect and can enhance the pain relieving effects of opioids. ^{[7] [31]}

FDA-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]} However, amphetamine pharmaceuticals are contraindicated in individuals with cardiovascular disease. ^{[sources 5]}

Psychological

At normal therapeutic doses, the most common psychological side effects of amphetamine include increased alertness, apprehension, concentration, initiative, self-confidence and sociability, mood swings (elated mood followed by mildly depressed mood), insomnia or wakefulness, and decreased sense of fatigue. ^{[20] [31]} Less common side effects include anxiety, change in libido, grandiosity, irritability, repetitive or obsessive behaviors, and restlessness; ^{[sources 6]} these effects depend on the user's personality and current mental state. ^[31] Amphetamine psychosis (e.g., delusions and paranoia) can occur in heavy users. ^{[20] [21] [112]} Although very rare, this psychosis can also occur at therapeutic doses during long-term therapy. ^{[20] [112] [22]} According to the FDA, "there is no systematic evidence" that stimulants produce aggressive behavior or hostility. ^[20]

Amphetamine has also been shown to produce a conditioned place preference in humans taking therapeutic doses, ^{[52] [113]} meaning that individuals acquire a preference for spending time in places where they have previously used amphetamine. ^{[113] [114]}

Reinforcement disorders

Addiction

Addiction and dependence glossary [114] [115] [116]
addiction – a biopsychosocial disorder characterized by persistent use of drugs (including alcohol) despite substantial harm and adverse consequences addictive drug – psychoactive substances that with repeated use are associated with significantly higher rates of substance use disorders, due in large part to the drug's effect on brain reward systems dependence – an adaptive state associated with a withdrawal syndrome upon cessation of repeated exposure to a stimulus (e.g., drug intake) drug sensitization or reverse tolerance – the escalating effect of a drug resulting from repeated administration at a given dose drug withdrawal – symptoms that occur upon cessation of repeated drug use physical dependence – dependence that involves persistent physical–somatic withdrawal symptoms (e.g., fatigue and delirium tremens) psychological dependence – dependence socially seen as being extremely mild compared to physical dependence (e.g., with enough willpower it could be overcome) reinforcing stimuli – stimuli that increase the probability of repeating behaviors paired with them rewarding stimuli – stimuli that the brain interprets as intrinsically positive and desirable or as something to approach sensitization – an amplified response to a stimulus resulting from repeated exposure to it substance use disorder – a condition in which the use of substances leads to clinically and functionally significant impairment or distress tolerance – the diminishing effect of a drug resulting from repeated administration at a given dose
v t e

Transcription factor glossary
gene expression – the process by which information from a gene is used in the synthesis of a functional gene product such as a protein transcription – the process of making messenger RNA (mRNA) from a DNA template by RNA polymerase transcription factor – a protein that binds to DNA and regulates gene expression by promoting or suppressing transcription transcriptional regulation – controlling the rate of gene transcription for example by helping or hindering RNA polymerase binding to DNA upregulation , activation, or promotion – increase the rate of gene transcription downregulation , repression, or suppression – decrease the rate of gene transcription coactivator – a protein (or a small molecule) that works with transcription factors to increase the rate of gene transcription corepressor – a protein (or a small molecule) that works with transcription factors to decrease the rate of gene transcription response element – a specific sequence of DNA that a transcription factor binds to
v t e

Signaling cascade in the nucleus accumbens that results in amphetamine addiction v t e Note: colored text contains article links. Nuclear pore Nuclear membrane Plasma membrane Cav1.2 NMDAR AMPAR DRD1 DRD5 DRD2 DRD3 DRD4 Gs Gi/o AC cAMP cAMP PKA CaM CaMKII DARPP-32 PP1 PP2B CREB ΔFosB JunD c-Fos SIRT1 HDAC1 [Color legend 1] This diagram depicts the signaling events in the brain's reward center that are induced by chronic high-dose exposure to psychostimulants that increase the concentration of synaptic dopamine, like amphetamine, methamphetamine, and phenethylamine. Following presynaptic dopamine and glutamate co-release by such psychostimulants, [117] [118] postsynaptic receptors for these neurotransmitters trigger internal signaling events through a cAMP-dependent pathway and a calcium-dependent pathway that ultimately result in increased CREB phosphorylation. [117] [119] [120] Phosphorylated CREB increases levels of ΔFosB, which in turn represses the c-Fos gene with the help of corepressors; [117] [121] [122] c-Fos repression acts as a molecular switch that enables the accumulation of ΔFosB in the neuron. [123] A highly stable (phosphorylated) form of ΔFosB, one that persists in neurons for 1–2 months, slowly accumulates following repeated high-dose exposure to stimulants through this process. [121] [122] ΔFosB functions as "one of the master control proteins" that produces addiction-related structural changes in the brain, and upon sufficient accumulation, with the help of its downstream targets (e.g., nuclear factor kappa B), it induces an addictive state. [121] [122]

Addiction is a serious risk with heavy recreational amphetamine use, but is unlikely to occur from long-term medical use at therapeutic doses; ^{[23] [24] [63]} in fact, lifetime stimulant therapy for ADHD that begins during childhood reduces the risk of developing substance use disorders as an adult. ^[43] Pathological overactivation of the mesolimbic pathway, a dopamine pathway that connects the ventral tegmental area to the nucleus accumbens, plays a central role in amphetamine addiction. ^{[124] [125]} Individuals who frequently self-administer high doses of amphetamine have a high risk of developing an amphetamine addiction, since chronic use at high doses gradually increases the level of accumbal ΔFosB, a "molecular switch" and "master control protein" for addiction. ^{[115] [126] [127]} Once nucleus accumbens ΔFosB is sufficiently overexpressed, it begins to increase the severity of addictive behavior (i.e., compulsive drug-seeking) with further increases in its expression. ^{[126] [128]} While there are currently no effective drugs for treating amphetamine addiction, regularly engaging in sustained aerobic exercise appears to reduce the risk of developing such an addiction. ^{[129] [130]} Exercise therapy improves clinical treatment outcomes and may be used as an adjunct therapy with behavioral therapies for addiction. ^{[129] [131] [sources 7]}

Biomolecular mechanisms

Chronic use of amphetamine at excessive doses causes alterations in gene expression in the mesocorticolimbic projection, which arise through transcriptional and epigenetic mechanisms. ^{[127] [132] [133]} The most important transcription factors ^{[note 8]} that produce these alterations are Delta FBJ murine osteosarcoma viral oncogene homolog B (ΔFosB), cAMP response element binding protein (CREB), and nuclear factor-kappa B (NF-κB). ^[127] ΔFosB is the most significant biomolecular mechanism in addiction because ΔFosB overexpression (i.e., an abnormally high level of gene expression which produces a pronounced gene-related phenotype) in the D1-type medium spiny neurons in the nucleus accumbens is necessary and sufficient ^{[note 9]} for many of the neural adaptations and regulates multiple behavioral effects (e.g., reward sensitization and escalating drug self-administration) involved in addiction. ^{[115] [126] [127]} Once ΔFosB is sufficiently overexpressed, it induces an addictive state that becomes increasingly more severe with further increases in ΔFosB expression. ^{[115] [126]} It has been implicated in addictions to alcohol, cannabinoids, cocaine, methylphenidate, nicotine, opioids, phencyclidine, propofol, and substituted amphetamines, among others. ^{[sources 8]}

ΔJunD, a transcription factor, and G9a, a histone methyltransferase enzyme, both oppose the function of ΔFosB and inhibit increases in its expression. ^{[115] [127] [137]} Sufficiently overexpressing ΔJunD in the nucleus accumbens with viral vectors can completely block many of the neural and behavioral alterations seen in chronic drug abuse (i.e., the alterations mediated by ΔFosB). ^[127] Similarly, accumbal G9a hyperexpression results in markedly increased histone 3 lysine residue 9 dimethylation (H3K9me2) and blocks the induction of ΔFosB-mediated neural and behavioral plasticity by chronic drug use, ^{[sources 9]} which occurs via H3K9me2-mediated repression of transcription factors for ΔFosB and H3K9me2-mediated repression of various ΔFosB transcriptional targets (e.g., CDK5). ^{[127] [137] [138]} ΔFosB also plays an important role in regulating behavioral responses to natural rewards, such as palatable food, sex, and exercise. ^{[128] [127] [141]} Since both natural rewards and addictive drugs induce the expression of ΔFosB (i.e., they cause the brain to produce more of it), chronic acquisition of these rewards can result in a similar pathological state of addiction. ^{[128] [127]} Consequently, ΔFosB is the most significant factor involved in both amphetamine addiction and amphetamine-induced sexual addictions, which are compulsive sexual behaviors that result from excessive sexual activity and amphetamine use. ^{[128] [142] [143]} These sexual addictions are associated with a dopamine dysregulation syndrome which occurs in some patients taking dopaminergic drugs. ^{[128] [141]}

The effects of amphetamine on gene regulation are both dose- and route-dependent. ^[133] Most of the research on gene regulation and addiction is based upon animal studies with intravenous amphetamine administration at very high doses. ^[133] 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. ^[133] This suggests that medical use of amphetamine does not significantly affect gene regulation. ^[133]

