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Adderall

Adderall and Mydayis[9] are trade names[note 2] for a combination drug called mixed amphetamine salts containing four salts of amphetamine. The mixture is composed of equal parts racemic amphetamine and dextroamphetamine, which produces a (3:1) ratio between dextroamphetamine and levoamphetamine, the two enantiomers of amphetamine. Both enantiomers are stimulants, but differ enough to give Adderall an effects profile distinct from those of racemic amphetamine or dextroamphetamine,[1][2] which are marketed as Evekeo and Dexedrine/Zenzedi, respectively.[1][11][12] 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]

Amphetamine/dextroamphetamine
salt mixture (1:1)[note 1]
Top: racemic amphetamine skeleton
Bottom: (D)-amphetamine ball-and-stick model
Combination of
amphetamine aspartate monohydrate25% – stimulant
(12.5% levo; 12.5% dextro)
amphetamine sulfate25% – stimulant
(12.5% levo; 12.5% dextro)
dextroamphetamine saccharate25% – stimulant
(0% levo; 25% dextro)
dextroamphetamine sulfate25% – stimulant
(0% levo; 25% dextro)
Clinical data
Trade namesAdderall, Adderall XR, Mydayis
Other namesMixed amphetamine salts; MAS
AHFS/Drugs.comMonograph
MedlinePlusa601234
License data
Dependence
liability
Moderate[3][4] – high[5][6][7]
Routes of
administration
By mouth, insufflation, rectal, sublingual
Drug classCNS stimulant
ATC code
Legal status
Legal status
Identifiers
CAS Number
  • 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 is generally well-tolerated and effective in treating symptoms of ADHD and narcolepsy. At therapeutic doses, Adderall causes emotional and cognitive effects such as euphoria, change in sex drive, increased wakefulness, and improved cognitive control. At these doses, it induces physical effects such as a faster reaction time, fatigue resistance, and increased muscle strength. In contrast, much larger doses of Adderall can impair cognitive control, cause rapid muscle breakdown, provoke panic attacks, or induce a psychosis (e.g., paranoia, delusions, hallucinations). The side effects of Adderall vary widely among individuals, but most commonly include insomnia, dry mouth, loss of appetite, and weight loss. The risk of developing an addiction or dependence is insignificant when Adderall is used as prescribed at fairly low daily doses, such as those used for treating ADHD; however, the routine use of Adderall in larger daily doses poses a significant risk of addiction or dependence due to the pronounced reinforcing effects that are present at high doses. Recreational doses of amphetamine are generally much larger than prescribed therapeutic doses, and carry a far greater risk of serious adverse effects.[sources 1]

The two amphetamine enantiomers that compose Adderall (levoamphetamine and dextroamphetamine) alleviate the symptoms of ADHD and narcolepsy by increasing the activity of the neurotransmitters norepinephrine and dopamine in the brain, which results in part from their interactions with human trace amine-associated receptor 1 (hTAAR1) and vesicular monoamine transporter 2 (VMAT2) in neurons. Dextroamphetamine is a more potent Central nervous system (CNS) stimulant than levoamphetamine, but levoamphetamine has slightly stronger cardiovascular and peripheral effects and a longer elimination half-life than dextroamphetamine. The levoamphetamine component of Adderall has been reported to improve the treatment response in some individuals relative to dextroamphetamine alone. Adderall's active ingredient, amphetamine, shares many chemical and pharmacological properties with the human trace amines, particularly phenethylamine and N-methylphenethylamine, the latter of which is a positional isomer of amphetamine.[sources 2] In 2021, Adderall was the seventeenth most commonly prescribed medication in the United States, with more than 30 million prescriptions.[32][33]

Uses edit

 
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 edit

Adderall is commonly used to treat attention deficit hyperactivity disorder (ADHD) and narcolepsy (a sleep disorder).[34][14] Long-term amphetamine exposure at sufficiently high doses in some animal species is known to produce abnormal dopamine system development or nerve damage,[35][36] but, in humans with ADHD, long-term use of pharmaceutical amphetamines at therapeutic doses appears to improve brain development and nerve growth.[37][38][39] 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.[37][38][39]

Reviews of clinical stimulant research have established the safety and effectiveness of long-term continuous amphetamine use for the treatment of ADHD.[40][41][42] Randomized controlled trials of continuous stimulant therapy for the treatment of ADHD spanning 2 years have demonstrated treatment effectiveness and safety.[40][41] 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.[40][42] 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.[41] 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.[40]

Current models of ADHD suggest that it is associated with functional impairments in some of the brain's neurotransmitter systems;[43] 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.[43] Psychostimulants like methylphenidate and amphetamine are effective in treating ADHD because they increase neurotransmitter activity in these systems.[15][43][44] Approximately 80% of those who use these stimulants see improvements in ADHD symptoms.[45] 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.[46][47] 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.[49][50] 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.[51]

Available forms edit

Adderall is available as immediate-release (IR) tablets and extended-release (XR) capsules.[14][52] Mydayis is only available in an extended-release formulation.[53] 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.[52] Upon ingestion, half of the beads provide immediate administration of medication, while the other half are enveloped in a coating which 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.[52] 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.[53] In the United States, the immediate and extended-release formulations of Adderall are both available as generic drugs.[54][55] Generic formulations of Mydayis became available in the US in October 2023.[56]

Enhancing performance edit

Cognitive performance edit

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;[57][58] these cognition-enhancing effects of amphetamine are known to be partially mediated through the indirect activation of both dopamine receptor D1 and adrenoceptor α2 in the prefrontal cortex.[15][57] A systematic review from 2014 found that low doses of amphetamine also improve memory consolidation, in turn leading to improved recall of information.[59] Therapeutic doses of amphetamine also enhance cortical network efficiency, an effect which mediates improvements in working memory in all individuals.[15][60] Amphetamine and other ADHD stimulants also improve task saliency (motivation to perform a task) and increase arousal (wakefulness), in turn promoting goal-directed behavior.[15][61][62] 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.[15][62][63] 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.[64][65][66] However, high amphetamine doses that are above the therapeutic range can interfere with working memory and other aspects of cognitive control.[15][62]

Physical performance edit

Amphetamine is used by some athletes for its psychological and athletic performance-enhancing effects, such as increased endurance and alertness;[16][28] however, non-medical amphetamine use is prohibited at sporting events that are regulated by collegiate, national, and international anti-doping agencies.[67][68] 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.[16][69][70] Amphetamine improves endurance and reaction time primarily through reuptake inhibition and release of dopamine in the central nervous system.[69][70][71] 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.[70][72][73] At therapeutic doses, the adverse effects of amphetamine do not impede athletic performance;[16][69] however, at much higher doses, amphetamine can induce effects that severely impair performance, such as rapid muscle breakdown and elevated body temperature.[17][69]

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).[74] 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.[74]

Recreational edit

Adderall has high potential for misuse as a recreational drug.[75][76][77] Adderall tablets can either be swallowed, crushed and snorted, or dissolved in water and injected.[78] Injection into the bloodstream can be dangerous because insoluble fillers within the tablets can block small blood vessels.[78]

Many postsecondary students have reported using Adderall for study purposes in different parts of the developed world.[77] 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.[77]

Contraindications edit

According to the International Programme on Chemical Safety (IPCS) and the United States Food and Drug Administration (USFDA),[note 5] amphetamine is contraindicated in people with a history of drug abuse,[note 6] cardiovascular disease, severe agitation, or severe anxiety.[81][82][83] 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.[81][82][83] 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,[81][82][83] although safe concurrent use of amphetamine and monoamine oxidase inhibitors has been documented.[84][85] 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.[82][83] 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.[83] Amphetamine has also been shown to pass into breast milk, so the IPCS and the USFDA advise mothers to avoid breastfeeding when using it.[82][83] Due to the potential for reversible growth impairments,[note 7] the USFDA advises monitoring the height and weight of children and adolescents prescribed an amphetamine pharmaceutical.[82]

Adverse effects edit

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.[17][28] Adderall is currently approved for long-term therapeutic use by the USFDA.[17] 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.[28]

Physical edit

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).[17][28][89] Sexual side effects in males may include erectile dysfunction, frequent erections, or prolonged erections.[17] Gastrointestinal side effects may include abdominal pain, constipation, diarrhea, and nausea.[7][17][90] 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.[28]

Amphetamine stimulates the medullary respiratory centers, producing faster and deeper breaths.[28] In a normal person at therapeutic doses, this effect is usually not noticeable, but when respiration is already compromised, it may be evident.[28] Amphetamine also induces contraction in the urinary bladder sphincter, the muscle which controls urination, which can result in difficulty urinating.[28] This effect can be useful in treating bed wetting and loss of bladder control.[28] The effects of amphetamine on the gastrointestinal tract are unpredictable.[28] If intestinal activity is high, amphetamine may reduce gastrointestinal motility (the rate at which content moves through the digestive system);[28] however, amphetamine may increase motility when the smooth muscle of the tract is relaxed.[28] Amphetamine also has a slight analgesic effect and can enhance the pain relieving effects of opioids.[7][28]

USFDA-commissioned studies from 2011 indicate that in children, young adults, and adults there is no association between serious adverse cardiovascular events (sudden death, heart attack, and stroke) and the medical use of amphetamine or other ADHD stimulants.[sources 4] However, amphetamine pharmaceuticals are contraindicated in individuals with cardiovascular disease.[sources 5]

Psychological edit

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.[17][28] 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.[28] Amphetamine psychosis (e.g., delusions and paranoia) can occur in heavy users.[17][18][98] Although very rare, this psychosis can also occur at therapeutic doses during long-term therapy.[17][98][19] According to the USFDA, "there is no systematic evidence" that stimulants produce aggressive behavior or hostility.[17]

Amphetamine has also been shown to produce a conditioned place preference in humans taking therapeutic doses,[49][99] meaning that individuals acquire a preference for spending time in places where they have previously used amphetamine.[99][100]

Reinforcement disorders edit

Addiction edit

Addiction and dependence glossary[100][101][102]
  • 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
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 regulationcontrolling the rate of gene transcription for example by helping or hindering RNA polymerase binding to DNA
  • upregulation, activation, or promotionincrease the rate of gene transcription
  • downregulation, repression, or suppressiondecrease 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
Signaling cascade in the nucleus accumbens that results in amphetamine addiction
 
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,[103][104] 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.[103][105][106] Phosphorylated CREB increases levels of ΔFosB, which in turn represses the c-Fos gene with the help of corepressors;[103][107][108] c-Fos repression acts as a molecular switch that enables the accumulation of ΔFosB in the neuron.[109] 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.[107][108] 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.[107][108]

Addiction is a serious risk with heavy recreational amphetamine use, but is unlikely to occur from long-term medical use at therapeutic doses;[40][20][21] in fact, lifetime stimulant therapy for ADHD that begins during childhood reduces the risk of developing substance use disorders as an adult.[40] 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.[110][111] 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.[101][112][113] 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.[112][114] 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.[115][116] Exercise therapy improves clinical treatment outcomes and may be used as an adjunct therapy with behavioral therapies for addiction.[115][117][sources 7]