Pharmacological treatments

Further information: Addiction § Research

As of December 2019, ^[update] there is no effective pharmacotherapy for amphetamine addiction. ^{[144] [145] [146]} Reviews from 2015 and 2016 indicated that TAAR1-selective agonists have significant therapeutic potential as a treatment for psychostimulant addictions; ^{[147] [148]} however, as of February 2016, ^[update] the only compounds which are known to function as TAAR1-selective agonists are experimental drugs. ^{[147] [148]} Amphetamine addiction is largely mediated through increased activation of dopamine receptors and co-localized NMDA receptors ^{[note 10]} in the nucleus accumbens; ^[125] magnesium ions inhibit NMDA receptors by blocking the receptor calcium channel. ^{[125] [149]} One review suggested that, based upon animal testing, pathological (addiction-inducing) psychostimulant use significantly reduces the level of intracellular magnesium throughout the brain. ^[125] Supplemental magnesium ^{[note 11]} treatment has been shown to reduce amphetamine self-administration (i.e., doses given to oneself) in humans, but it is not an effective monotherapy for amphetamine addiction. ^[125]

A systematic review and meta-analysis from 2019 assessed the efficacy of 17 different pharmacotherapies used in randomized controlled trials (RCTs) for amphetamine and methamphetamine addiction; ^[145] it found only low-strength evidence that methylphenidate might reduce amphetamine or methamphetamine self-administration. ^[145] There was low- to moderate-strength evidence of no benefit for most of the other medications used in RCTs, which included antidepressants (bupropion, mirtazapine, sertraline), antipsychotics (aripiprazole), anticonvulsants (topiramate, baclofen, gabapentin), naltrexone, varenicline, citicoline, ondansetron, prometa, riluzole, atomoxetine, dextroamphetamine, and modafinil. ^[145]

Behavioral treatments

A 2018 systematic review and network meta-analysis of 50 trials involving 12 different psychosocial interventions for amphetamine, methamphetamine, or cocaine addiction found that combination therapy with both contingency management and community reinforcement approach had the highest efficacy (i.e., abstinence rate) and acceptability (i.e., lowest dropout rate). ^[150] Other treatment modalities examined in the analysis included monotherapy with contingency management or community reinforcement approach, cognitive behavioral therapy, 12-step programs, non-contingent reward-based therapies, psychodynamic therapy, and other combination therapies involving these. ^[150]

Additionally, research on the neurobiological effects of physical exercise suggests that daily aerobic exercise, especially endurance exercise (e.g., marathon running), prevents the development of drug addiction and is an effective adjunct therapy (i.e., a supplemental treatment) for amphetamine addiction. ^{[sources 7]} Exercise leads to better treatment outcomes when used as an adjunct treatment, particularly for psychostimulant addictions. ^{[129] [131] [151]} In particular, aerobic exercise decreases psychostimulant self-administration, reduces the reinstatement (i.e., relapse) of drug-seeking, and induces increased dopamine receptor D₂ (DRD2) density in the striatum. ^{[128] [151]} This is the opposite of pathological stimulant use, which induces decreased striatal DRD2 density. ^[128] One review noted that exercise may also prevent the development of a drug addiction by altering ΔFosB or c-Fos immunoreactivity in the striatum or other parts of the reward system. ^[130]

Summary of addiction-related plasticity

Form of neuroplasticity or behavioral plasticity	Type of reinforcer						Sources
	Opiates	Psychostimulants	High fat or sugar food	Sexual intercourse	Physical exercise (aerobic)	Environmental enrichment
ΔFosB expression in nucleus accumbens D1-type MSNs Tooltip medium spiny neurons	↑	↑	↑	↑	↑	↑	[128]
Behavioral plasticity
Escalation of intake	Yes	Yes	Yes				[128]
Psychostimulant cross-sensitization	Yes	Not applicable	Yes	Yes	Attenuated	Attenuated	[128]
Psychostimulant self-administration	↑	↑	↓		↓	↓	[128]
Psychostimulant conditioned place preference	↑	↑	↓	↑	↓	↑	[128]
Reinstatement of drug-seeking behavior	↑	↑			↓	↓	[128]
Neurochemical plasticity
CREB Tooltip cAMP response element-binding protein phosphorylation in the nucleus accumbens	↓	↓	↓		↓	↓	[128]
Sensitized dopamine response in the nucleus accumbens	No	Yes	No	Yes			[128]
Altered striatal dopamine signaling	↓DRD2, ↑DRD3	↑DRD1, ↓DRD2, ↑DRD3	↑DRD1, ↓DRD2, ↑DRD3		↑DRD2	↑DRD2	[128]
Altered striatal opioid signaling	No change or ↑μ-opioid receptors	↑μ-opioid receptors ↑κ-opioid receptors	↑μ-opioid receptors	↑μ-opioid receptors	No change	No change	[128]
Changes in striatal opioid peptides	↑dynorphin No change: enkephalin	↑dynorphin	↓enkephalin		↑dynorphin	↑dynorphin	[128]
Mesocorticolimbic synaptic plasticity
Number of dendrites in the nucleus accumbens	↓	↑		↑			[128]
Dendritic spine density in the nucleus accumbens	↓	↑		↑			[128]

Dependence and withdrawal

Drug tolerance develops rapidly in amphetamine abuse (i.e., recreational amphetamine use), so periods of extended abuse require increasingly larger doses of the drug in order to achieve the same effect. ^{[152] [153]} According to a Cochrane review on withdrawal in individuals who compulsively use amphetamine and methamphetamine, "when chronic heavy users abruptly discontinue amphetamine use, many report a time-limited withdrawal syndrome that occurs within 24 hours of their last dose." ^[154] This review noted that withdrawal symptoms in chronic, high-dose users are frequent, occurring in roughly 88% of cases, and persist for 3–4 weeks with a marked "crash" phase occurring during the first week. ^[154] 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. ^[154] The review indicated that the severity of withdrawal symptoms is positively correlated with the age of the individual and the extent of their dependence. ^[154] Mild withdrawal symptoms from the discontinuation of amphetamine treatment at therapeutic doses can be avoided by tapering the dose. ^[7]

Overdose

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

An amphetamine overdose can lead to many different symptoms, but is rarely fatal with appropriate care. ^{[155] [97] [156]} The severity of overdose symptoms increases with dosage and decreases with drug tolerance to amphetamine. ^{[157] [97]} Tolerant individuals have been known to take as much as 5 grams of amphetamine in a day, which is roughly 100 times the maximum daily therapeutic dose. ^[97] Symptoms of a moderate and extremely large overdose are listed below; fatal amphetamine poisoning usually also involves convulsions and coma. ^{[96] [157]} In 2013, overdose on amphetamine, methamphetamine, and other compounds implicated in an "amphetamine use disorder" resulted in an estimated 3,788 deaths worldwide (3,425–4,145 deaths, 95% confidence). ^{[note 12] [158]}

Overdose symptoms by system

System	Minor or moderate overdose [96] [157] [97]	Severe overdose [sources 10]
Cardiovascular	Abnormal heartbeat High or low blood pressure	Cardiogenic shock (heart not pumping enough blood) Cerebral hemorrhage (bleeding in the brain) Circulatory collapse (partial or complete failure of the circulatory system)
Central nervous system	Confusion Abnormally fast reflexes Severe agitation Tremor (involuntary muscle twitching)	Acute amphetamine psychosis (e.g., delusions and paranoia) Compulsive and repetitive movement Serotonin syndrome (excessive serotonergic nerve activity) Sympathomimetic toxidrome (excessive adrenergic nerve activity)
Musculoskeletal	Muscle pain	Rhabdomyolysis (rapid muscle breakdown)
Respiratory	Rapid breathing	Pulmonary edema (fluid accumulation in the lungs) Pulmonary hypertension (high blood pressure in the arteries of the lung) Respiratory alkalosis (reduced blood CO2)
Urinary	Painful urination Urinary retention (inability to urinate)	No urine production Kidney failure
Other	Elevated body temperature Mydriasis (dilated pupils)	Elevated or low blood potassium Hyperpyrexia (extremely elevated core body temperature) Metabolic acidosis (excessively acidic bodily fluids)

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. ^[161]
• Inhibitors of enzymes that directly metabolize amphetamine (particularly CYP2D6 and FMO3) will prolong the elimination of amphetamine and increase drug effects. ^{[161] [162] [163]}
• Serotonergic drugs (such as most antidepressants) co-administered with amphetamine increases the risk of serotonin syndrome. ^[163]
• Stimulants and antidepressants (sedatives and depressants) may increase (decrease) the drug effects of amphetamine, and vice versa. ^[161]
• 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. ^[161]
• Proton-pump inhibitors (PPIs) modify the absorption of Adderall XR and Mydayis. ^{[161] [163]}
• Zinc supplementation may reduce the minimum effective dose of amphetamine when it is used for the treatment of ADHD. ^{[note 13] [167]}

Pharmacology

Mechanism of action

For a more complete and detailed description of amphetamine pharmacodynamics, see Amphetamine § Pharmacodynamics.

Monoamine release of amphetamine and related agents (EC₅₀ Tooltip Half maximal effective concentration, nM)

Compound	NE Tooltip Norepinephrine	DA Tooltip Dopamine	5-HT Tooltip Serotonin	Ref
Phenethylamine	10.9	39.5	>10000	[168] [169] [170]
Dextroamphetamine	6.6–7.2	5.8–24.8	698–1765	[171] [172]
Levoamphetamine	9.5	27.7	ND	[169] [170]
Dextromethamphetamine	12.3–13.8	8.5–24.5	736–1291.7	[171] [173]
Levomethamphetamine	28.5	416	4640	[171]
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: [174] [175]

Pharmacodynamics of amphetamine in a dopamine neuron v t e via AADC Amphetamine enters the presynaptic neuron across the neuronal membrane or through DAT. [28] Once inside, it binds to TAAR1 or enters synaptic vesicles through VMAT2. [28] [29] 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. [29] [176] When amphetamine binds to TAAR1, it reduces the firing rate of the dopamine neuron via G protein-coupled inwardly rectifying potassium channels (GIRKs) and activates protein kinase A (PKA) and protein kinase C (PKC), which subsequently phosphorylate DAT. [28] [177] [178] PKA phosphorylation causes DAT to withdraw into the presynaptic neuron (internalize) and cease transport. [28] PKC-phosphorylated DAT may either operate in reverse or, like PKA-phosphorylated DAT, internalize and cease transport. [28] 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. [179] [180]

Amphetamine, the active ingredient of Adderall, works primarily by increasing the activity of the neurotransmitters dopamine and norepinephrine in the brain. ^{[27] [47]} 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). ^{[29] [181]} Both active ingredients of Adderall, dextroamphetamine and levoamphetamine, bind to the same biological targets, ^{[31] [32]} but their binding affinities (that is, potency) differ somewhat. ^{[31] [32]} 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. ^[32] Consequently, dextroamphetamine produces more CNS stimulation than levoamphetamine; ^{[32] [182]} however, levoamphetamine has slightly greater cardiovascular and peripheral effects. ^[31] It has been reported that certain children have a better clinical response to levoamphetamine. ^{[33] [34]}

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. ^[29] 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. ^[29] 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; ^[28] 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. ^[28] 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). ^{[28] [29]}

Pharmacokinetics

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

The oral bioavailability of amphetamine varies with gastrointestinal pH; ^[20] it is well absorbed from the gut, and bioavailability is typically 90%. ^[10] Amphetamine is a weak base with a pK_a of 9.9; ^[183] consequently, when the pH is basic, more of the drug is in its lipid soluble free base form, and more is absorbed through the lipid-rich cell membranes of the gut epithelium. ^{[183] [20]} Conversely, an acidic pH means the drug is predominantly in a water-soluble cationic (salt) form, and less is absorbed. ^[183] Approximately 20% of amphetamine circulating in the bloodstream is bound to plasma proteins. ^[184] Following absorption, amphetamine readily distributes into most tissues in the body, with high concentrations occurring in cerebrospinal fluid and brain tissue. ^[185]

The half-lives of amphetamine enantiomers differ and vary with urine pH. ^[183] At normal urine pH, the half-lives of dextroamphetamine and levoamphetamine are 9–11 hours and 11–14 hours, respectively. ^[183] Highly acidic urine will reduce the enantiomer half-lives to 7 hours; ^[185] highly alkaline urine will increase the half-lives up to 34 hours. ^[185] The immediate-release and extended release variants of salts of both isomers reach peak plasma concentrations at 3 hours and 7 hours post-dose respectively. ^[183] Amphetamine is eliminated via the kidneys, with 30–40% of the drug being excreted unchanged at normal urinary pH. ^[183] When the urinary pH is basic, amphetamine is in its free base form, so less is excreted. ^[183] When urine pH is abnormal, the urinary recovery of amphetamine may range from a low of 1% to a high of 75%, depending mostly upon whether urine is too basic or acidic, respectively. ^[183] Following oral administration, amphetamine appears in urine within 3 hours. ^[185] Roughly 90% of ingested amphetamine is eliminated 3 days after the last oral dose. ^[185]

CYP2D6, dopamine β-hydroxylase (DBH), flavin-containing monooxygenase 3 (FMO3), butyrate-CoA ligase (XM-ligase), and glycine N-acyltransferase (GLYAT) are the enzymes known to metabolize amphetamine or its metabolites in humans. ^{[sources 11]} Amphetamine has a variety of excreted metabolic products, including 4-hydroxyamphetamine , 4-hydroxynorephedrine , 4-hydroxyphenylacetone , benzoic acid, hippuric acid, norephedrine, and phenylacetone. ^{[183] [186]} Among these metabolites, the active sympathomimetics are 4-hydroxyamphetamine, ^[187] 4-hydroxynorephedrine, ^[188] and norephedrine. ^[189] The main metabolic pathways involve aromatic para-hydroxylation, aliphatic alpha- and beta-hydroxylation, N-oxidation, N-dealkylation, and deamination. ^{[183] [190]} The known metabolic pathways, detectable metabolites, and metabolizing enzymes in humans include the following:

Metabolic pathways of amphetamine in humans [sources 11] 4-Hydroxyphenylacetone Phenylacetone Benzoic acid Hippuric acid Amphetamine Norephedrine 4-Hydroxyamphetamine 4-Hydroxynorephedrine Para- Hydroxylation Para- Hydroxylation Para- Hydroxylation CYP2D6 CYP2D6 unidentified Beta- Hydroxylation Beta- Hydroxylation DBH DBH [note 14] Oxidative Deamination FMO3 Oxidation unidentified Glycine Conjugation XM-ligase GLYAT The primary active metabolites of amphetamine are 4-hydroxyamphetamine and norephedrine; [186] at normal urine pH, about 30–40% of amphetamine is excreted unchanged and roughly 50% is excreted as the inactive metabolites (bottom row). [183] The remaining 10–20% is excreted as the active metabolites. [183] Benzoic acid is metabolized by XM-ligase into an intermediate product, benzoyl-CoA, which is then metabolized by GLYAT into hippuric acid. [195]

Pharmacomicrobiomics

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

The human metagenome (i.e., the genetic composition of an individual and all microorganisms that reside on or within the individual's body) varies considerably between individuals. ^{[199] [200]} Since the total number of microbial and viral cells in the human body (over 100 trillion) greatly outnumbers human cells (tens of trillions), ^{[note 15] [199] [201]} there is considerable potential for interactions between drugs and an individual's microbiome, including: drugs altering the composition of the human microbiome, drug metabolism by microbial enzymes modifying the drug's pharmacokinetic profile, and microbial drug metabolism affecting a drug's clinical efficacy and toxicity profile. ^{[199] [200] [202]} The field that studies these interactions is known as pharmacomicrobiomics. ^[199]

Similar to most biomolecules and other orally administered xenobiotics (i.e., drugs), amphetamine is predicted to undergo promiscuous metabolism by human gastrointestinal microbiota (primarily bacteria) prior to absorption into the blood stream. ^[202] The first amphetamine-metabolizing microbial enzyme, tyramine oxidase from a strain of E. coli commonly found in the human gut, was identified in 2019. ^[202] This enzyme was found to metabolize amphetamine, tyramine, and phenethylamine with roughly the same binding affinity for all three compounds. ^[202]

Related endogenous compounds

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

Further informationon related compounds: Trace amine

Amphetamine has a very similar structure and function to the endogenous trace amines, which are naturally occurring neuromodulator molecules produced in the human body and brain. ^{[28] [203] [204]} Among this group, the most closely related compounds are phenethylamine, the parent compound of amphetamine, and N-methylphenethylamine , a structural isomer of amphetamine (i.e., it has an identical molecular formula). ^{[28] [203] [205]} 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. ^{[203] [205]} In turn, N-methylphenethylamine is metabolized from phenethylamine by phenylethanolamine N-methyltransferase, the same enzyme that metabolizes norepinephrine into epinephrine. ^{[203] [205]} Like amphetamine, both phenethylamine and N-methylphenethylamine regulate monoamine neurotransmission via TAAR1; ^{[28] [204] [205]} unlike amphetamine, both of these substances are broken down by monoamine oxidase B, and therefore have a shorter half-life than amphetamine. ^{[203] [205]}

History

Main article: History and culture of substituted amphetamines

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. ^[206] 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. ^{[207] [208]} In 1997 Richwood Pharmaceuticals was acquired by Shire Pharmaceuticals in a $186 million transaction. ^[206]

Richwood Pharmaceuticals, which later merged with Shire plc, introduced the current Adderall brand in 1996 as an instant-release tablet. ^[209] In 2006, Shire agreed to sell rights to the Adderall name for the instant-release form of the medication to Duramed Pharmaceuticals. ^[210] DuraMed Pharmaceuticals was acquired by Teva Pharmaceuticals in 2008 during their acquisition of Barr Pharmaceuticals, including Barr's Duramed division. ^[211]

The first generic version of Adderall IR was introduced to the market in 2002. ^[12] 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. ^{[12] [212]}

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. ^[66] This drug mixture has slightly stronger CNS effects than racemic amphetamine due to the higher proportion of dextroamphetamine. ^{[28] [31]} Adderall is produced as both an immediate-release (IR) and extended-release (XR) formulation. ^{[12] [17] [66]} As of December 2013 ^[update] , ten different companies produced generic Adderall IR, while Teva Pharmaceutical Industries, Actavis, and Barr Pharmaceuticals manufactured generic Adderall XR. ^[12] As of 2013 ^[update] , Shire plc, the company that held the original patent for Adderall and Adderall XR, still manufactured brand name Adderall XR, but not Adderall IR. ^[12]