Biomolecular mechanisms edit

Chronic use of amphetamine at excessive doses causes alterations in gene expression in the mesocorticolimbic projection, which arise through transcriptional and epigenetic mechanisms.[113][118][119] 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).[113] 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.[101][112][113] Once ΔFosB is sufficiently overexpressed, it induces an addictive state that becomes increasingly more severe with further increases in ΔFosB expression.[101][112] 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.[101][113][123] 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).[113] 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).[113][123][124] ΔFosB also plays an important role in regulating behavioral responses to natural rewards, such as palatable food, sex, and exercise.[114][113][127] 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.[114][113] 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.[114][128][129] These sexual addictions are associated with a dopamine dysregulation syndrome which occurs in some patients taking dopaminergic drugs.[114][127]

The effects of amphetamine on gene regulation are both dose- and route-dependent.[119] Most of the research on gene regulation and addiction is based upon animal studies with intravenous amphetamine administration at very high doses.[119] 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.[119] This suggests that medical use of amphetamine does not significantly affect gene regulation.[119]

Pharmacological treatments edit

As of December 2019, there is no effective pharmacotherapy for amphetamine addiction.[130][131][132] Reviews from 2015 and 2016 indicated that TAAR1-selective agonists have significant therapeutic potential as a treatment for psychostimulant addictions;[133][134] however, as of February 2016, the only compounds which are known to function as TAAR1-selective agonists are experimental drugs.[133][134] Amphetamine addiction is largely mediated through increased activation of dopamine receptors and co-localized NMDA receptors[note 10] in the nucleus accumbens;[111] magnesium ions inhibit NMDA receptors by blocking the receptor calcium channel.[111][135] One review suggested that, based upon animal testing, pathological (addiction-inducing) psychostimulant use significantly reduces the level of intracellular magnesium throughout the brain.[111] 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.[111]

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;[131] it found only low-strength evidence that methylphenidate might reduce amphetamine or methamphetamine self-administration.[131] 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.[131]

Behavioral treatments edit

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).[136] 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.[136]

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.[115][117][137] 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.[114][137] This is the opposite of pathological stimulant use, which induces decreased striatal DRD2 density.[114] 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.[116]

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 MSNsTooltip medium spiny neurons
[114]
Behavioral plasticity
Escalation of intake Yes Yes Yes [114]
Psychostimulant
cross-sensitization
Yes Not applicable Yes Yes Attenuated Attenuated [114]
Psychostimulant
self-administration
[114]
Psychostimulant
conditioned place preference
[114]
Reinstatement of drug-seeking behavior [114]
Neurochemical plasticity
CREBTooltip cAMP response element-binding protein phosphorylation
in the nucleus accumbens
[114]
Sensitized dopamine response
in the nucleus accumbens
No Yes No Yes [114]
Altered striatal dopamine signaling DRD2, ↑DRD3 DRD1, ↓DRD2, ↑DRD3 DRD1, ↓DRD2, ↑DRD3 DRD2 DRD2 [114]
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 [114]
Changes in striatal opioid peptides dynorphin
No change: enkephalin
dynorphin enkephalin dynorphin dynorphin [114]
Mesocorticolimbic synaptic plasticity
Number of dendrites in the nucleus accumbens [114]
Dendritic spine density in
the nucleus accumbens
[114]

Dependence and withdrawal edit

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.[138][139] 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."[140] 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.[140] 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.[140] The review indicated that the severity of withdrawal symptoms is positively correlated with the age of the individual and the extent of their dependence.[140] Mild withdrawal symptoms from the discontinuation of amphetamine treatment at therapeutic doses can be avoided by tapering the dose.[7]

Overdose edit

An amphetamine overdose can lead to many different symptoms, but is rarely fatal with appropriate care.[141][83][142] The severity of overdose symptoms increases with dosage and decreases with drug tolerance to amphetamine.[143][83] 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.[83] Symptoms of a moderate and extremely large overdose are listed below; fatal amphetamine poisoning usually also involves convulsions and coma.[82][143] 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][144]

Overdose symptoms by system
System Minor or moderate overdose[82][143][83] Severe overdose[sources 10]
Cardiovascular
Central nervous
system
Musculoskeletal
Respiratory
  • Rapid breathing
Urinary
Other

Interactions edit

Pharmacology edit

Pharmacodynamics of amphetamine in a dopamine neuron
 
via AADC
 
Amphetamine enters the presynaptic neuron across the neuronal membrane or through DAT.[25] Once inside, it binds to TAAR1 or enters synaptic vesicles through VMAT2.[25][26] 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.[26][154] 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.[25][155][156] PKA phosphorylation causes DAT to withdraw into the presynaptic neuron (internalize) and cease transport.[25] PKC-phosphorylated DAT may either operate in reverse or, like PKA-phosphorylated DAT, internalize and cease transport.[25] 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.[157][158]

Mechanism of action edit

Amphetamine, the active ingredient of Adderall, works primarily by increasing the activity of the neurotransmitters dopamine and norepinephrine in the brain.[24][44] 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).[26][159] Both active ingredients of Adderall, dextroamphetamine and levoamphetamine, bind to the same biological targets,[28][29] but their binding affinities (that is, potency) differ somewhat.[28][29] 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.[29] Consequently, dextroamphetamine produces more CNS stimulation than levoamphetamine;[29][160] however, levoamphetamine has slightly greater cardiovascular and peripheral effects.[28] It has been reported that certain children have a better clinical response to levoamphetamine.[30][31]

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.[26] 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.[26] 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;[25] 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.[25] 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).[25][26]

Pharmacokinetics edit

The oral bioavailability of amphetamine varies with gastrointestinal pH;[17] it is well absorbed from the gut, and bioavailability is typically over 75% for dextroamphetamine.[161] Amphetamine is a weak base with a pKa of 9.9;[162] 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.[162][17] Conversely, an acidic pH means the drug is predominantly in a water-soluble cationic (salt) form, and less is absorbed.[162] Approximately 20% of amphetamine circulating in the bloodstream is bound to plasma proteins.[163] Following absorption, amphetamine readily distributes into most tissues in the body, with high concentrations occurring in cerebrospinal fluid and brain tissue.[164]

The half-lives of amphetamine enantiomers differ and vary with urine pH.[162] At normal urine pH, the half-lives of dextroamphetamine and levoamphetamine are 9–11 hours and 11–14 hours, respectively.[162] Highly acidic urine will reduce the enantiomer half-lives to 7 hours;[164] highly alkaline urine will increase the half-lives up to 34 hours.[164] 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.[162] Amphetamine is eliminated via the kidneys, with 30–40% of the drug being excreted unchanged at normal urinary pH.[162] When the urinary pH is basic, amphetamine is in its free base form, so less is excreted.[162] 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.[162] Following oral administration, amphetamine appears in urine within 3 hours.[164] Roughly 90% of ingested amphetamine is eliminated 3 days after the last oral dose.[164]

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.[162][165] Among these metabolites, the active sympathomimetics are 4-hydroxyamphetamine,[166] 4-hydroxynorephedrine,[167] and norephedrine.[168] The main metabolic pathways involve aromatic para-hydroxylation, aliphatic alpha- and beta-hydroxylation, N-oxidation, N-dealkylation, and deamination.[162][169] The known metabolic pathways, detectable metabolites, and metabolizing enzymes in humans include the following:

Metabolic pathways of amphetamine in humans[sources 11]
 
Para-
Hydroxylation
Para-
Hydroxylation
Para-
Hydroxylation
unidentified
Beta-
Hydroxylation
Beta-
Hydroxylation
Oxidative
Deamination
Oxidation
unidentified
Glycine
Conjugation
 
The primary active metabolites of amphetamine are 4-hydroxyamphetamine and norephedrine;[165] at normal urine pH, about 30–40% of amphetamine is excreted unchanged and roughly 50% is excreted as the inactive metabolites (bottom row).[162] The remaining 10–20% is excreted as the active metabolites.[162] Benzoic acid is metabolized by XM-ligase into an intermediate product, benzoyl-CoA, which is then metabolized by GLYAT into hippuric acid.[174]

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.[178][179] 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][178][180] 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.[178][179][181] The field that studies these interactions is known as pharmacomicrobiomics.[178]

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.[181] The first amphetamine-metabolizing microbial enzyme, tyramine oxidase from a strain of E. coli commonly found in the human gut, was identified in 2019.[181] This enzyme was found to metabolize amphetamine, tyramine, and phenethylamine with roughly the same binding affinity for all three compounds.[181]

Related endogenous compounds edit

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.[25][182][183] 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).[25][182][184] 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.[182][184] In turn, N-methylphenethylamine is metabolized from phenethylamine by phenylethanolamine N-methyltransferase, the same enzyme that metabolizes norepinephrine into epinephrine.[182][184] Like amphetamine, both phenethylamine and N-methylphenethylamine regulate monoamine neurotransmission via TAAR1;[25][183][184] unlike amphetamine, both of these substances are broken down by monoamine oxidase B, and therefore have a shorter half-life than amphetamine.[182][184]

History edit

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.[185] 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.[186][187] In 1997 Richwood Pharmaceuticals was acquired by Shire Pharmaceuticals in a $186 million transaction.[185]

Richwood Pharmaceuticals, which later merged with Shire plc, introduced the current Adderall brand in 1996 as an instant-release tablet.[188] In 2006, Shire agreed to sell rights to the Adderall name for the instant-release form of the medication to Duramed Pharmaceuticals.[189] DuraMed Pharmaceuticals was acquired by Teva Pharmaceuticals in 2008 during their acquisition of Barr Pharmaceuticals, including Barr's Duramed division.[190]

The first generic version of Adderall IR was introduced to market in 2002.[10] 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.[10][191]

Commercial formulation edit

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.[52] This drug mixture has slightly stronger CNS effects than racemic amphetamine due to the higher proportion of dextroamphetamine.[25][28] Adderall is produced as both an immediate-release (IR) and extended-release (XR) formulation.[10][14][52] As of December 2013, ten different companies produced generic Adderall IR, while Teva Pharmaceutical Industries, Actavis, and Barr Pharmaceuticals manufactured generic Adderall XR.[10] As of 2013, Shire plc, the company that held the original patent for Adderall and Adderall XR, still manufactured brand name Adderall XR, but not Adderall IR.[10]

Comparison to other formulations edit

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[193][194] (C9H13N)2•H2SO4
368.49
270.41
73.38%
73.38%
22.0 mg
30.0 mg
amphetamine sulfate[195] (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[193][194] (C9H13N)2•H2SO4
368.49
270.41
73.38%
73.38%
25% amphetamine sulfate[195] (C9H13N)2•H2SO4
368.49
270.41
73.38%
36.69%
36.69%
25% dextroamphetamine saccharate[196] (C9H13N)2•C6H10O8
480.55
270.41
56.27%
56.27%
25% amphetamine aspartate monohydrate[197] (C9H13N)•C4H7NO4•H2O
286.32
135.21
47.22%
23.61%
23.61%
lisdexamfetamine dimesylate[198] C15H25N3O•(CH4O3S)2
455.49
135.21
29.68%
29.68%
8.9 mg
74.2 mg
amphetamine base suspension[90] C9H13N
135.21
135.21
100%
76.19%
23.81%
22.9 mg
7.1 mg
22.0 mg