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	molar mass [note 16]		amphetamine base [note 17]			amphetamine base in equal doses		doses with equal base content [note 18]
			(g/mol)		(percent)			(30 mg dose)
			total	base	total	dextro-	levo-	dextro-	levo-
dextroamphetamine sulfate [214] [215]		(C9H13N)2•H2SO4	368.49	270.41	73.38%	73.38%	—	22.0 mg	—	30.0 mg
amphetamine sulfate [216]		(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 [214] [215]	(C9H13N)2•H2SO4	368.49	270.41	73.38%	73.38%	—
25%	amphetamine sulfate [216]	(C9H13N)2•H2SO4	368.49	270.41	73.38%	36.69%	36.69%
25%	dextroamphetamine saccharate [217]	(C9H13N)2•C6H10O8	480.55	270.41	56.27%	56.27%	—
25%	amphetamine aspartate monohydrate [218]	(C9H13N)•C4H7NO4•H2O	286.32	135.21	47.22%	23.61%	23.61%
lisdexamfetamine dimesylate [219]		C15H25N3O•(CH4O3S)2	455.49	135.21	29.68%	29.68%	—	8.9 mg	—	74.2 mg
amphetamine base suspension [104]		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. ^[220]
• In Japan, the use, production, and import of any medicine containing amphetamines is prohibited. ^[221]
• In South Korea, amphetamines are prohibited. ^[222]
• In Taiwan, amphetamines including Adderall are Schedule 2 drugs with a minimum five-year prison term for possession. ^[223] On the contrary, Ritalin can be legally prescribed as a form of treatment of ADHD. ^[224]
• In Thailand, amphetamines are classified as Type 1 Narcotics. ^[225]
• 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. ^[226]
• In the United States, amphetamine is a Schedule II prescription drug, classified as a central nervous system (CNS) stimulant. ^[9]
• Internationally, amphetamine is in Schedule II of the Convention on Psychotropic Substances. ^{[227] [228]}

Shortages

In February 2023, news organizations began reporting on shortages of Adderall in the United States that have lasted for over five months. ^{[229] [230]} The Food and Drug Administration first reported the shortage in October 2022. ^[231] In May 2023, seven 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". ^{[232] [233]} The shortage has continued into 2024. ^{[234] [235] [236]} 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 and the weight-loss drug semaglutide, raising concerns that patients who cannot afford to outsource their search would be left behind. ^[237]

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. ^[12] Mydayis is a relatively new trade name that is not commonly used to refer generally to the mixture. ^[11]
3. The ADHD-related outcome domains with the greatest proportion of significantly improved outcomes from long-term continuous stimulant therapy include academics (≈55% of academic outcomes improved), driving (100% of driving outcomes improved), non-medical drug use (47% of addiction-related outcomes improved), obesity (≈65% of obesity-related outcomes improved), self-esteem (50% of self-esteem outcomes improved), and social function (67% of social function outcomes improved). ^[45]
   
   The largest effect sizes for outcome improvements from long-term stimulant therapy occur in the domains involving academics (e.g., grade point average, achievement test scores, length of education, and education level), self-esteem (e.g., self-esteem questionnaire assessments, number of suicide attempts, and suicide rates), and social function (e.g., peer nomination scores, social skills, and quality of peer, family, and romantic relationships). ^[45]
   
   Long-term combination therapy for ADHD (i.e., treatment with both a stimulant and behavioral therapy) produces even larger effect sizes for outcome improvements and improves a larger proportion of outcomes across each domain compared to long-term stimulant therapy alone. ^[45]
4. Cochrane reviews are high quality meta-analytic systematic reviews of randomized controlled trials. ^[51]
5. The statements supported by the USFDA come from prescribing information, which is the copyrighted intellectual property of the manufacturer and approved by the USFDA. USFDA contraindications are not necessarily intended to limit medical practice but limit claims by pharmaceutical companies. ^[93]
6. According to one review, amphetamine can be prescribed to individuals with a history of abuse provided that appropriate medication controls are employed, such as requiring daily pick-ups of the medication from the prescribing physician. ^[94]
7. 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. ^{[100] [101] [102]} The average reduction in final adult height from 3 years of continuous stimulant therapy is 2 cm. ^[102]
8. Transcription factors are proteins that increase or decrease the expression of specific genes. ^[134]
9. In simpler terms, this necessary and sufficient relationship means that ΔFosB overexpression in the nucleus accumbens and addiction-related behavioral and neural adaptations always occur together and never occur alone.
10. NMDA receptors are voltage-dependent ligand-gated ion channels that requires simultaneous binding of glutamate and a co-agonist ( D-serine or glycine) to open the ion channel. ^[149]
11. The review indicated that magnesium L-aspartate and magnesium chloride produce significant changes in addictive behavior; ^[125] other forms of magnesium were not mentioned.
12. The 95% confidence interval indicates that there is a 95% probability that the true number of deaths lies between 3,425 and 4,145.
13. 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 . ^{[164] [165] [166]} The human serotonin transporter and norepinephrine transporter do not contain zinc binding sites. ^[166]
14. 4-Hydroxyamphetamine has been shown to be metabolized into 4-hydroxynorephedrine by dopamine beta-hydroxylase (DBH) in vitro and it is presumed to be metabolized similarly in vivo . ^{[191] [194]} Evidence from studies that measured the effect of serum DBH concentrations on 4-hydroxyamphetamine metabolism in humans suggests that a different enzyme may mediate the conversion of 4-hydroxyamphetamine to 4-hydroxynorephedrine; ^{[194] [196]} however, other evidence from animal studies suggests that this reaction is catalyzed by DBH in synaptic vesicles within noradrenergic neurons in the brain. ^{[197] [198]}
15. There is substantial variation in microbiome composition and microbial concentrations by anatomical site. ^{[199] [200]} Fluid from the human colon – which contains the highest concentration of microbes of any anatomical site – contains approximately one trillion (10^12) bacterial cells/ml. ^[199]
16. For uniformity, molar masses were calculated using the Lenntech Molecular Weight Calculator ^[213] and were within 0.01 g/mol of published pharmaceutical values.
17. Amphetamine base percentage = molecular mass_base / molecular mass_total. Amphetamine base percentage for Adderall = sum of component percentages / 4.
18. dose = (1 / amphetamine base percentage) × scaling factor = (molecular mass_total / molecular mass_base) × 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.

Image legend

1.    Ion channel
      G proteins & linked receptors
     (Text color) Transcription factors

Reference notes

1. ^{[16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26]}
2. ^{[27] [28] [29] [30] [31] [32] [33] [34]}
3. ^{[7] [20] [31] [103] [104] [105]}
4. ^{[106] [107] [108] [109]}
5. ^{[20] [110] [106] [108]}
6. ^{[16] [20] [31] [111]}
7. ^{[128] [129] [130] [131] [151]}
8. ^{[126] [128] [127] [135] [136]}
9. ^{[127] [138] [139] [140]}
10. ^{[159] [96] [157] [156] [160]}
11. ^{[183] [191] [192] [162] [193] [186] [194] [195]}

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18. Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 13: Higher Cognitive Function and Behavioral Control". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York, US: McGraw-Hill Medical. pp. 318, 321. ISBN   9780071481274. Therapeutic (relatively low) doses of psychostimulants, such as methylphenidate and amphetamine, improve performance on working memory tasks both in normal subjects and those with ADHD. ... stimulants act not only on working memory function, but also on general levels of arousal and, within the nucleus accumbens, improve the saliency of tasks. Thus, stimulants improve performance on effortful but tedious tasks ... through indirect stimulation of dopamine and norepinephrine receptors. ...
    Beyond these general permissive effects, dopamine (acting via D1 receptors) and norepinephrine (acting at several receptors) can, at optimal levels, enhance working memory and aspects of attention.
19. Liddle DG, Connor DJ (June 2013). "Nutritional supplements and ergogenic AIDS". Primary Care: Clinics in Office Practice. 40 (2): 487–505. doi:10.1016/j.pop.2013.02.009. PMID   23668655. Amphetamines and caffeine are stimulants that increase alertness, improve focus, decrease reaction time, and delay fatigue, allowing for an increased intensity and duration of training ...
    Physiologic and performance effects
     •Amphetamines increase dopamine/norepinephrine release and inhibit their reuptake, leading to central nervous system (CNS) stimulation
     •Amphetamines seem to enhance athletic performance in anaerobic conditions 39 40
     •Improved reaction time
     •Increased muscle strength and delayed muscle fatigue
     •Increased acceleration
     •Increased alertness and attention to task
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21. Shoptaw SJ, Kao U, Ling W (January 2009). Shoptaw SJ, Ali R (eds.). "Treatment for amphetamine psychosis". Cochrane Database of Systematic Reviews. 2009 (1): CD003026. doi:10.1002/14651858.CD003026.pub3. PMC   7004251 . PMID   19160215. A minority of individuals who use amphetamines develop full-blown psychosis requiring care at emergency departments or psychiatric hospitals. In such cases, symptoms of amphetamine psychosis commonly include paranoid and persecutory delusions as well as auditory and visual hallucinations in the presence of extreme agitation. More common (about 18%) is for frequent amphetamine users to report psychotic symptoms that are sub-clinical and that do not require high-intensity intervention ...
    About 5–15% of the users who develop an amphetamine psychosis fail to recover completely (Hofmann 1983) ...
    Findings from one trial indicate use of antipsychotic medications effectively resolves symptoms of acute amphetamine psychosis.
    psychotic symptoms of individuals with amphetamine psychosis may be due exclusively to heavy use of the drug or heavy use of the drug may exacerbate an underlying vulnerability to schizophrenia.
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23. Malenka RC, Nestler EJ, Hyman SE, Holtzman DM (2015). "Chapter 16: Reinforcement and Addictive Disorders". Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (3rd ed.). New York: McGraw-Hill Medical. ISBN   9780071827706. Such agents also have important therapeutic uses; cocaine, for example, is used as a local anesthetic (Chapter 2), and amphetamines and methylphenidate are used in low doses to treat attention deficit hyperactivity disorder and in higher doses to treat narcolepsy (Chapter 12). Despite their clinical uses, these drugs are strongly reinforcing, and their long-term use at high doses is linked with potential addiction, especially when they are rapidly administered or when high-potency forms are given.
24. Kollins SH (May 2008). "A qualitative review of issues arising in the use of psycho-stimulant medications in patients with ADHD and co-morbid substance use disorders". Current Medical Research and Opinion. 24 (5): 1345–1357. doi:10.1185/030079908X280707. PMID   18384709. S2CID   71267668. When oral formulations of psychostimulants are used at recommended doses and frequencies, they are unlikely to yield effects consistent with abuse potential in patients with ADHD.
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37. Heal DJ, Smith SL, Gosden J, Nutt DJ (June 2013). "Amphetamine, past and present – a pharmacological and clinical perspective". Journal of Psychopharmacology. 27 (6): 479–496. doi:10.1177/0269881113482532. PMC   3666194 . 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).
38. Carvalho M, Carmo H, Costa VM, Capela JP, Pontes H, Remião F, et al. (August 2012). "Toxicity of amphetamines: an update". Archives of Toxicology. 86 (8): 1167–1231. Bibcode:2012ArTox..86.1167C. doi:10.1007/s00204-012-0815-5. PMID   22392347. S2CID   2873101.
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40. Hart H, Radua J, Nakao T, Mataix-Cols D, Rubia K (February 2013). "Meta-analysis of functional magnetic resonance imaging studies of inhibition and attention in attention-deficit/hyperactivity disorder: exploring task-specific, stimulant medication, and age effects". JAMA Psychiatry. 70 (2): 185–198. doi: 10.1001/jamapsychiatry.2013.277 . PMID   23247506.
41. Spencer TJ, Brown A, Seidman LJ, Valera EM, Makris N, Lomedico A, et al. (September 2013). "Effect of psychostimulants on brain structure and function in ADHD: a qualitative literature review of magnetic resonance imaging-based neuroimaging studies". The Journal of Clinical Psychiatry. 74 (9): 902–917. doi:10.4088/JCP.12r08287. PMC   3801446 . PMID   24107764.
42. Frodl T, Skokauskas N (February 2012). "Meta-analysis of structural MRI studies in children and adults with attention deficit hyperactivity disorder indicates treatment effects". Acta Psychiatrica Scandinavica. 125 (2): 114–126. doi: 10.1111/j.1600-0447.2011.01786.x . PMID   22118249. S2CID   25954331. Basal ganglia regions like the right globus pallidus, the right putamen, and the nucleus caudatus are structurally affected in children with ADHD. These changes and alterations in limbic regions like ACC and amygdala are more pronounced in non-treated populations and seem to diminish over time from child to adulthood. Treatment seems to have positive effects on brain structure.
43. Huang YS, Tsai MH (July 2011). "Long-term outcomes with medications for attention-deficit hyperactivity disorder: current status of knowledge". CNS Drugs. 25 (7): 539–554. doi:10.2165/11589380-000000000-00000. PMID   21699268. S2CID   3449435. Several other studies,^[97-101] including a meta-analytic review^[98] and a retrospective study,^[97] suggested that stimulant therapy in childhood is associated with a reduced risk of subsequent substance use, cigarette smoking and alcohol use disorders. ... Recent studies have demonstrated that stimulants, along with the non-stimulants atomoxetine and extended-release guanfacine, are continuously effective for more than 2-year treatment periods with few and tolerable adverse effects. The effectiveness of long-term therapy includes not only the core symptoms of ADHD, but also improved quality of life and academic achievements. The most concerning short-term adverse effects of stimulants, such as elevated blood pressure and heart rate, waned in long-term follow-up studies. ... The current data do not support the potential impact of stimulants on the worsening or development of tics or substance abuse into adulthood. In the longest follow-up study (of more than 10 years), lifetime stimulant treatment for ADHD was effective and protective against the development of adverse psychiatric disorders.
44. Millichap JG (2010). "Chapter 9: Medications for ADHD". In Millichap JG (ed.). Attention Deficit Hyperactivity Disorder Handbook: A Physician's Guide to ADHD (2nd ed.). New York, US: Springer. pp. 121–123, 125–127. ISBN   9781441913968. Ongoing research has provided answers to many of the parents' concerns, and has confirmed the effectiveness and safety of the long-term use of medication.
45. Arnold LE, Hodgkins P, Caci H, Kahle J, Young S (February 2015). "Effect of treatment modality on long-term outcomes in attention-deficit/hyperactivity disorder: a systematic review". PLOS ONE. 10 (2): e0116407. doi: 10.1371/journal.pone.0116407 . PMC   4340791 . PMID   25714373. The highest proportion of improved outcomes was reported with combination treatment (83% of outcomes). Among significantly improved outcomes, the largest effect sizes were found for combination treatment. The greatest improvements were associated with academic, self-esteem, or social function outcomes.
    Figure 3: Treatment benefit by treatment type and outcome group
46. Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York, US: McGraw-Hill Medical. pp. 154–157. ISBN   9780071481274.
47. Bidwell LC, McClernon FJ, Kollins SH (August 2011). "Cognitive enhancers for the treatment of ADHD". Pharmacology Biochemistry and Behavior. 99 (2): 262–274. doi:10.1016/j.pbb.2011.05.002. PMC   3353150 . PMID   21596055.
48. Parker J, Wales G, Chalhoub N, Harpin V (September 2013). "The long-term outcomes of interventions for the management of attention-deficit hyperactivity disorder in children and adolescents: a systematic review of randomized controlled trials". Psychology Research and Behavior Management. 6: 87–99. doi: 10.2147/PRBM.S49114 . PMC   3785407 . PMID   24082796. Only one paper⁵³ examining outcomes beyond 36 months met the review criteria. ... There is high level evidence suggesting that pharmacological treatment can have a major beneficial effect on the core symptoms of ADHD (hyperactivity, inattention, and impulsivity) in approximately 80% of cases compared with placebo controls, in the short term.
49. Millichap JG (2010). "Chapter 9: Medications for ADHD". In Millichap JG (ed.). Attention Deficit Hyperactivity Disorder Handbook: A Physician's Guide to ADHD (2nd ed.). New York, US: Springer. pp. 111–113. ISBN   9781441913968.
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52. Castells X, Blanco-Silvente L, Cunill R (August 2018). "Amphetamines for attention deficit hyperactivity disorder (ADHD) in adults". Cochrane Database of Systematic Reviews. 2018 (8): CD007813. doi:10.1002/14651858.CD007813.pub3. PMC   6513464 . PMID   30091808.
53. Punja S, Shamseer L, Hartling L, Urichuk L, Vandermeer B, Nikles J, et al. (February 2016). "Amphetamines for attention deficit hyperactivity disorder (ADHD) in children and adolescents". Cochrane Database of Systematic Reviews. 2016 (2): CD009996. doi:10.1002/14651858.CD009996.pub2. PMC   10329868 . PMID   26844979.
54. Osland ST, Steeves TD, Pringsheim T (June 2018). "Pharmacological treatment for attention deficit hyperactivity disorder (ADHD) in children with comorbid tic disorders". Cochrane Database of Systematic Reviews. 2018 (6): CD007990. doi:10.1002/14651858.CD007990.pub3. PMC   6513283 . PMID   29944175.
55. Mahlios J, De la Herrán-Arita AK, Mignot E (October 2013). "The autoimmune basis of narcolepsy". Current Opinion in Neurobiology. 23 (5): 767–773. doi:10.1016/j.conb.2013.04.013. PMC   3848424 . PMID   23725858.