Society and culture edit

Legal status edit

  • In Canada, amphetamines are in Schedule I of the Controlled Drugs and Substances Act, and can only be obtained by prescription.[199]
  • In Japan, the use, production, and import of any medicine containing amphetamines is prohibited.[200]
  • In South Korea, amphetamines are prohibited.[201]
  • In Taiwan, amphetamines including Adderall are Schedule 2 drugs with a minimum five years prison term for possession.[202] Only Ritalin can be legally prescribed for treatment of ADHD[citation needed].
  • In Thailand, amphetamines are classified as Type 1 Narcotics.[203]
  • 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.[204]
  • In the United States, amphetamine is a Schedule II prescription drug, classified as a central nervous system (CNS) stimulant.[205]
  • Internationally, amphetamine is in Schedule II of the Convention on Psychotropic Substances.[206][207]

Shortages edit

In February 2023, news organizations began reporting on shortages of Adderall in the United States that have lasted for over five months.[208][209] The Food and Drug Administration first reported the shortage in October 2022.[210] In May 2023, 7 months into the shortage, the Food and Drug Administration commissioner Robert Califf stated that "a number of generic drugs are in shortage at any given time because there's not enough profit". He points out that Adderall is a special case because it is a controlled substance and the amount available for prescription is controlled by the Drug Enforcement Administration. He also faults a "tremendous increase in prescribing" due to virtual prescribing and general overprescribing and overdiagnosing, adding that "if only the people that needed these drugs got them, there probably wouldn't be a [stimulant medication] shortage".[211][212]

Notes edit

  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.[10] Mydayis is a relatively new trade name that is not commonly used to refer generally to the mixture.[9]
  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).[42]

    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).[42]

    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.[42]
  4. ^ Cochrane reviews are high quality meta-analytic systematic reviews of randomized controlled trials.[48]
  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.[79]
  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.[80]
  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.[86][87][88] The average reduction in final adult height from 3 years of continuous stimulant therapy is 2 cm.[88]
  8. ^ Transcription factors are proteins that increase or decrease the expression of specific genes.[120]
  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.[135]
  11. ^ The review indicated that magnesium L-aspartate and magnesium chloride produce significant changes in addictive behavior;[111] 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.[150][151][152] The human serotonin transporter and norepinephrine transporter do not contain zinc binding sites.[152]
  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.[170][173] 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;[173][175] however, other evidence from animal studies suggests that this reaction is catalyzed by DBH in synaptic vesicles within noradrenergic neurons in the brain.[176][177]
  15. ^ There is substantial variation in microbiome composition and microbial concentrations by anatomical site.[178][179] 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.[178]
  16. ^ For uniformity, molar masses were calculated using the Lenntech Molecular Weight Calculator[192] and were within 0.01 g/mol of published pharmaceutical values.
  17. ^ Amphetamine base percentage = molecular massbase / molecular masstotal. Amphetamine base percentage for Adderall = sum of component percentages / 4.
  18. ^ dose = (1 / amphetamine base percentage) × scaling factor = (molecular masstotal / molecular massbase) × scaling factor. The values in this column were scaled to a 30 mg dose of dextroamphetamine sulfate. Due to pharmacological differences between these medications (e.g., differences in the release, absorption, conversion, concentration, differing effects of enantiomers, half-life, etc.), the listed values should not be considered equipotent doses.
Image legend
  1. ^
      (Text color) Transcription factors

Reference notes edit

References edit

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    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.
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    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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  18. ^ a b Shoptaw SJ, Kao U, Ling W (January 2009). Shoptaw SJ, Ali R (ed.). "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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    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]
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    DOSAGE FORMS AND STRENGTHS
    Extended-release oral suspension contains 2.5 mg amphetamine base equivalents per mL.
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  101. ^ a b c d e 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.
  102. ^ 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.
  103. ^ a b c 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
  104. ^ 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.
  105. ^ 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.
  106. ^ 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.
  107. ^ a b c 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
  108. ^ a b c 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
  109. ^ 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
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  113. ^ a b c d e f g h i j k 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 exposure14,22–24. 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 consumption14,26–30. 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.
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  115. ^ a b c d 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.
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  117. ^ a b c 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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    There is accelerating evidence that physical exercise is a useful treatment for preventing and reducing drug addiction ... In some individuals, exercise has its own rewarding effects, and a behavioral economic interaction may occur, such that physical and social rewards of exercise can substitute for the rewarding effects of drug abuse. ... The value of this form of treatment for drug addiction in laboratory animals and humans is that exercise, if it can substitute for the rewarding effects of drugs, could be self-maintained over an extended period of time. Work to date in [laboratory animals and humans] regarding exercise as a treatment for drug addiction supports this hypothesis. ... Animal and human research on physical exercise as a treatment for stimulant addiction indicates that this is one of the most promising treatments on the horizon.
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adderall, this, article, about, common, mixture, amphetamine, salts, general, information, about, drug, racemate, amphetamine, 2023, slipknot, mydayis, trade, names, note, combination, drug, called, mixed, amphetamine, salts, containing, four, salts, amphetami. 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 Adderall and Mydayis 9 are trade names note 2 for a combination drug called mixed amphetamine salts containing four salts of amphetamine The mixture is composed of equal parts racemic amphetamine and dextroamphetamine which produces a 3 1 ratio between dextroamphetamine and levoamphetamine the two enantiomers of amphetamine Both enantiomers are stimulants but differ enough to give Adderall an effects profile distinct from those of racemic amphetamine or dextroamphetamine 1 2 which are marketed as Evekeo and Dexedrine Zenzedi respectively 1 11 12 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 Amphetamine dextroamphetaminesalt mixture 1 1 note 1 Top racemic amphetamine skeleton Bottom D amphetamine ball and stick modelCombination ofamphetamine aspartate monohydrate25 stimulant 12 5 levo 12 5 dextro amphetamine sulfate25 stimulant 12 5 levo 12 5 dextro dextroamphetamine saccharate25 stimulant 0 levo 25 dextro dextroamphetamine sulfate25 stimulant 0 levo 25 dextro Clinical dataTrade namesAdderall Adderall XR MydayisOther namesMixed amphetamine salts MASAHFS Drugs comMonographMedlinePlusa601234License dataUS DailyMed AdderallDependenceliabilityModerate 3 4 high 5 6 7 Routes ofadministrationBy mouth insufflation rectal sublingualDrug classCNS stimulantATC codeN06BA02 WHO N06BA01 WHO Legal statusLegal statusAU S8 Controlled drug CA Schedule I DE Anlage III Special prescription form required NZ Class B UK Class B US WARNING 8 Schedule II UN Psychotropic Schedule IIIdentifiersCAS Number300 62 9 Y 51 64 9PubChem CID3007IUPHAR BPS4804DrugBankDB00182 YChemSpider13852819 YUNIICK833KGX7EKEGGD11624 YChEBICHEBI 2679 YChEMBLChEMBL405 Y verify Adderall is generally well tolerated and effective in treating symptoms of ADHD and narcolepsy At therapeutic doses Adderall causes emotional and cognitive effects such as euphoria change in sex drive increased wakefulness and improved cognitive control At these doses it induces physical effects such as a faster reaction time fatigue resistance and increased muscle strength In contrast much larger doses of Adderall can impair cognitive control cause rapid muscle breakdown provoke panic attacks or induce a psychosis e g paranoia delusions hallucinations The side effects of Adderall vary widely among individuals but most commonly include insomnia dry mouth loss of appetite and weight loss The risk of developing an addiction or dependence is insignificant when Adderall is used as prescribed at fairly low daily doses such as those used for treating ADHD however the routine use of Adderall in larger daily doses poses a significant risk of addiction or dependence due to the pronounced reinforcing effects that are present at high doses Recreational doses of amphetamine are generally much larger than prescribed therapeutic doses and carry a far greater risk of serious adverse effects sources 1 The two amphetamine enantiomers that compose Adderall levoamphetamine and dextroamphetamine alleviate the symptoms of ADHD and narcolepsy by increasing the activity of the neurotransmitters norepinephrine and dopamine in the brain which results in part from their interactions with human trace amine associated receptor 1 hTAAR1 and vesicular monoamine transporter 2 VMAT2 in neurons Dextroamphetamine is a more potent Central nervous system CNS stimulant than levoamphetamine but levoamphetamine has slightly stronger cardiovascular and peripheral effects and a longer elimination half life than dextroamphetamine The levoamphetamine component of Adderall has been reported to improve the treatment response in some individuals relative to dextroamphetamine alone Adderall s active ingredient amphetamine shares many chemical and pharmacological properties with the human trace amines particularly phenethylamine and N methylphenethylamine the latter of which is a positional isomer of amphetamine sources 2 In 2021 Adderall was the seventeenth most commonly prescribed medication in the United States with more than 30 million prescriptions 32 33 Contents 1 Uses 1 1 Medical 1 1 1 Available forms 1 2 Enhancing performance 1 2 1 Cognitive performance 1 2 2 Physical performance 1 3 Recreational 2 Contraindications 3 Adverse effects 3 1 Physical 3 2 Psychological 3 3 Reinforcement disorders 3 3 1 Addiction 3 3 2 Biomolecular mechanisms 3 3 2 1 Pharmacological treatments 3 3 2 2 Behavioral treatments 3 3 3 Dependence and withdrawal 4 Overdose 5 Interactions 6 Pharmacology 6 1 Mechanism of action 6 2 Pharmacokinetics 6 3 Pharmacomicrobiomics 6 4 Related endogenous compounds 7 History 7 1 Commercial formulation 7 2 Comparison to other formulations 8 Society and culture 8 1 Legal status 8 2 Shortages 9 Notes 10 Reference notes 11 References 12 External linksUses edit nbsp 30 capsules of 10 mg Adderall XR nbsp 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 edit Part of this section is transcluded from Amphetamine edit history Adderall is commonly used to treat attention deficit hyperactivity disorder ADHD and narcolepsy a sleep disorder 34 14 Long term amphetamine exposure at sufficiently high doses in some animal species is known to produce abnormal dopamine system development or nerve damage 35 36 but in humans with ADHD long term use of pharmaceutical amphetamines at therapeutic doses appears to improve brain development and nerve growth 37 38 39 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 37 38 39 Reviews of clinical stimulant research have established the safety and effectiveness of long term continuous amphetamine use for the treatment of ADHD 40 41 42 Randomized controlled trials of continuous stimulant therapy for the treatment of ADHD spanning 2 years have demonstrated treatment effectiveness and safety 40 41 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 40 42 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 41 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 40 Current models of ADHD suggest that it is associated with functional impairments in some of the brain s neurotransmitter systems 43 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 43 Psychostimulants like methylphenidate and amphetamine are effective in treating ADHD because they increase neurotransmitter activity in these systems 15 43 44 Approximately 80 of those who use these stimulants see improvements in ADHD symptoms 45 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 46 47 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 49 50 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 51 Available forms edit Adderall is available as immediate release IR tablets and extended release XR capsules 14 52 Mydayis is only available in an extended release formulation 53 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 52 Upon ingestion half of the beads provide immediate administration of medication while the other half are enveloped in a coating which 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 52 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 53 In the United States the immediate and extended release formulations of Adderall are both available as generic drugs 54 55 Generic formulations of Mydayis became available in the US in October 2023 56 Enhancing performance edit Part of this section is transcluded from Amphetamine edit history Cognitive performance edit 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 57 58 these cognition enhancing effects of amphetamine are known to be partially mediated through the indirect activation of both dopamine receptor D1 and adrenoceptor a2 in the prefrontal cortex 15 57 A systematic review from 2014 found that low doses of amphetamine also improve memory consolidation in turn leading to improved recall of information 59 Therapeutic doses of amphetamine also enhance cortical network efficiency an effect which mediates improvements in working memory in all individuals 15 60 Amphetamine and other ADHD stimulants also improve task saliency motivation to perform a task and increase arousal wakefulness in turn promoting goal directed behavior 15 61 62 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 15 62 63 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 64 65 66 However high amphetamine doses that are above the therapeutic range can interfere with working memory and other aspects of cognitive control 15 62 Physical performance edit Amphetamine is used by some athletes for its psychological and athletic performance enhancing effects such as increased endurance and alertness 16 28 however non medical amphetamine use is prohibited at sporting events that are regulated by collegiate national and international anti doping agencies 67 68 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 16 69 70 Amphetamine improves endurance and reaction time primarily through reuptake inhibition and release of dopamine in the central nervous system 69 70 71 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 70 72 73 At therapeutic doses the adverse effects of amphetamine do not impede athletic performance 16 69 however at much higher doses amphetamine can induce effects that severely impair performance such as rapid muscle breakdown and elevated body temperature 17 69 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 74 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 74 Recreational edit See also History and culture of substituted amphetamines Adderall has high potential for misuse as a recreational drug 75 76 77 Adderall tablets can either be swallowed crushed and snorted or dissolved in water and injected 78 Injection into the bloodstream can be dangerous because insoluble fillers within the tablets can block small blood vessels 78 Many postsecondary students have reported using Adderall for study purposes in different parts of the developed world 77 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 77 Contraindications editThis section is an excerpt from Amphetamine Contraindications edit According to the International Programme on Chemical Safety IPCS and the United States Food and Drug Administration USFDA note 5 amphetamine is contraindicated in people with a history of drug abuse note 6 cardiovascular disease severe agitation or severe anxiety 81 82 83 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 81 82 83 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 81 82 83 although safe concurrent use of amphetamine and monoamine oxidase inhibitors has been documented 84 85 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 82 83 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 83 Amphetamine has also been shown to pass into breast milk so the IPCS and the USFDA advise mothers to avoid breastfeeding when using it 82 83 Due to the potential for reversible growth impairments note 7 the USFDA advises monitoring the height and weight of children and adolescents prescribed an amphetamine pharmaceutical 82 Adverse effects editPart 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 17 28 Adderall is currently approved for long term therapeutic use by the USFDA 17 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 28 Physical edit 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 17 28 89 Sexual side effects in males may include erectile dysfunction frequent erections or prolonged erections 17 Gastrointestinal side effects may include abdominal pain constipation diarrhea and nausea 7 17 90 