56. Barateau L, Pizza F, Plazzi G, Dauvilliers Y (August 2022). "Narcolepsy". Journal of Sleep Research. 31 (4): e13631. doi:10.1111/jsr.13631. PMID   35624073. Narcolepsy type 1 was called "narcolepsy with cataplexy" before 2014 (AASM, 2005), but was renamed NT1 in the third and last international classification of sleep disorders (AASM, 2014). ... A low level of Hcrt-1 in the CSF is very sensitive and specific for the diagnosis of NT1. ...
    All patients with low CSF Hcrt-1 levels are considered as NT1 patients, even if they report no cataplexy (in about 10–20% of cases), and all patients with normal CSF Hcrt-1 levels (or without cataplexy when the lumbar puncture is not performed) as NT2 patients (Baumann et al., 2014). ...
    In patients with NT1, the absence of Hcrt leads to the inhibition of regions that suppress REM sleep, thus allowing the activation of descending pathways inhibiting motoneurons, leading to cataplexy.
57. Mignot EJ (October 2012). "A practical guide to the therapy of narcolepsy and hypersomnia syndromes". Neurotherapeutics. 9 (4): 739–752. doi:10.1007/s13311-012-0150-9. PMC   3480574 . PMID   23065655. At the pathophysiological level, it is now clear that most narcolepsy cases with cataplexy, and a minority of cases (5–30 %) without cataplexy or with atypical cataplexy-like symptoms, are caused by a lack of hypocretin (orexin) of likely an autoimmune origin. In these cases, once the disease is established, the majority of the 70,000 hypocretin-producing cells have been destroyed, and the disorder is irreversible. ...
    Amphetamines are exceptionally wake-promoting, and at high doses also reduce cataplexy in narcoleptic patients, an effect best explained by its action on adrenergic and serotoninergic synapses. ...
    The D-isomer is more specific for DA transmission and is a better stimulant compound. Some effects on cataplexy (especially for the L-isomer), secondary to adrenergic effects, occur at higher doses. ...
    Numerous studies have shown that increased dopamine release is the main property explaining wake-promotion, although norepinephrine effects also contribute.
58. Malenka RC, Nestler EJ, Hyman SE, Holtzman DM (2015). "Chapter 10: Neural and Neuroendocrine Control of the Internal Milieu". Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (3rd ed.). New York: McGraw-Hill Medical. pp. 456–457. ISBN   9780071827706. More recently, the lateral hypothalamus was also found to play a central role in arousal. Neurons in this region contain cell bodies that produce the orexin (also called hypocretin) peptides (Chapter 6). These neurons project widely throughout the brain and are involved in sleep, arousal, feeding, reward,aspects of emotion, and learning. In fact, orexin is thought to promote feeding primarily by promoting arousal. Mutations in orexin receptors are responsible for narcolepsy in a canine model, knockout of the orexin gene produces narcolepsy in mice, and humans with narcolepsy have low or absent levels of orexin peptides in cerebrospinal fluid (Chapter 13). Lateral hypothalamus neurons have reciprocal connections with neurons that produce monoamine neurotransmitters (Chapter 6).
59. Malenka RC, Nestler EJ, Hyman SE, Holtzman DM (2015). "Chapter 13: Sleep and Arousal". Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (3rd ed.). McGraw-Hill Medical. p. 521. ISBN   9780071827706. The ARAS consists of several different circuits including the four main monoaminergic pathways discussed in Chapter 6. The norepinephrine pathway originates from the LC and related brainstem nuclei; the serotonergic neurons originate from the RN within the brainstem as well; the dopaminergic neurons originate in the ventral tegmental area (VTA); and the histaminergic pathway originates from neurons in the tuberomammillary nucleus (TMN) of the posterior hypothalamus. As discussed in Chapter 6, these neurons project widely throughout the brain from restricted collections of cell bodies. Norepinephrine, serotonin,dopamine, and histamine have complex modulatory functions and, in general, promote wakefulness. The PT in the brainstem is also an important component of the ARAS. Activity of PT cholinergic neurons (REM-on cells) promotes REM sleep, as noted earlier. During waking, REM-on cells are inhibited by a subset of ARAS norepinephrine and serotonin neurons called REM-off cells.
60. Shneerson JM (2009). Sleep medicine a guide to sleep and its disorders (2nd ed.). John Wiley & Sons. p. 81. ISBN   9781405178518. All the amphetamines enhance activity at dopamine, noradrenaline and 5HT synapses. They cause presynaptic release of preformed transmitters, and also inhibit the re-uptake of dopamine and noradrenaline. These actions are most prominent in the brainstem ascending reticular activating system and the cerebral cortex.
61. Schwartz JR, Roth T (2008). "Neurophysiology of sleep and wakefulness: basic science and clinical implications". Current Neuropharmacology. 6 (4): 367–378. doi:10.2174/157015908787386050. PMC   2701283 . PMID   19587857. Alertness and associated forebrain and cortical arousal are mediated by several ascending pathways with distinct neuronal components that project from the upper brain stem near the junction of the pons and the midbrain. ...
    Key cell populations of the ascending arousal pathway include cholinergic, noradrenergic, serotoninergic, dopaminergic, and histaminergic neurons located in the pedunculopontine and laterodorsal tegmental nucleus (PPT/LDT), locus coeruleus, dorsal and median raphe nucleus, and tuberomammillary nucleus (TMN), respectively. ...
    The mechanism of action of sympathomimetic alerting drugs (eg, dextro- and methamphetamine, methylphenidate) is direct or indirect stimulation of dopaminergic and noradrenergic nuclei, which in turn heightens the efficacy of the ventral periaqueductal grey area and locus coeruleus, both components of the secondary branch of the ascending arousal system. ...
    Sympathomimetic drugs have long been used to treat narcolepsy
62. Maski K, Trotti LM, Kotagal S, Robert Auger R, Rowley JA, Hashmi SD, et al. (September 2021). "Treatment of central disorders of hypersomnolence: an American Academy of Sleep Medicine clinical practice guideline". Journal of Clinical Sleep Medicine. 17 (9): 1881–1893. doi:10.5664/jcsm.9328. PMC   8636351 . PMID   34743789. The TF identified 1 double-blind RCT, 1 single-blind RCT, and 1 retrospective observational long-term self-reported case series assessing the efficacy of dextroamphetamine in patients with narcolepsy type 1 and narcolepsy type 2. These studies demonstrated clinically significant improvements in excessive daytime sleepiness and cataplexy.
63. Barateau L, Lopez R, Dauvilliers Y (October 2016). "Management of Narcolepsy". Current Treatment Options in Neurology. 18 (10): 43. doi:10.1007/s11940-016-0429-y. PMID   27549768. The usefulness of amphetamines is limited by a potential risk of abuse, and their cardiovascular adverse effects (Table 1). That is why, even though they are cheaper than other drugs, and efficient, they remain third-line therapy in narcolepsy. Three class II studies showed an improvement of EDS in that disease. ...
    Despite the potential for drug abuse or tolerance using stimulants, patients with narcolepsy rarely exhibit addiction to their medication. ...
    Some stimulants, such as mazindol, amphetamines, and pitolisant, may also have some anticataplectic effects.
64. Dauvilliers Y, Barateau L (August 2017). "Narcolepsy and Other Central Hypersomnias". Continuum. 23 (4, Sleep Neurology): 989–1004. doi:10.1212/CON.0000000000000492. PMID   28777172. Recent clinical trials and practice guidelines have confirmed that stimulants such as modafinil, armodafinil, or sodium oxybate (as first line); methylphenidate and pitolisant (as second line [pitolisant is currently only available in Europe]); and amphetamines (as third line) are appropriate medications for excessive daytime sleepiness.
65. Thorpy MJ, Bogan RK (April 2020). "Update on the pharmacologic management of narcolepsy: mechanisms of action and clinical implications". Sleep Medicine. 68: 97–109. doi:10.1016/j.sleep.2019.09.001. PMID   32032921. The first agents used to treat EDS (ie, amphetamines, methylphenidate) are now considered second- or third-line options because newer medications have been developed with improved tolerability and lower abuse potential (eg, modafinil/armodafinil, solriamfetol, pitolisant)
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71. Spencer RC, Devilbiss DM, Berridge CW (June 2015). "The Cognition-Enhancing Effects of Psychostimulants Involve Direct Action in the Prefrontal Cortex". Biological Psychiatry. 77 (11): 940–950. doi:10.1016/j.biopsych.2014.09.013. PMC   4377121 . PMID   25499957. The procognitive actions of psychostimulants are only associated with low doses. Surprisingly, despite nearly 80 years of clinical use, the neurobiology of the procognitive actions of psychostimulants has only recently been systematically investigated. Findings from this research unambiguously demonstrate that the cognition-enhancing effects of psychostimulants involve the preferential elevation of catecholamines in the PFC and the subsequent activation of norepinephrine α2 and dopamine D1 receptors. ... This differential modulation of PFC-dependent processes across dose appears to be associated with the differential involvement of noradrenergic α2 versus α1 receptors. Collectively, this evidence indicates that at low, clinically relevant doses, psychostimulants are devoid of the behavioral and neurochemical actions that define this class of drugs and instead act largely as cognitive enhancers (improving PFC-dependent function). ... In particular, in both animals and humans, lower doses maximally improve performance in tests of working memory and response inhibition, whereas maximal suppression of overt behavior and facilitation of attentional processes occurs at higher doses.
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83. Parr JW (July 2011). "Attention-deficit hyperactivity disorder and the athlete: new advances and understanding". Clinics in Sports Medicine. 30 (3): 591–610. doi:10.1016/j.csm.2011.03.007. PMID   21658550. In 1980, Chandler and Blair⁴⁷ showed significant increases in knee extension strength, acceleration, anaerobic capacity, time to exhaustion during exercise, pre-exercise and maximum heart rates, and time to exhaustion during maximal oxygen consumption (VO2 max) testing after administration of 15 mg of dextroamphetamine versus placebo. Most of the information to answer this question has been obtained in the past decade through studies of fatigue rather than an attempt to systematically investigate the effect of ADHD drugs on exercise.