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 28 Amphetamine stimulates the medullary respiratory centers producing faster and deeper breaths 28 In a normal person at therapeutic doses this effect is usually not noticeable but when respiration is already compromised it may be evident 28 Amphetamine also induces contraction in the urinary bladder sphincter the muscle which controls urination which can result in difficulty urinating 28 This effect can be useful in treating bed wetting and loss of bladder control 28 The effects of amphetamine on the gastrointestinal tract are unpredictable 28 If intestinal activity is high amphetamine may reduce gastrointestinal motility the rate at which content moves through the digestive system 28 however amphetamine may increase motility when the smooth muscle of the tract is relaxed 28 Amphetamine also has a slight analgesic effect and can enhance the pain relieving effects of opioids 7 28 USFDA commissioned studies from 2011 indicate that in children young adults and adults there is no association between serious adverse cardiovascular events sudden death heart attack and stroke and the medical use of amphetamine or other ADHD stimulants sources 4 However amphetamine pharmaceuticals are contraindicated in individuals with cardiovascular disease sources 5 Psychological edit 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 17 28 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 28 Amphetamine psychosis e g delusions and paranoia can occur in heavy users 17 18 98 Although very rare this psychosis can also occur at therapeutic doses during long term therapy 17 98 19 According to the USFDA there is no systematic evidence that stimulants produce aggressive behavior or hostility 17 Amphetamine has also been shown to produce a conditioned place preference in humans taking therapeutic doses 49 99 meaning that individuals acquire a preference for spending time in places where they have previously used amphetamine 99 100 Reinforcement disorders edit Addiction edit Addiction and dependence glossary 100 101 102 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 dosevteTranscription factor glossarygene 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 tovteSignaling cascade in the nucleus accumbens that results in amphetamine addictionvte nbsp 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 DFosB JunD c Fos SIRT1 HDAC1 Color legend 1 nbsp 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 103 104 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 103 105 106 Phosphorylated CREB increases levels of DFosB which in turn represses the c Fos gene with the help of corepressors 103 107 108 c Fos repression acts as a molecular switch that enables the accumulation of DFosB in the neuron 109 A highly stable phosphorylated form of DFosB one that persists in neurons for 1 2 months slowly accumulates following repeated high dose exposure to stimulants through this process 107 108 DFosB 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 107 108 Addiction is a serious risk with heavy recreational amphetamine use but is unlikely to occur from long term medical use at therapeutic doses 40 20 21 in fact lifetime stimulant therapy for ADHD that begins during childhood reduces the risk of developing substance use disorders as an adult 40 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 110 111 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 DFosB a molecular switch and master control protein for addiction 101 112 113 Once nucleus accumbens DFosB is sufficiently overexpressed it begins to increase the severity of addictive behavior i e compulsive drug seeking with further increases in its expression 112 114 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 115 116 Exercise therapy improves clinical treatment outcomes and may be used as an adjunct therapy with behavioral therapies for addiction 115 117 sources 7 Biomolecular mechanisms edit Chronic use of amphetamine at excessive doses causes alterations in gene expression in the mesocorticolimbic projection which arise through transcriptional and epigenetic mechanisms 113 118 119 The most important transcription factors note 8 that produce these alterations are Delta FBJ murine osteosarcoma viral oncogene homolog B DFosB cAMP response element binding protein CREB and nuclear factor kappa B NF kB 113 DFosB is the most significant biomolecular mechanism in addiction because DFosB 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 101 112 113 Once DFosB is sufficiently overexpressed it induces an addictive state that becomes increasingly more severe with further increases in DFosB expression 101 112 It has been implicated in addictions to alcohol cannabinoids cocaine methylphenidate nicotine opioids phencyclidine propofol and substituted amphetamines among others sources 8 DJunD a transcription factor and G9a a histone methyltransferase enzyme both oppose the function of DFosB and inhibit increases in its expression 101 113 123 Sufficiently overexpressing DJunD 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 DFosB 113 Similarly accumbal G9a hyperexpression results in markedly increased histone 3 lysine residue 9 dimethylation H3K9me2 and blocks the induction of DFosB mediated neural and behavioral plasticity by chronic drug use sources 9 which occurs via H3K9me2 mediated repression of transcription factors for DFosB and H3K9me2 mediated repression of various DFosB transcriptional targets e g CDK5 113 123 124 DFosB also plays an important role in regulating behavioral responses to natural rewards such as palatable food sex and exercise 114 113 127 Since both natural rewards and addictive drugs induce the expression of DFosB 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 114 113 Consequently DFosB 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 114 128 129 These sexual addictions are associated with a dopamine dysregulation syndrome which occurs in some patients taking dopaminergic drugs 114 127 The effects of amphetamine on gene regulation are both dose and route dependent 119 Most of the research on gene regulation and addiction is based upon animal studies with intravenous amphetamine administration at very high doses 119 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 119 This suggests that medical use of amphetamine does not significantly affect gene regulation 119 Pharmacological treatments edit Further information Addiction Research As of December 2019 update there is no effective pharmacotherapy for amphetamine addiction 130 131 132 Reviews from 2015 and 2016 indicated that TAAR1 selective agonists have significant therapeutic potential as a treatment for psychostimulant addictions 133 134 however as of February 2016 update the only compounds which are known to function as TAAR1 selective agonists are experimental drugs 133 134 Amphetamine addiction is largely mediated through increased activation of dopamine receptors and co localized NMDA receptors note 10 in the nucleus accumbens 111 magnesium ions inhibit NMDA receptors by blocking the receptor calcium channel 111 135 One review suggested that based upon animal testing pathological addiction inducing psychostimulant use significantly reduces the level of intracellular magnesium throughout the brain 111 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 111 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 131 it found only low strength evidence that methylphenidate might reduce amphetamine or methamphetamine self administration 131 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 131 Behavioral treatments edit 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 136 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 136 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 115 117 137 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 114 137 This is the opposite of pathological stimulant use which induces decreased striatal DRD2 density 114 One review noted that exercise may also prevent the development of a drug addiction by altering DFosB or c Fos immunoreactivity in the striatum or other parts of the reward system 116 Summary of addiction related plasticity Form of neuroplasticity or behavioral plasticity Type of reinforcer SourcesOpiates Psychostimulants High fat or sugar food Sexual intercourse Physical exercise aerobic EnvironmentalenrichmentDFosB expression innucleus accumbens D1 type MSNsTooltip medium spiny neurons 114 Behavioral plasticityEscalation of intake Yes Yes Yes 114 Psychostimulantcross sensitization Yes Not applicable Yes Yes Attenuated Attenuated 114 Psychostimulantself administration 114 Psychostimulantconditioned place preference 114 Reinstatement of drug seeking behavior 114 Neurochemical plasticityCREBTooltip cAMP response element binding protein phosphorylationin the nucleus accumbens 114 Sensitized dopamine responsein the nucleus accumbens No Yes No Yes 114 Altered striatal dopamine signaling DRD2 DRD3 DRD1 DRD2 DRD3 DRD1 DRD2 DRD3 DRD2 DRD2 114 Altered striatal opioid signaling No change or m opioid receptors m opioid receptors k opioid receptors m opioid receptors m opioid receptors No change No change 114 Changes in striatal opioid peptides dynorphinNo change enkephalin dynorphin enkephalin dynorphin dynorphin 114 Mesocorticolimbic synaptic plasticityNumber of dendrites in the nucleus accumbens 114 Dendritic spine density inthe nucleus accumbens 114 Dependence and withdrawal edit 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 138 139 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 140 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 140 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 140 The review indicated that the severity of withdrawal symptoms is positively correlated with the age of the individual and the extent of their dependence 140 Mild withdrawal symptoms from the discontinuation of amphetamine treatment at therapeutic doses can be avoided by tapering the dose 7 Overdose editThis section is an excerpt from Amphetamine Overdose edit An amphetamine overdose can lead to many different symptoms but is rarely fatal with appropriate care 141 83 142 The severity of overdose symptoms increases with dosage and decreases with drug tolerance to amphetamine 143 83 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 83 Symptoms of a moderate and extremely large overdose are listed below fatal amphetamine poisoning usually also involves convulsions and coma 82 143 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 12 144 Overdose symptoms by system System Minor or moderate overdose 82 143 83 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 nervoussystem 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 failureOther Elevated body temperature Mydriasis dilated pupils Elevated or low blood potassium Hyperpyrexia extremely elevated core body temperature Metabolic acidosis excessively acidic bodily fluids Interactions editMonoamine 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 147 Inhibitors of enzymes that directly metabolize amphetamine particularly CYP2D6 and FMO3 will prolong the elimination of amphetamine and increase drug effects 147 148 149 Serotonergic drugs such as most antidepressants co administered with amphetamine increases the risk of serotonin syndrome 149 Stimulants and antidepressants sedatives and depressants may increase decrease the drug effects of amphetamine and vice versa 147 Gastrointestinal and urinary pH affect the absorption and elimination of amphetamine respectively Gastrointestinal alkalinizing agents increase the absorption of amphetamine Urinary alkalinizing agents increase concentration of non ionized species decreasing urinary excretion 147 Proton pump inhibitors PPIs modify the absorption of Adderall XR and Mydayis 147 149 Zinc supplementation may reduce the minimum effective dose of amphetamine when it is used for the treatment of ADHD note 13 153 Pharmacology editPharmacodynamics of amphetamine in a dopamine neuronvte nbsp via AADC nbsp Amphetamine enters the presynaptic neuron across the neuronal membrane or through DAT 25 Once inside it binds to TAAR1 or enters synaptic vesicles through VMAT2 25 26 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 26 154 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 25 155 156 PKA phosphorylation causes DAT to withdraw into the presynaptic neuron internalize and cease transport 25 PKC phosphorylated DAT may either operate in reverse or like PKA phosphorylated DAT internalize and cease transport 25 Amphetamine is also known to increase intracellular calcium an effect which is associated with DAT phosphorylation through a CAMKIIa dependent pathway in turn producing dopamine efflux 157 158 Mechanism of action edit For a more complete and detailed description of amphetamine pharmacodynamics see Amphetamine Pharmacodynamics Amphetamine the active ingredient of Adderall works primarily by increasing the activity of the neurotransmitters dopamine and norepinephrine in the brain 24 44 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 26 159 Both active ingredients of Adderall dextroamphetamine and levoamphetamine bind to the same biological targets 28 29 but their binding affinities that is potency differ somewhat 28 29 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 29 Consequently dextroamphetamine produces more CNS stimulation than levoamphetamine 29 160 however levoamphetamine has slightly greater cardiovascular and peripheral effects 28 It has been reported that certain children have a better clinical response to levoamphetamine 30 31 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 26 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 26 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 25 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 25 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 25 26 Pharmacokinetics edit This section is transcluded from Amphetamine Pharmacokinetics edit history The oral bioavailability of amphetamine varies with gastrointestinal pH 17 it is well absorbed from the gut and bioavailability is typically over 75 for dextroamphetamine 161 Amphetamine is a weak base with a pKa of 9 9 162 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 162 17 Conversely an acidic pH means the drug is predominantly in a water soluble cationic salt form and less is absorbed 162 Approximately 20 of amphetamine circulating in the bloodstream is bound to plasma proteins 163 Following absorption amphetamine readily distributes into most tissues in the body with high concentrations occurring in cerebrospinal fluid and brain tissue 164 The half lives of amphetamine enantiomers differ and vary with urine pH 162 At normal urine pH the half lives of dextroamphetamine and levoamphetamine are 9 11 hours and 11 14 hours respectively 162 Highly acidic urine will reduce the enantiomer half lives to 7 hours 164 highly alkaline urine will increase the half lives up to 34 hours 164 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 162 Amphetamine is eliminated via the kidneys with 30 40 of the drug being excreted unchanged at normal urinary pH 162 When the urinary pH is basic amphetamine is in its free base form so less is excreted 162 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 162 Following oral administration amphetamine appears in urine within 3 hours 164 Roughly 90 of ingested amphetamine is eliminated 3 days after the last oral dose 164 CYP2D6 dopamine b 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 162 165 Among these metabolites the active sympathomimetics are 4 hydroxyamphetamine 166 4 hydroxynorephedrine 167 and norephedrine 168 The main metabolic pathways involve aromatic para hydroxylation aliphatic alpha and beta hydroxylation N oxidation N dealkylation and deamination 162 169 The known metabolic pathways detectable metabolites and metabolizing enzymes in humans include the following Metabolic pathways of amphetamine in humans sources 11 nbsp 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 OxidativeDeamination FMO3 Oxidation unidentified GlycineConjugation XM ligaseGLYAT nbsp The primary active metabolites of amphetamine are 4 hydroxyamphetamine and norephedrine 165 at normal urine pH about 30 40 of amphetamine is excreted unchanged and roughly 50 is excreted as the inactive metabolites bottom row 162 The remaining 10 20 is excreted as the active metabolites 162 Benzoic acid is metabolized by XM ligase into an intermediate product benzoyl CoA which is then metabolized by GLYAT into hippuric acid 174 Pharmacomicrobiomics edit 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 178 179 Since the total number of microbial and viral cells in the human body over 100 trillion greatly outnumbers human cells tens of trillions note 15 178 180 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 178 179 181 The field that studies these interactions is known as pharmacomicrobiomics 178 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 181 The first amphetamine metabolizing microbial enzyme tyramine oxidase from a strain of E coli commonly found in the human gut was identified in 2019 181 This enzyme was found to metabolize amphetamine tyramine and phenethylamine with roughly the same binding affinity for all three compounds 181 Related endogenous compounds edit This section is transcluded from Amphetamine Related endogenous compounds edit history Further information on 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 25 182 183 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 25 182 184 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 182 184 In turn N methylphenethylamine is metabolized from phenethylamine by phenylethanolamine N methyltransferase the same enzyme that metabolizes norepinephrine into epinephrine 182 184 Like amphetamine both phenethylamine and N methylphenethylamine regulate monoamine neurotransmission via TAAR1 25 183 184 unlike amphetamine both of these substances are broken down by monoamine oxidase B and therefore have a shorter half life than amphetamine 182 184 History editMain 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 185 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 amp 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 186 187 In 1997 Richwood Pharmaceuticals was acquired by Shire Pharmaceuticals in a 186 million transaction 185 Richwood Pharmaceuticals which later merged with Shire plc introduced the current Adderall brand in 1996 as an instant release tablet 188 In 2006 Shire agreed to sell rights to the Adderall name for the instant release form of the medication to Duramed Pharmaceuticals 189 DuraMed Pharmaceuticals was acquired by Teva Pharmaceuticals in 2008 during their acquisition of Barr Pharmaceuticals including Barr s Duramed division 190 The first generic version of Adderall IR was introduced to market in 2002 10 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 10 191 Commercial formulation edit 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 52 This drug mixture has slightly stronger CNS effects than racemic amphetamine due to the higher proportion of dextroamphetamine 25 28 Adderall is produced as both an immediate release IR and extended release XR formulation 10 14 52 As of December 2013 update ten different companies produced generic Adderall IR while Teva Pharmaceutical Industries Actavis and Barr Pharmaceuticals manufactured generic Adderall XR 10 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 10 Comparison to other formulations edit 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 basein equal doses doses withequal basecontent note 18 g mol percent 30 mg dose total base total dextro levo dextro levo dextroamphetamine sulfate 193 194 C9H13N 2 H2SO4 368 49 270 41 73 38 73 38 22 0 mg 30 0 mgamphetamine sulfate 195 C9H13N 2 H2SO4 368 49 270 41 73 38 36 69 36 69 11 0 mg 11 0 mg 30 0 mgAdderall 62 57 47 49 15 08 14 2 mg 4 5 mg 35 2 mg25 dextroamphetamine sulfate 193 194 C9H13N 2 H2SO4 368 49 270 41 73 38 73 38 25 amphetamine sulfate 195 C9H13N 2 H2SO4 368 49 270 41 73 38 36 69 36 69 25 dextroamphetamine saccharate 196 C9H13N 2 C6H10O8 480 55 270 41 56 27 56 27 25 amphetamine aspartate monohydrate 197 C9H13N C4H7NO4 H2O 286 32 135 21 47 22 23 61 23 61 lisdexamfetamine dimesylate 198 C15H25N3O CH4O3S 2 455 49 135 21 29 68 29 68 8 9 mg 74 2 mgamphetamine base suspension 90 C9H13N 135 21 135 21 100 76 19 23 81 22 9 mg 7 1 mg 22 0 mgSociety and culture editLegal status edit In Canada amphetamines are in Schedule I of the Controlled Drugs and Substances Act and can only be obtained by prescription 199 In Japan the use production and import of any medicine containing amphetamines is prohibited 200 In South Korea amphetamines are prohibited 201 In Taiwan amphetamines including Adderall are Schedule 2 drugs with a minimum five years prison term for possession 202 Only Ritalin can be legally prescribed for treatment of ADHD citation needed In Thailand amphetamines are classified as Type 1 Narcotics 203 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 204 In the United States amphetamine is a Schedule II prescription drug classified as a central nervous system CNS stimulant 205 Internationally amphetamine is in Schedule II of the Convention on Psychotropic Substances 206 207 Shortages edit In February 2023 news organizations began reporting on shortages of Adderall in the United States that have lasted for over five months 208 209 The Food and Drug Administration first reported the shortage in October 2022 210 In May 2023 7 months into the shortage the Food and Drug Administration commissioner Robert Califf stated that a number of generic drugs are in shortage at any given time because there s not enough profit He points out that Adderall is a special case because it is a controlled substance and the amount available for prescription is controlled by the Drug Enforcement Administration He also faults a tremendous increase in prescribing due to virtual prescribing and general overprescribing and overdiagnosing adding that if only the people that needed these drugs got them there probably wouldn t be a stimulant medication shortage 211 212 Notes edit 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 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 10 Mydayis is a relatively new trade name that is not commonly used to refer generally to the mixture 9 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 42 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 42 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 42 Cochrane reviews are high quality meta analytic systematic reviews of randomized controlled trials 48 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 79 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 80 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 86 87 88 The average reduction in final adult height from 3 years of continuous stimulant therapy is 2 cm 88 Transcription factors are proteins that increase or decrease the expression of specific genes 120 In simpler terms this necessary and sufficient relationship means that DFosB overexpression in the nucleus accumbens and addiction related behavioral and neural adaptations always occur together and never occur alone 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 135 The review indicated that magnesium L aspartate and magnesium chloride produce significant changes in addictive behavior 111 other forms of magnesium were not mentioned The 95 confidence interval indicates that there is a 95 probability that the true number of deaths lies between 3 425 and 4 145 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 150 151 152 The human serotonin transporter and norepinephrine transporter do not contain zinc binding sites 152 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 170 173 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 173 175 however other evidence from animal studies suggests that this reaction is catalyzed by DBH in synaptic vesicles within noradrenergic neurons in the brain 176 177 There is substantial variation in microbiome composition and microbial concentrations by anatomical site 178 179 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 178 For uniformity molar masses were calculated using the Lenntech Molecular Weight Calculator 192 and were within 0 01 g mol of published pharmaceutical values Amphetamine base percentage molecular massbase molecular masstotal Amphetamine base percentage for Adderall sum of component percentages 4 dose 1 amphetamine base percentage scaling factor molecular masstotal molecular massbase scaling factor The values in this column were scaled to a 30 mg dose of dextroamphetamine sulfate Due to pharmacological differences between these medications e g differences in the release absorption conversion concentration differing effects of enantiomers half life etc the listed values should not be considered equipotent doses Image legend Ion channel G proteins amp linked receptors Text color Transcription factorsReference notes edit 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 7 17 28 89 90 91 92 93 94 95 17 96 92 94 13 17 28 97 a b 114 115 116 117 137 112 114 113 121 122 113 124 125 126 145 82 143 142 146 a b 162 170 171 148 172 165 173 174 References edit a b c d 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 a b Joyce BM Glaser PE Gerhardt GA April 2007 Adderall produces increased striatal dopamine release and a prolonged time course compared to amphetamine isomers Psychopharmacology 191 3 669 677 doi 10 1007 s00213 006 0550 9 PMID 17031708 S2CID 20283057 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 74 xi doi 10 1016 j chc 2007 11 010 PMC 2408826 PMID 18295156 Graham J Banaschewski T Buitelaar J Coghill D Danckaerts M Dittmann RW et al January 2011 European guidelines on managing adverse effects of medication for ADHD European Child amp Adolescent Psychiatry 20 1 17 37 doi 10 1007 s00787 010 0140 6 eISSN 1435 165X PMC 3012210 PMID 21042924 Kociancic T Reed MD Findling RL March 2004 Evaluation of risks associated with short and long term psychostimulant therapy for treatment of ADHD in children Expert Opinion on Drug Safety 3 2 93 100 doi 10 1517 14740338 3 2 93 eISSN 1744 764X PMID 15006715 S2CID 31114829 Clemow DB Walker DJ September 2014 The potential for misuse and abuse of medications in ADHD a review Postgraduate Medicine 126 5 64 81 doi 10 3810 pgm 2014 09 2801 eISSN 1941 9260 PMID 25295651 S2CID 207580823 a b c d e Stahl SM March 2017 Amphetamine D L Prescriber s Guide Stahl s Essential Psychopharmacology 6th ed Cambridge United Kingdom Cambridge University Press pp 45 51 ISBN 9781108228749 Retrieved 5 August 2017 FDA sourced list of all drugs with black box warnings Use Download Full Results and View Query links nctr crs fda gov FDA Retrieved 22 October 2023 a b Sagonowsky E 28 August 2017 Shire launches new ADHD drug Mydayis as it weighs a neuroscience exit Fierce Pharma Questex LLC Archived from the original on 16 December 2019 Retrieved 2 May 2020 a b c d e f National Drug Code Amphetamine Search Results National Drug Code Directory United States Food and Drug Administration Archived from the original on 16 December 2013 Retrieved 16 December 2013 Pharmacology Evekeo CII amphetamine sulfate HCP Arbor Pharmaceuticals LLC Archived from the original on 21 September 2020 Retrieved 2 May 2020 Prescribing Information amp Medication Guide PDF Zenzedi dextroamphetamine sulfate USP Arbor Pharmaceuticals LLC Archived PDF from the original on 11 November 2020 Retrieved 2 May 2020 a b Montgomery KA June 2008 Sexual desire disorders Psychiatry 5 6 50 55 PMC 2695750 PMID 19727285 a b c d Adderall dextroamphetamine saccharate amphetamine aspartate dextroamphetamine sulfate and amphetamine sulfate tablet DailyMed Teva Pharmaceuticals USA Inc 8 November 2019 Archived from the original on 2 October 2019 Retrieved 22 December 2019 a b c d e f g 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 a b c d 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 a b c d e f g h i j k l m n o p Adderall XR dextroamphetamine sulfate dextroamphetamine saccharate amphetamine sulfate and amphetamine aspartate capsule extended release DailyMed Shire US Inc 17 July 2019 Retrieved 22 December 2019 a b Shoptaw SJ Kao U Ling W January 2009 Shoptaw SJ Ali R ed 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 a b Greydanus D Stimulant Misuse Strategies to Manage a Growing Problem PDF American College Health Association Review Article ACHA Professional Development Program p 20 Archived from the original PDF on 3 November 2013 Retrieved 2 November 2013 a b 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 a b 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 Stolerman IP 2010 Stolerman IP ed Encyclopedia of Psychopharmacology Berlin Germany London England Springer p 78 ISBN 9783540686989 Howell LL Kimmel HL January 2008 Monoamine transporters and psychostimulant addiction Biochemical Pharmacology 75 1 196 217 doi 10 1016 j bcp 2007 08 003 PMID 17825265 a b 