84. Roelands B, de Koning J, Foster C, Hettinga F, Meeusen R (May 2013). "Neurophysiological determinants of theoretical concepts and mechanisms involved in pacing". Sports Medicine. 43 (5): 301–311. doi:10.1007/s40279-013-0030-4. PMID   23456493. S2CID   30392999. In high-ambient temperatures, dopaminergic manipulations clearly improve performance. The distribution of the power output reveals that after dopamine reuptake inhibition, subjects are able to maintain a higher power output compared with placebo. ... Dopaminergic drugs appear to override a safety switch and allow athletes to use a reserve capacity that is 'off-limits' in a normal (placebo) situation.
85. Parker KL, Lamichhane D, Caetano MS, Narayanan NS (October 2013). "Executive dysfunction in Parkinson's disease and timing deficits". Frontiers in Integrative Neuroscience. 7: 75. doi: 10.3389/fnint.2013.00075 . PMC   3813949 . PMID   24198770. Manipulations of dopaminergic signaling profoundly influence interval timing, leading to the hypothesis that dopamine influences internal pacemaker, or "clock," activity. For instance, amphetamine, which increases concentrations of dopamine at the synaptic cleft advances the start of responding during interval timing, whereas antagonists of D2 type dopamine receptors typically slow timing;... Depletion of dopamine in healthy volunteers impairs timing, while amphetamine releases synaptic dopamine and speeds up timing.
86. Rattray B, Argus C, Martin K, Northey J, Driller M (March 2015). "Is it time to turn our attention toward central mechanisms for post-exertional recovery strategies and performance?". Frontiers in Physiology. 6: 79. doi: 10.3389/fphys.2015.00079 . PMC   4362407 . PMID   25852568. Aside from accounting for the reduced performance of mentally fatigued participants, this model rationalizes the reduced RPE and hence improved cycling time trial performance of athletes using a glucose mouthwash (Chambers et al., 2009) and the greater power output during a RPE matched cycling time trial following amphetamine ingestion (Swart, 2009). ... Dopamine stimulating drugs are known to enhance aspects of exercise performance (Roelands et al., 2008)
87. Roelands B, De Pauw K, Meeusen R (June 2015). "Neurophysiological effects of exercise in the heat". Scandinavian Journal of Medicine & Science in Sports. 25 (Suppl 1): 65–78. doi: 10.1111/sms.12350 . PMID   25943657. S2CID   22782401. This indicates that subjects did not feel they were producing more power and consequently more heat. The authors concluded that the "safety switch" or the mechanisms existing in the body to prevent harmful effects are overridden by the drug administration (Roelands et al., 2008b). Taken together, these data indicate strong ergogenic effects of an increased DA concentration in the brain, without any change in the perception of effort.
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94. Heal DJ, Smith SL, Gosden J, Nutt DJ (June 2013). "Amphetamine, past and present – a pharmacological and clinical perspective". Journal of Psychopharmacology. 27 (6): 479–496. doi:10.1177/0269881113482532. PMC   3666194 . 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).
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99. Stewart JW, Deliyannides DA, McGrath PJ (June 2014). "How treatable is refractory depression?". Journal of Affective Disorders. 167: 148–152. doi:10.1016/j.jad.2014.05.047. PMID   24972362.
100. Huang YS, Tsai MH (July 2011). "Long-term outcomes with medications for attention-deficit hyperactivity disorder: current status of knowledge". CNS Drugs. 25 (7): 539–554. doi:10.2165/11589380-000000000-00000. PMID   21699268. S2CID   3449435. Several other studies,^[97-101] including a meta-analytic review^[98] and a retrospective study,^[97] suggested that stimulant therapy in childhood is associated with a reduced risk of subsequent substance use, cigarette smoking and alcohol use disorders. ... Recent studies have demonstrated that stimulants, along with the non-stimulants atomoxetine and extended-release guanfacine, are continuously effective for more than 2-year treatment periods with few and tolerable adverse effects. The effectiveness of long-term therapy includes not only the core symptoms of ADHD, but also improved quality of life and academic achievements. The most concerning short-term adverse effects of stimulants, such as elevated blood pressure and heart rate, waned in long-term follow-up studies. ... The current data do not support the potential impact of stimulants on the worsening or development of tics or substance abuse into adulthood. In the longest follow-up study (of more than 10 years), lifetime stimulant treatment for ADHD was effective and protective against the development of adverse psychiatric disorders.
101. Millichap JG (2010). "Chapter 9: Medications for ADHD". In Millichap JG (ed.). Attention Deficit Hyperactivity Disorder Handbook: A Physician's Guide to ADHD (2nd ed.). New York: Springer. p. 112. ISBN   9781441913968.
     Table 9.2 Dextroamphetamine formulations of stimulant medication
     Dexedrine [Peak:2–3 h] [Duration:5–6 h] ...
     Adderall [Peak:2–3 h] [Duration:5–7 h]
     Dexedrine spansules [Peak:7–8 h] [Duration:12 h] ...
     Adderall XR [Peak:7–8 h] [Duration:12 h]
     Vyvanse [Peak:3–4 h] [Duration:12 h]
102. Vitiello B (April 2008). "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): 459–474. doi:10.1016/j.chc.2007.11.010. PMC   2408826 . PMID   18295156.
103. Vitiello B (April 2008). "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): 459–474. doi:10.1016/j.chc.2007.11.010. PMC   2408826 . PMID   18295156.
104. "Dyanavel XR- amphetamine suspension, extended release". DailyMed. Tris Pharma, Inc. 6 February 2019. Retrieved 22 December 2019. DYANAVEL XR contains d-amphetamine and l-amphetamine in a ratio of 3.2 to 1 ... The most common (≥2% in the DYANAVEL XR group and greater than placebo) adverse reactions reported in the Phase 3 controlled study conducted in 108 patients with ADHD (aged 6 to 12 years) were: epistaxis, allergic rhinitis and upper abdominal pain. ...
     DOSAGE FORMS AND STRENGTHS
     Extended-release oral suspension contains 2.5 mg amphetamine base equivalents per mL.
105. Ramey JT, Bailen E, Lockey RF (2006). "Rhinitis medicamentosa" (PDF). Journal of Investigational Allergology & Clinical Immunology. 16 (3): 148–155. PMID   16784007 . Retrieved 29 April 2015. Table 2. Decongestants Causing Rhinitis Medicamentosa
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      – Sympathomimetic:
        • Amphetamine
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107. Cooper WO, Habel LA, Sox CM, Chan KA, Arbogast PG, Cheetham TC, et al. (November 2011). "ADHD drugs and serious cardiovascular events in children and young adults". New England Journal of Medicine. 365 (20): 1896–1904. doi:10.1056/NEJMoa1110212. PMC   4943074 . PMID   22043968.
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109. Habel LA, Cooper WO, Sox CM, Chan KA, Fireman BH, Arbogast PG, et al. (December 2011). "ADHD medications and risk of serious cardiovascular events in young and middle-aged adults". JAMA. 306 (24): 2673–2683. doi:10.1001/jama.2011.1830. PMC   3350308 . PMID   22161946.
110. Heedes G, Ailakis J. "Amphetamine (PIM 934)". INCHEM. International Programme on Chemical Safety. Retrieved 24 June 2014.
111. O'Connor PG (February 2012). "Amphetamines". Merck Manual for Health Care Professionals. Merck. Retrieved 8 May 2012.
112. Bramness JG, Gundersen ØH, Guterstam J, Rognli EB, Konstenius M, Løberg EM, et al. (December 2012). "Amphetamine-induced psychosis—a separate diagnostic entity or primary psychosis triggered in the vulnerable?". BMC Psychiatry. 12: 221. doi: 10.1186/1471-244X-12-221 . PMC   3554477 . PMID   23216941. In these studies, amphetamine was given in consecutively higher doses until psychosis was precipitated, often after 100–300 mg of amphetamine ... Secondly, psychosis has been viewed as an adverse event, although rare, in children with ADHD who have been treated with amphetamine
113. Childs E, de Wit H (May 2009). "Amphetamine-induced place preference in humans". Biological Psychiatry. 65 (10): 900–904. doi:10.1016/j.biopsych.2008.11.016. PMC   2693956 . PMID   19111278. This study demonstrates that humans, like nonhumans, prefer a place associated with amphetamine administration. These findings support the idea that subjective responses to a drug contribute to its ability to establish place conditioning.
114. Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and Addictive Disorders". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 364–375. ISBN   9780071481274.
115. Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues in Clinical Neuroscience. 15 (4): 431–443. PMC   3898681 . PMID   24459410. Despite the importance of numerous psychosocial factors, at its core, drug addiction involves a biological process: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. ... A large body of literature has demonstrated that such ΔFosB induction in D1-type [nucleus accumbens] neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement ... Another ΔFosB target is cFos: as ΔFosB accumulates with repeated drug exposure it represses c-Fos and contributes to the molecular switch whereby ΔFosB is selectively induced in the chronic drug-treated state.⁴¹. ... Moreover, there is increasing evidence that, despite a range of genetic risks for addiction across the population, exposure to sufficiently high doses of a drug for long periods of time can transform someone who has relatively lower genetic loading into an addict.
116. Volkow ND, Koob GF, McLellan AT (January 2016). "Neurobiologic Advances from the Brain Disease Model of Addiction". New England Journal of Medicine. 374 (4): 363–371. doi:10.1056/NEJMra1511480. PMC   6135257 . PMID   26816013. Substance-use disorder: A diagnostic term in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) referring to recurrent use of alcohol or other drugs that causes clinically and functionally significant impairment, such as health problems, disability, and failure to meet major responsibilities at work, school, or home. Depending on the level of severity, this disorder is classified as mild, moderate, or severe.
     Addiction: A term used to indicate the most severe, chronic stage of substance-use disorder, in which there is a substantial loss of self-control, as indicated by compulsive drug taking despite the desire to stop taking the drug. In the DSM-5, the term addiction is synonymous with the classification of severe substance-use disorder.
117. Renthal W, Nestler EJ (September 2009). "Chromatin regulation in drug addiction and depression". Dialogues in Clinical Neuroscience. 11 (3): 257–268. doi:10.31887/DCNS.2009.11.3/wrenthal. PMC   2834246 . PMID   19877494. [Psychostimulants] increase cAMP levels in striatum, which activates protein kinase A (PKA) and leads to phosphorylation of its targets. This includes the cAMP response element binding protein (CREB), the phosphorylation of which induces its association with the histone acetyltransferase, CREB binding protein (CBP) to acetylate histones and facilitate gene activation. This is known to occur on many genes including fosB and c-fos in response to psychostimulant exposure. ΔFosB is also upregulated by chronic psychostimulant treatments, and is known to activate certain genes (eg, cdk5) and repress others (eg, c-fos) where it recruits HDAC1 as a corepressor. ... Chronic exposure to psychostimulants increases glutamatergic [signaling] from the prefrontal cortex to the NAc. Glutamatergic signaling elevates Ca2+ levels in NAc postsynaptic elements where it activates CaMK (calcium/calmodulin protein kinases) signaling, which, in addition to phosphorylating CREB, also phosphorylates HDAC5.