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 USA McGraw Hill Medical pp 154 157 ISBN 9780071481274 a b c d e f g h i j k l m Miller GM January 2011 The emerging role of trace amine associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity J Neurochem 116 2 164 76 doi 10 1111 j 1471 4159 2010 07109 x PMC 3005101 PMID 21073468 a b c d e f g Eiden LE Weihe E January 2011 VMAT2 a dynamic regulator of brain monoaminergic neuronal function interacting with drugs of abuse Ann N Y Acad Sci 1216 1 86 98 Bibcode 2011NYASA1216 86E doi 10 1111 j 1749 6632 2010 05906 x PMC 4183197 PMID 21272013 VMAT2 is the CNS vesicular transporter for not only the biogenic amines DA NE EPI 5 HT and HIS but likely also for the trace amines TYR PEA and thyronamine THYR Trace aminergic neurons in mammalian CNS would be identifiable as neurons expressing VMAT2 for storage and the biosynthetic enzyme aromatic amino acid decarboxylase AADC Broadley KJ March 2010 The vascular effects of trace amines and amphetamines Pharmacology amp Therapeutics 125 3 363 375 doi 10 1016 j pharmthera 2009 11 005 PMID 19948186 a b c d e f g h i j k l m n o p q r s t u v Westfall DP Westfall TC 2010 Miscellaneous Sympathomimetic Agonists In Brunton LL Chabner BA Knollmann BC eds Goodman amp Gilman s Pharmacological Basis of Therapeutics 12th ed New York US McGraw Hill ISBN 9780071624428 a b c d e Lewin AH Miller GM Gilmour B December 2011 Trace amine associated receptor 1 is a stereoselective binding site for compounds in the amphetamine class Bioorg Med Chem 19 23 7044 7048 doi 10 1016 j bmc 2011 10 007 PMC 3236098 PMID 22037049 a b Anthony E 11 November 2013 Explorations in Child Psychiatry Springer Science amp Business Media pp 93 94 ISBN 9781468421279 Archived from the original on 21 May 2016 Retrieved 28 April 2015 a b Arnold LE 2000 Methyiphenidate vs Amphetamine Comparative review Journal of Attention Disorders 3 4 200 211 doi 10 1177 108705470000300403 S2CID 15901046 The Top 300 of 2021 ClinCalc Archived from the original on 15 January 2024 Retrieved 14 January 2024 Dextroamphetamine Dextroamphetamine Saccharate Amphetamine Amphetamine Aspartate Drug Usage Statistics ClinCalc Retrieved 14 January 2024 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 Carvalho M Carmo H Costa VM Capela JP Pontes H Remiao F Carvalho F Bastos Mde L August 2012 Toxicity of amphetamines an update Archives of Toxicology 86 8 1167 1231 doi 10 1007 s00204 012 0815 5 PMID 22392347 S2CID 2873101 Berman S O Neill J Fears S Bartzokis G London ED October 2008 Abuse of amphetamines and structural abnormalities in the brain Annals of the New York Academy of Sciences 1141 1 195 220 doi 10 1196 annals 1441 031 PMC 2769923 PMID 18991959 a b 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 a b Spencer TJ Brown A Seidman LJ Valera EM Makris N Lomedico A Faraone SV Biederman J September 2013 Effect of psychostimulants on brain structure and function in ADHD a qualitative literature review of magnetic resonance imaging based neuroimaging studies The Journal of Clinical Psychiatry 74 9 902 917 doi 10 4088 JCP 12r08287 PMC 3801446 PMID 24107764 a b 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 a b c d e f 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 a b c 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 a b c d e 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 a b c 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 a b 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 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 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 Stimulants for Attention Deficit Hyperactivity Disorder WebMD Healthwise 12 April 2010 Retrieved 12 November 2013 Scholten RJ Clarke M Hetherington J August 2005 The Cochrane Collaboration European Journal of Clinical Nutrition 59 Suppl 1 S147 S149 discussion S195 S196 doi 10 1038 sj ejcn 1602188 PMID 16052183 S2CID 29410060 a b 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 Punja S Shamseer L Hartling L Urichuk L Vandermeer B Nikles J Vohra S 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 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 a b c d e Adderall XR Prescribing Information PDF United States Food and Drug Administration Shire US Inc December 2013 Archived PDF from the original on 30 December 2013 Retrieved 30 December 2013 a b Mydayis medication guide PDF Mydayis com October 2023 Retrieved 6 February 2024 Generic Adderall Availability Drugs com Archived from the original on 28 May 2020 Retrieved 6 February 2020 Generic Adderall XR Availability Drugs com Archived from the original on 6 February 2020 Retrieved 6 February 2020 Mydayis mixed salts of a single entity amphetamine product First time generic PDF OptumRx Retrieved 6 February 2023 a b 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 a2 and dopamine D1 receptors This differential modulation of PFC dependent processes across dose appears to be associated with the differential involvement of noradrenergic a2 versus a1 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 Ilieva IP Hook CJ Farah MJ June 2015 Prescription Stimulants Effects on Healthy Inhibitory Control Working Memory and Episodic Memory A Meta analysis Journal of Cognitive Neuroscience 27 6 1069 1089 doi 10 1162 jocn a 00776 PMID 25591060 S2CID 15788121 Specifically in a set of experiments limited to high quality designs we found significant enhancement of several cognitive abilities The results of this meta analysis do confirm the reality of cognitive enhancing effects for normal healthy adults in general while also indicating that these effects are modest in size Bagot KS Kaminer Y April 2014 Efficacy of stimulants for cognitive enhancement in non attention deficit hyperactivity disorder youth a systematic review Addiction 109 4 547 557 doi 10 1111 add 12460 PMC 4471173 PMID 24749160 Amphetamine has been shown to improve consolidation of information 0 02 P 0 05 leading to improved recall Devous MD Trivedi MH Rush AJ April 2001 Regional cerebral blood flow response to oral amphetamine challenge in healthy volunteers Journal of Nuclear Medicine 42 4 535 542 PMID 11337538 Malenka RC Nestler EJ Hyman SE 2009 Chapter 10 Neural and Neuroendocrine Control of the Internal Milieu In Sydor A Brown RY eds Molecular Neuropharmacology A Foundation for Clinical Neuroscience 2nd ed New York US McGraw Hill Medical p 266 ISBN 9780071481274 Dopamine acts in the nucleus accumbens to attach motivational significance to stimuli associated with reward a b c Wood S Sage JR Shuman T Anagnostaras SG January 2014 Psychostimulants and cognition a continuum of behavioral and cognitive activation Pharmacological Reviews 66 1 193 221 doi 10 1124 pr 112 007054 PMC 3880463 PMID 24344115 Twohey M 26 March 2006 Pills become an addictive study aid JS Online Archived from the original on 15 August 2007 Retrieved 2 December 2007 Teter CJ McCabe SE LaGrange K Cranford JA Boyd CJ October 2006 Illicit use of specific prescription stimulants among college students prevalence motives and routes of administration Pharmacotherapy 26 10 1501 1510 doi 10 1592 phco 26 10 1501 PMC 1794223 PMID 16999660 Weyandt LL Oster DR Marraccini ME Gudmundsdottir BG Munro BA Zavras BM Kuhar B September 2014 Pharmacological interventions for adolescents and adults with ADHD stimulant and nonstimulant medications and misuse of prescription stimulants Psychology Research and Behavior Management 7 223 249 doi 10 2147 PRBM S47013 PMC 4164338 PMID 25228824 misuse of prescription stimulants has become a serious problem on college campuses across the US and has been recently documented in other countries as well Indeed large numbers of students claim to have engaged in the nonmedical use of prescription stimulants which is reflected in lifetime prevalence rates of prescription stimulant misuse ranging from 5 to nearly 34 of students Clemow DB Walker DJ September 2014 The potential for misuse and abuse of medications in ADHD a review Postgraduate Medicine 126 5 64 81 doi 10 3810 pgm 2014 09 2801 PMID 25295651 S2CID 207580823 Overall the data suggest that ADHD medication misuse and diversion are common health care problems for stimulant medications with the prevalence believed to be approximately 5 to 10 of high school students and 5 to 35 of college students depending on the study Bracken NM January 2012 National Study of Substance Use Trends Among NCAA College Student Athletes PDF NCAA Publications National Collegiate Athletic Association Archived PDF from the original on 9 October 2022 Retrieved 8 October 2013 Docherty JR June 2008 Pharmacology of stimulants prohibited by the World Anti Doping Agency WADA British Journal of Pharmacology 154 3 606 622 doi 10 1038 bjp 2008 124 PMC 2439527 PMID 18500382 a b c d 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 a b c 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 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 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 Roelands B De Pauw K Meeusen R June 2015 Neurophysiological effects of exercise in the heat Scandinavian Journal of Medicine amp 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 a b Moore DL Do pro sports leagues have an Adderall problem USA TODAY Archived from the original on 23 November 2014 Retrieved 4 May 2014 Commonly Abused Prescription Drugs Chart National Institute on Drug Abuse Archived from the original on 1 May 2012 Retrieved 7 May 2012 Stimulant ADHD Medications Methylphenidate and Amphetamines National Institute on Drug Abuse Archived from the original on 2 May 2012 Retrieved 7 May 2012 a b c Abelman DD 6 October 2017 Mitigating risks of students use of study drugs through understanding motivations for use and applying harm reduction theory a literature review Harm Reduction Journal 14 1 68 doi 10 1186 s12954 017 0194 6 ISSN 1477 7517 PMC 5639593 PMID 28985738 a b National Institute on Drug Abuse 2009 Stimulant ADHD Medications Methylphenidate and Amphetamines National Institute on Drug Abuse Archived from the original on 12 March 2013 Retrieved 27 February 2013 Kessler S January 1996 Drug therapy in attention deficit hyperactivity disorder Southern Medical Journal 89 1 33 38 doi 10 1097 00007611 199601000 00005 PMID 8545689 S2CID 12798818 statements on package inserts are not intended to limit medical practice Rather they are intended to limit claims by pharmaceutical companies the FDA asserts explicitly and the courts have upheld that clinical decisions are to be made by physicians and patients in individual situations 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 a b c Evekeo amphetamine sulfate tablet DailyMed Arbor Pharmaceuticals LLC 14 August 2019 Retrieved 22 December 2019 a b c d e f g h i Adderall XR dextroamphetamine sulfate dextroamphetamine saccharate amphetamine sulfate and amphetamine aspartate capsule extended release DailyMed Shire US Inc 17 July 2019 Retrieved 22 December 2019 a b c d e f g h i j Heedes G Ailakis J Amphetamine PIM 934 INCHEM International Programme on Chemical Safety Retrieved 24 June 2014 Feinberg SS November 2004 Combining stimulants with monoamine oxidase inhibitors a review of uses and one possible additional indication The Journal of Clinical Psychiatry 65 11 1520 1524 doi 10 4088 jcp v65n1113 PMID 15554766 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 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 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 medicationDexedrine 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 a b 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 a b 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 a b c 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 STRENGTHSExtended release oral suspension contains 2 5 mg amphetamine base equivalents per mL Ramey JT Bailen E Lockey RF 2006 Rhinitis medicamentosa PDF Journal of Investigational Allergology amp Clinical Immunology 16 3 148 155 PMID 16784007 Retrieved 29 April 2015 Table 2 Decongestants Causing Rhinitis Medicamentosa Nasal decongestants Sympathomimetic Amphetamine a b FDA Drug Safety Communication Safety Review Update of Medications used to treat Attention Deficit Hyperactivity Disorder ADHD in children and young adults United States Food and Drug Administration 1 November 2011 Archived from the original on 25 August 2019 Retrieved 24 December 2019 Cooper WO Habel LA Sox CM Chan KA Arbogast PG Cheetham TC Murray KT Quinn VP Stein CM Callahan ST Fireman BH Fish FA Kirshner HS O Duffy A Connell FA Ray WA November 2011 ADHD drugs and serious cardiovascular events in children and young adults New England Journal of Medicine 365 20 1896 1904 doi 10 1056 NEJMoa1110212 PMC 4943074 PMID 22043968 a b FDA Drug Safety Communication Safety Review Update of Medications used to treat Attention Deficit Hyperactivity Disorder ADHD in adults United States Food and Drug Administration 12 December 2011 Archived from the original on 14 December 2019 Retrieved 24 December 2013 Habel LA Cooper WO Sox CM Chan KA Fireman BH Arbogast PG Cheetham TC Quinn VP Dublin S Boudreau DM Andrade SE Pawloski PA Raebel MA Smith DH Achacoso N Uratsu C Go AS Sidney S Nguyen Huynh MN Ray WA Selby JV December 2011 ADHD medications and risk of serious cardiovascular events in young and middle aged adults JAMA 306 24 2673 2683 doi 10 1001 jama 2011 1830 PMC 3350308 PMID 22161946 Heedes G Ailakis J Amphetamine PIM 934 INCHEM International Programme on Chemical Safety Retrieved 24 June 2014 O Connor PG February 2012 Amphetamines Merck Manual for Health Care Professionals Merck Retrieved 8 May 2012 a b Bramness JG Gundersen OH Guterstam J Rognli EB Konstenius M Loberg EM Medhus S Tanum L Franck J 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 a b 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 a b 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 a b c d e 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 DFosB 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 DFosB target is cFos as DFosB accumulates with repeated drug exposure it represses c Fos and contributes to the molecular switch whereby DFosB 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 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 a b c 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 DFosB 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 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 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 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 a b c 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 