     Figure 2: Psychostimulant-induced signaling events
118. Broussard JI (January 2012). "Co-transmission of dopamine and glutamate". The Journal of General Physiology. 139 (1): 93–96. doi:10.1085/jgp.201110659. PMC   3250102 . PMID   22200950. Coincident and convergent input often induces plasticity on a postsynaptic neuron. The NAc integrates processed information about the environment from basolateral amygdala, hippocampus, and prefrontal cortex (PFC), as well as projections from midbrain dopamine neurons. Previous studies have demonstrated how dopamine modulates this integrative process. For example, high frequency stimulation potentiates hippocampal inputs to the NAc while simultaneously depressing PFC synapses (Goto and Grace, 2005). The converse was also shown to be true; stimulation at PFC potentiates PFC–NAc synapses but depresses hippocampal–NAc synapses. In light of the new functional evidence of midbrain dopamine/glutamate co-transmission (references above), new experiments of NAc function will have to test whether midbrain glutamatergic inputs bias or filter either limbic or cortical inputs to guide goal-directed behavior.
119. Kanehisa Laboratories (10 October 2014). "Amphetamine – Homo sapiens (human)". KEGG Pathway. Retrieved 31 October 2014. Most addictive drugs increase extracellular concentrations of dopamine (DA) in nucleus accumbens (NAc) and medial prefrontal cortex (mPFC), projection areas of mesocorticolimbic DA neurons and key components of the "brain reward circuit". Amphetamine achieves this elevation in extracellular levels of DA by promoting efflux from synaptic terminals. ... Chronic exposure to amphetamine induces a unique transcription factor delta FosB, which plays an essential role in long-term adaptive changes in the brain.
120. Cadet JL, Brannock C, Jayanthi S, Krasnova IN (2015). "Transcriptional and epigenetic substrates of methamphetamine addiction and withdrawal: evidence from a long-access self-administration model in the rat". Molecular Neurobiology. 51 (2): 696–717 (Figure 1). doi:10.1007/s12035-014-8776-8. PMC   4359351 . PMID   24939695.
121. Robison AJ, Nestler EJ (November 2011). "Transcriptional and epigenetic mechanisms of addiction". Nature Reviews Neuroscience. 12 (11): 623–637. doi:10.1038/nrn3111. PMC   3272277 . PMID   21989194. ΔFosB serves as one of the master control proteins governing this structural plasticity. ... ΔFosB also represses G9a expression, leading to reduced repressive histone methylation at the cdk5 gene. The net result is gene activation and increased CDK5 expression. ... In contrast, ΔFosB binds to the c-fos gene and recruits several co-repressors, including HDAC1 (histone deacetylase 1) and SIRT 1 (sirtuin 1). ... The net result is c-fos gene repression.
     Figure 4: Epigenetic basis of drug regulation of gene expression
122. Nestler EJ (December 2012). "Transcriptional mechanisms of drug addiction". Clinical Psychopharmacology and Neuroscience. 10 (3): 136–143. doi:10.9758/cpn.2012.10.3.136. PMC   3569166 . PMID   23430970. The 35-37 kD ΔFosB isoforms accumulate with chronic drug exposure due to their extraordinarily long half-lives. ... As a result of its stability, the ΔFosB protein persists in neurons for at least several weeks after cessation of drug exposure. ... ΔFosB overexpression in nucleus accumbens induces NFκB ... In contrast, the ability of ΔFosB to repress the c-Fos gene occurs in concert with the recruitment of a histone deacetylase and presumably several other repressive proteins such as a repressive histone methyltransferase
123. Nestler EJ (October 2008). "Transcriptional mechanisms of addiction: Role of ΔFosB". Philosophical Transactions of the Royal Society B: Biological Sciences. 363 (1507): 3245–3255. doi:10.1098/rstb.2008.0067. PMC   2607320 . PMID   18640924. Recent evidence has shown that ΔFosB also represses the c-fos gene that helps create the molecular switch—from the induction of several short-lived Fos family proteins after acute drug exposure to the predominant accumulation of ΔFosB after chronic drug exposure
124. Kanehisa Laboratories (10 October 2014). "Amphetamine – Homo sapiens (human)". KEGG Pathway. Retrieved 31 October 2014.
125. Nechifor M (March 2008). "Magnesium in drug dependences". Magnesium Research. 21 (1): 5–15. doi:10.1684/mrh.2008.0124 (inactive 1 November 2024). PMID   18557129.
126. Ruffle JK (November 2014). "Molecular neurobiology of addiction: what's all the (Δ)FosB about?". The American Journal of Drug and Alcohol Abuse. 40 (6): 428–437. doi:10.3109/00952990.2014.933840. PMID   25083822. S2CID   19157711. ΔFosB is an essential transcription factor implicated in the molecular and behavioral pathways of addiction following repeated drug exposure.
127. Robison AJ, Nestler EJ (November 2011). "Transcriptional and epigenetic mechanisms of addiction". Nature Reviews Neuroscience. 12 (11): 623–637. doi:10.1038/nrn3111. PMC   3272277 . PMID   21989194. ΔFosB has been linked directly to several addiction-related behaviors ... Importantly, genetic or viral overexpression of ΔJunD, a dominant negative mutant of JunD which antagonizes ΔFosB- and other AP-1-mediated transcriptional activity, in the NAc or OFC blocks these key effects of drug exposure^14,22–24. This indicates that ΔFosB is both necessary and sufficient for many of the changes wrought in the brain by chronic drug exposure. ΔFosB is also induced in D1-type NAc MSNs by chronic consumption of several natural rewards, including sucrose, high fat food, sex, wheel running, where it promotes that consumption^14,26–30. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states. ... ΔFosB serves as one of the master control proteins governing this structural plasticity.
128. 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).
129. 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". Neuroscience & Biobehavioral Reviews. 37 (8): 1622–1644. doi:10.1016/j.neubiorev.2013.06.011. PMC   3788047 . PMID   23806439. These findings suggest that exercise may "magnitude"-dependently prevent the development of an addicted phenotype possibly by blocking/reversing behavioral and neuroadaptive 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 ... 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.
130. Zhou Y, Zhao M, Zhou C, Li R (July 2015). "Sex differences in drug addiction and response to exercise intervention: From human to animal studies". Frontiers in Neuroendocrinology. 40: 24–41. doi:10.1016/j.yfrne.2015.07.001. PMC   4712120 . PMID   26182835. Collectively, these findings demonstrate that exercise may serve as a substitute or competition for drug abuse by changing ΔFosB or cFos immunoreactivity in the reward system to protect against later or previous drug use. ... The postulate that exercise serves as an ideal intervention for drug addiction has been widely recognized and used in human and animal rehabilitation.
131. Linke SE, Ussher M (January 2015). "Exercise-based treatments for substance use disorders: evidence, theory, and practicality". The American Journal of Drug and Alcohol Abuse. 41 (1): 7–15. doi:10.3109/00952990.2014.976708. PMC   4831948 . PMID   25397661. The limited research conducted suggests that exercise may be an effective adjunctive treatment for SUDs. In contrast to the scarce intervention trials to date, a relative abundance of literature on the theoretical and practical reasons supporting the investigation of this topic has been published. ... numerous theoretical and practical reasons support exercise-based treatments for SUDs, including psychological, behavioral, neurobiological, nearly universal safety profile, and overall positive health effects.
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165. Sulzer D (February 2011). "How addictive drugs disrupt presynaptic dopamine neurotransmission". Neuron. 69 (4): 628–649. doi:10.1016/j.neuron.2011.02.010. PMC   3065181 . 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).
166. Scholze P, Nørregaard L, Singer EA, Freissmuth M, Gether U, Sitte HH (June 2002). "The role of zinc ions in reverse transport mediated by monoamine transporters". J. Biol. Chem. 277 (24): 21505–21513. 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.
167. Scassellati C, Bonvicini C, Faraone SV, Gennarelli M (October 2012). "Biomarkers and attention-deficit/hyperactivity disorder: a systematic review and meta-analyses". J. Am. Acad. Child Adolesc. Psychiatry. 51 (10): 1003–1019.e20. 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 studies^20,57,58 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
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177. Ledonne A, Berretta N, Davoli A, Rizzo GR, Bernardi G, Mercuri NB (July 2011). "Electrophysiological effects of trace amines on mesencephalic dopaminergic neurons". Front. Syst. Neurosci. 5: 56. doi: 10.3389/fnsys.2011.00056 . PMC   3131148 . 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.
178. "TAAR1". GenAtlas. University of Paris. 28 January 2012. 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)
179. Underhill SM, Wheeler DS, Li M, Watts SD, Ingram SL, Amara SG (July 2014). "Amphetamine modulates excitatory neurotransmission through endocytosis of the glutamate transporter EAAT3 in dopamine neurons". Neuron. 83 (2): 404–416. doi:10.1016/j.neuron.2014.05.043. PMC   4159050 . 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
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191. Glennon RA (2013). "Phenylisopropylamine stimulants: amphetamine-related agents". In Lemke TL, Williams DA, Roche VF, Zito W (eds.). Foye's principles of medicinal chemistry (7th ed.). Philadelphia, US: Wolters Kluwer Health/Lippincott Williams & Wilkins. pp. 646–648. ISBN   9781609133450. The simplest unsubstituted phenylisopropylamine, 1-phenyl-2-aminopropane, or amphetamine, serves as a common structural template for hallucinogens and psychostimulants. Amphetamine produces central stimulant, anorectic, and sympathomimetic actions, and it is the prototype member of this class (39). ... The phase 1 metabolism of amphetamine analogs is catalyzed by two systems: cytochrome P450 and flavin monooxygenase. ... Amphetamine can also undergo aromatic hydroxylation to p-hydroxyamphetamine. ... Subsequent oxidation at the benzylic position by DA β-hydroxylase affords p-hydroxynorephedrine. Alternatively, direct oxidation of amphetamine by DA β-hydroxylase can afford norephedrine.
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External links

• "Amphetamine". MedlinePlus.