DFosB serves as one of the master control proteins governing this structural plasticity DFosB 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 DFosB 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 a b c 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 DFosB isoforms accumulate with chronic drug exposure due to their extraordinarily long half lives As a result of its stability the DFosB protein persists in neurons for at least several weeks after cessation of drug exposure DFosB overexpression in nucleus accumbens induces NFkB In contrast the ability of DFosB 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 Nestler EJ October 2008 Transcriptional mechanisms of addiction Role of DFosB 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 DFosB 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 DFosB after chronic drug exposure Kanehisa Laboratories 10 October 2014 Amphetamine Homo sapiens human KEGG Pathway Retrieved 31 October 2014 a b c d e f Nechifor M March 2008 Magnesium in drug dependences Magnesium Research 21 1 5 15 doi 10 1684 mrh 2008 0124 inactive 31 January 2024 PMID 18557129 a href Template Cite journal html title Template Cite journal cite journal a CS1 maint DOI inactive as of January 2024 link a b c d e Ruffle JK November 2014 Molecular neurobiology of addiction what s all the D FosB about The American Journal of Drug and Alcohol Abuse 40 6 428 437 doi 10 3109 00952990 2014 933840 PMID 25083822 S2CID 19157711 DFosB is an essential transcription factor implicated in the molecular and behavioral pathways of addiction following repeated drug exposure a b c d e f g h i j k 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 DFosB has been linked directly to several addiction related behaviors Importantly genetic or viral overexpression of DJunD a dominant negative mutant of JunD which antagonizes DFosB and other AP 1 mediated transcriptional activity in the NAc or OFC blocks these key effects of drug exposure14 22 24 This indicates that DFosB is both necessary and sufficient for many of the changes wrought in the brain by chronic drug exposure DFosB 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 consumption14 26 30 This implicates DFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive like states DFosB serves as one of the master control proteins governing this structural plasticity a b c d e f g h i j k l m n o p q r s t u v 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 a b c d 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 amp 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 a b c 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 DFosB 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 a b c 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 Hyman SE Malenka RC Nestler EJ July 2006 Neural mechanisms of addiction the role of reward related learning and memory PDF Annual Review of Neuroscience 29 565 598 doi 10 1146 annurev neuro 29 051605 113009 PMID 16776597 S2CID 15139406 Archived from the original PDF on 19 September 2018 a b c d e Steiner H Van Waes V January 2013 Addiction related gene regulation risks of exposure to cognitive enhancers vs other psychostimulants Progress in Neurobiology 100 60 80 doi 10 1016 j pneurobio 2012 10 001 PMC 3525776 PMID 23085425 Malenka RC Nestler EJ Hyman SE 2009 Chapter 4 Signal Transduction in the Brain In Sydor A Brown RY eds Molecular Neuropharmacology A Foundation for Clinical Neuroscience 2nd ed New York US McGraw Hill Medical p 94 ISBN 9780071481274 Kanehisa Laboratories 29 October 2014 Alcoholism Homo sapiens human KEGG Pathway Retrieved 31 October 2014 Kim Y Teylan MA Baron M Sands A Nairn AC Greengard P February 2009 Methylphenidate induced dendritic spine formation and DeltaFosB expression in nucleus accumbens Proceedings of the National Academy of Sciences 106 8 2915 2920 Bibcode 2009PNAS 106 2915K doi 10 1073 pnas 0813179106 PMC 2650365 PMID 19202072 a b Nestler EJ January 2014 Epigenetic mechanisms of drug addiction Neuropharmacology 76 Pt B 259 268 doi 10 1016 j neuropharm 2013 04 004 PMC 3766384 PMID 23643695 a b Bilinski P Wojtyla A Kapka Skrzypczak L Chwedorowicz R Cyranka M Studzinski T 2012 Epigenetic regulation in drug addiction Annals of Agricultural and Environmental Medicine 19 3 491 496 PMID 23020045 Kennedy PJ Feng J Robison AJ Maze I Badimon A Mouzon E Chaudhury D Damez Werno DM Haggarty SJ Han MH Bassel Duby R Olson EN Nestler EJ April 2013 Class I HDAC inhibition blocks cocaine induced plasticity by targeted changes in histone methylation Nature Neuroscience 16 4 434 440 doi 10 1038 nn 3354 PMC 3609040 PMID 23475113 Whalley K December 2014 Psychiatric disorders a feat of epigenetic engineering Nature Reviews Neuroscience 15 12 768 769 doi 10 1038 nrn3869 PMID 25409693 S2CID 11513288 a b Blum K Werner T Carnes S Carnes P Bowirrat A Giordano J Oscar Berman M Gold M March 2012 Sex drugs and rock n roll hypothesizing common mesolimbic activation as a function of reward gene polymorphisms Journal of Psychoactive Drugs 44 1 38 55 doi 10 1080 02791072 2012 662112 PMC 4040958 PMID 22641964 It has been found that deltaFosB gene in the NAc is critical for reinforcing effects of sexual reward Pitchers and colleagues 2010 reported that sexual experience was shown to cause DeltaFosB accumulation in several limbic brain regions including the NAc medial pre frontal cortex VTA caudate and putamen but not the medial preoptic nucleus these findings support a critical role for DeltaFosB expression in the NAc in the reinforcing effects of sexual behavior and sexual experience induced facilitation of sexual performance both drug addiction and sexual addiction represent pathological forms of neuroplasticity along with the emergence of aberrant behaviors involving a cascade of neurochemical changes mainly in the brain s rewarding circuitry Pitchers KK Vialou V Nestler EJ Laviolette SR Lehman MN Coolen LM February 2013 Natural and drug rewards act on common neural plasticity mechanisms with DFosB as a key mediator The Journal of Neuroscience 33 8 3434 3442 doi 10 1523 JNEUROSCI 4881 12 2013 PMC 3865508 PMID 23426671 Beloate LN Weems PW Casey GR Webb IC Coolen LM February 2016 Nucleus accumbens NMDA receptor activation regulates amphetamine cross sensitization and deltaFosB expression following sexual experience in male rats Neuropharmacology 101 154 164 doi 10 1016 j neuropharm 2015 09 023 PMID 26391065 S2CID 25317397 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 Pharmacologic treatment for psychostimulant addiction is generally unsatisfactory As previously discussed cessation of cocaine use and the use of other psychostimulants in dependent individuals does not produce a physical withdrawal syndrome but may produce dysphoria anhedonia and an intense desire to reinitiate drug use a b c d Chan B Freeman M Kondo K Ayers C Montgomery J Paynter R Kansagara D December 2019 Pharmacotherapy for methamphetamine amphetamine use disorder a systematic review and meta analysis Addiction 114 12 2122 2136 doi 10 1111 add 14755 PMID 31328345 S2CID 198136436 Stoops WW Rush CR May 2014 Combination pharmacotherapies for stimulant use disorder a review of clinical findings and recommendations for future research Expert Review of Clinical Pharmacology 7 3 363 374 doi 10 1586 17512433 2014 909283 PMC 4017926 PMID 24716825 Despite concerted efforts to identify a pharmacotherapy for managing stimulant use disorders no widely effective medications have been approved a b Grandy DK Miller GM Li JX February 2016 TAARgeting Addiction The Alamo Bears Witness to Another Revolution An Overview of the Plenary Symposium of the 2015 Behavior Biology and Chemistry Conference Drug and Alcohol Dependence 159 9 16 doi 10 1016 j drugalcdep 2015 11 014 PMC 4724540 PMID 26644139 When considered together with the rapidly growing literature in the field a compelling case emerges in support of developing TAAR1 selective agonists as medications for preventing relapse to psychostimulant abuse a b Jing L Li JX August 2015 Trace amine associated receptor 1 A promising target for the treatment of psychostimulant addiction European Journal of Pharmacology 761 345 352 doi 10 1016 j ejphar 2015 06 019 PMC 4532615 PMID 26092759 Existing data provided robust preclinical evidence supporting the development of TAAR1 agonists as potential treatment for psychostimulant abuse and addiction a b Malenka RC Nestler EJ Hyman SE 2009 Chapter 5 Excitatory and Inhibitory Amino Acids In Sydor A Brown RY eds Molecular Neuropharmacology A Foundation for Clinical Neuroscience 2nd ed New York US McGraw Hill Medical pp 124 125 ISBN 9780071481274 a b De Crescenzo F Ciabattini M D Alo GL De Giorgi R Del Giovane C Cassar C Janiri L Clark N Ostacher MJ Cipriani A December 2018 Comparative efficacy and acceptability of psychosocial interventions for individuals with cocaine and amphetamine addiction A systematic review and network meta analysis PLOS Medicine 15 12 e1002715 doi 10 1371 journal pmed 1002715 PMC 6306153 PMID 30586362 a b c Carroll ME Smethells JR February 2016 Sex Differences in Behavioral Dyscontrol Role in Drug Addiction and Novel Treatments Frontiers in Psychiatry 6 175 doi 10 3389 fpsyt 2015 00175 PMC 4745113 PMID 26903885 Physical ExerciseThere is accelerating evidence that physical exercise is a useful treatment for preventing and reducing drug addiction In some individuals exercise has its own rewarding effects and a behavioral economic interaction may occur such that physical and social rewards of exercise can substitute for the rewarding effects of drug abuse The value of this form of treatment for drug addiction in laboratory animals and humans is that exercise if it can substitute for the rewarding effects of drugs could be self maintained over an extended period of time Work to date in laboratory animals and humans regarding exercise as a treatment for drug addiction supports this hypothesis Animal and human research on physical exercise as a treatment for stimulant addiction indicates that this is one of the most promising treatments on the horizon Perez Mana C Castells X Torrens M Capella D Farre M September 2013 Efficacy of psychostimulant drugs for amphetamine abuse or dependence Cochrane Database of Systematic Reviews 9 9 CD009695 doi 10 1002 14651858 CD009695 pub2 PMID 23996457 Amphetamines Drug Use and Abuse Merck Manual Home Edition Merck February 2003 Archived from the original on 17 February 2007 Retrieved 28 February 2007 a b c d Shoptaw SJ Kao U Heinzerling K Ling W April 2009 Shoptaw SJ ed Treatment for amphetamine withdrawal Cochrane Database of Systematic Reviews 2009 2 CD003021 doi 10 1002 14651858 CD003021 pub2 PMC 7138250 PMID 19370579 The prevalence of this withdrawal syndrome is extremely common Cantwell 1998 Gossop 1982 with 87 6 of 647 individuals with amphetamine dependence reporting six or more signs of amphetamine withdrawal listed in the DSM when the drug is not available Schuckit 1999 The severity of withdrawal symptoms is greater in amphetamine dependent individuals who are older and who have more extensive amphetamine use disorders McGregor 2005 Withdrawal symptoms typically present within 24 hours of the last use of amphetamine with a withdrawal syndrome involving two general phases that can last 3 weeks or more The first phase of this syndrome is the initial crash that resolves within about a week Gossop 1982 McGregor 2005 Stahl SM March 2017 Amphetamine D L Prescriber s Guide Stahl s Essential Psychopharmacology 6th ed Cambridge United Kingdom Cambridge University Press pp 45 51 ISBN 9781108228749 Retrieved 5 August 2017 a b Spiller HA Hays HL Aleguas A June 2013 Overdose of drugs for attention deficit hyperactivity disorder clinical presentation mechanisms of toxicity and management CNS Drugs 27 7 531 543 doi 10 1007 s40263 013 0084 8 PMID 23757186 S2CID 40931380 Amphetamine dextroamphetamine and methylphenidate act as substrates for the cellular monoamine transporter especially the dopamine transporter DAT and less so the norepinephrine NET and serotonin transporter The mechanism of toxicity is primarily related to excessive extracellular dopamine norepinephrine and serotonin a b c d Westfall DP Westfall TC 2010 Miscellaneous Sympathomimetic Agonists In Brunton LL Chabner BA Knollmann BC eds Goodman amp Gilman s Pharmacological Basis of Therapeutics 12th ed New York US McGraw Hill ISBN 9780071624428 Collaborators 2015 Global regional and national age sex specific all cause and cause specific mortality for 240 causes of death 1990 2013 a systematic analysis for the Global Burden of Disease Study 2013 The Lancet 385 9963 117 171 doi 10 1016 S0140 6736 14 61682 2 hdl 11655 15525 PMC 4340604 PMID 25530442 Amphetamine use disorders 3 788 3 425 4 145 Greene SL Kerr F Braitberg G October 2008 Review article amphetamines and related drugs of abuse Emergency Medicine Australasia 20 5 391 402 doi 10 1111 j 1742 6723 2008 01114 x PMID 18973636 S2CID 20755466 Albertson TE 2011 Amphetamines In Olson KR Anderson IB Benowitz NL Blanc PD Kearney TE Kim Katz SY Wu AH eds Poisoning amp Drug Overdose 6th ed New York McGraw Hill Medical pp 77 79 ISBN 9780071668330 a b c d e Adderall XR Prescribing Information PDF United States Food and Drug Administration December 2013 pp 8 10 Archived PDF from the original on 30 December 2013 Retrieved 30 December 2013 a b Krueger SK Williams DE June 2005 Mammalian flavin containing monooxygenases structure function genetic polymorphisms and role in drug metabolism Pharmacology amp Therapeutics 106 3 357 387 doi 10 1016 j pharmthera 2005 01 001 PMC 1828602 PMID 15922018 Table 5 N containing drugs and xenobiotics oxygenated by FMO a b c Mydayis Prescribing Information PDF United States Food and Drug Administration Shire US Inc June 2017 pp 1 21 Archived PDF from the original on 9 June 2019 Retrieved 8 August 2017 Krause J April 2008 SPECT and PET of the dopamine transporter in attention deficit hyperactivity disorder Expert Rev Neurother 8 4 611 625 doi 10 1586 14737175 8 4 611 PMID 18416663 S2CID 24589993 Zinc binds at extracellular sites of the DAT 103 serving as a DAT inhibitor In this context controlled double blind studies in children are of interest which showed positive effects of zinc supplementation on symptoms of ADHD 105 106 It should be stated that at this time supplementation with zinc is not integrated in any ADHD treatment algorithm 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 a, wikipedia, wiki, book, books, library,

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