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Wikipedia

Amphetamine

Amphetamine[note 2] (contracted from alpha-methylphenethylamine) is a strong central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity. It is also commonly used as a recreational drug. Amphetamine was discovered in 1887 and exists as two enantiomers:[note 3] levoamphetamine and dextroamphetamine. Amphetamine properly refers to a specific chemical, the racemic free base, which is equal parts of the two enantiomers in their pure amine forms. The term is frequently used informally to refer to any combination of the enantiomers, or to either of them alone. Historically, it has been used to treat nasal congestion and depression. Amphetamine is also used as an athletic performance enhancer and cognitive enhancer, and recreationally as an aphrodisiac and euphoriant. It is a prescription drug in many countries, and unauthorized possession and distribution of amphetamine are often tightly controlled due to the significant health risks associated with recreational use.[sources 1]

Amphetamine
INN: Amfetamine
Clinical data
Pronunciation/æmˈfɛtəmn/ (listen)
Trade namesEvekeo, Adderall,[note 1] others
Other namesα-methylphenethylamine
AHFS/Drugs.comMonograph
MedlinePlusa616004
License data
Dependence
liability
Moderate[1]
Addiction
liability
Moderate
Routes of
administration
Medical: oral, intravenous[2]
Recreational: oral, insufflation, rectal, intravenous, intramuscular
Drug classCNS stimulant, anorectic
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityOral: 75–100%[3]
Protein binding20%[4]
MetabolismCYP2D6,[5] DBH,[13][14] FMO3[13][15][16]
Metabolites4-hydroxyamphetamine, 4-hydroxynorephedrine, 4-hydroxyphenylacetone, benzoic acid, hippuric acid, norephedrine, phenylacetone[5][6]
Onset of actionIR dosing: 30–60 minutes[7]
XR dosing: 1.5–2 hours[8][9]
Elimination half-lifeD-amph: 9–11 hours[5][10]
L-amph: 11–14 hours[5][10]
pH-dependent: 7–34 hours[11]
Duration of actionIR dosing: 3–6 hours[1][8][12]
XR dosing: 8–12 hours[1][8][12]
ExcretionPrimarily renal;
pH-dependent range: 1–75%[5]
Identifiers
  • (RS)-1-phenylpropan-2-amine
CAS Number
  • 300-62-9 Y
PubChem CID
  • 3007
IUPHAR/BPS
  • 4804
DrugBank
  • DB00182 Y
ChemSpider
  • 13852819 Y
UNII
  • CK833KGX7E
KEGG
  • D07445 Y
ChEBI
  • CHEBI:2679 Y
ChEMBL
  • ChEMBL405 Y
NIAID ChemDB
  • 018564
CompTox Dashboard (EPA)
  • DTXSID4022600
ECHA InfoCard100.005.543
Chemical and physical data
FormulaC9H13N
Molar mass135.210 g·mol−1
3D model (JSmol)
  • Interactive image
ChiralityRacemic mixture[17]
Density.936 g/cm3 at 25 °C[18]
Melting point146 °C (295 °F) [19]
Boiling point203 °C (397 °F) at 760 mmHg[20]
  • NC(C)Cc1ccccc1
  • InChI=1S/C9H13N/c1-8(10)7-9-5-3-2-4-6-9/h2-6,8H,7,10H2,1H3 Y
  • Key:KWTSXDURSIMDCE-UHFFFAOYSA-N Y
  (verify)

The first amphetamine pharmaceutical was Benzedrine, a brand which was used to treat a variety of conditions. Currently, pharmaceutical amphetamine is prescribed as racemic amphetamine, Adderall,[note 4] dextroamphetamine, or the inactive prodrug lisdexamfetamine. Amphetamine increases monoamine and excitatory neurotransmission in the brain, with its most pronounced effects targeting the norepinephrine and dopamine neurotransmitter systems.[sources 2]

At therapeutic doses, amphetamine causes emotional and cognitive effects such as euphoria, change in desire for sex, increased wakefulness, and improved cognitive control. It induces physical effects such as improved reaction time, fatigue resistance, and increased muscle strength. Larger doses of amphetamine may impair cognitive function and induce rapid muscle breakdown. Addiction is a serious risk with heavy recreational amphetamine use, but is unlikely to occur from long-term medical use at therapeutic doses. Very high doses can result in psychosis (e.g., delusions and paranoia) which rarely occurs at therapeutic doses even during long-term use. Recreational doses are generally much larger than prescribed therapeutic doses and carry a far greater risk of serious side effects.[sources 3]

Amphetamine belongs to the phenethylamine class. It is also the parent compound of its own structural class, the substituted amphetamines,[note 5] which includes prominent substances such as bupropion, cathinone, MDMA, and methamphetamine. As a member of the phenethylamine class, amphetamine is also chemically related to the naturally occurring trace amine neuromodulators, specifically phenethylamine and N-methylphenethylamine, both of which are produced within the human body. Phenethylamine is the parent compound of amphetamine, while N-methylphenethylamine is a positional isomer of amphetamine that differs only in the placement of the methyl group.[sources 4]

Uses

Medical

Amphetamine is used to treat attention deficit hyperactivity disorder (ADHD), narcolepsy (a sleep disorder), and obesity, and is sometimes prescribed off-label for its past medical indications, particularly for depression and chronic pain.[1][33][47] Long-term amphetamine exposure at sufficiently high doses in some animal species is known to produce abnormal dopamine system development or nerve damage,[48][49] but in humans with ADHD, pharmaceutical amphetamines at therapeutic dosages appear to improve brain development and nerve growth.[50][51][52] 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.[50][51][52]

Reviews of clinical stimulant research have established the safety and effectiveness of long-term continuous amphetamine use for the treatment of ADHD.[41][53][54] Randomized controlled trials of continuous stimulant therapy for the treatment of ADHD spanning 2 years have demonstrated treatment effectiveness and safety.[41][53] 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 6] 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.[41][54] 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.[53] 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.[41]

Current models of ADHD suggest that it is associated with functional impairments in some of the brain's neurotransmitter systems;[55] 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.[55] Psychostimulants like methylphenidate and amphetamine are effective in treating ADHD because they increase neurotransmitter activity in these systems.[24][55][56] Approximately 80% of those who use these stimulants see improvements in ADHD symptoms.[57] 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.[58][59] The Cochrane reviews[note 7] 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.[61][62] 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.[63]

Enhancing performance

Cognitive performance

In 2015, a systematic review and a meta-analysis of high quality clinical trials found that, when used at low (therapeutic) doses, amphetamine produces modest yet unambiguous improvements in cognition, including working memory, long-term episodic memory, inhibitory control, and some aspects of attention, in normal healthy adults;[64][65] 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.[24][64] A systematic review from 2014 found that low doses of amphetamine also improve memory consolidation, in turn leading to improved recall of information.[66] Therapeutic doses of amphetamine also enhance cortical network efficiency, an effect which mediates improvements in working memory in all individuals.[24][67] Amphetamine and other ADHD stimulants also improve task saliency (motivation to perform a task) and increase arousal (wakefulness), in turn promoting goal-directed behavior.[24][68][69] 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.[24][69][70] 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.[71][72][73] However, high amphetamine doses that are above the therapeutic range can interfere with working memory and other aspects of cognitive control.[24][69]

Physical performance

Amphetamine is used by some athletes for its psychological and athletic performance-enhancing effects, such as increased endurance and alertness;[25][37] however, non-medical amphetamine use is prohibited at sporting events that are regulated by collegiate, national, and international anti-doping agencies.[74][75] 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.[25][76][77] Amphetamine improves endurance and reaction time primarily through reuptake inhibition and release of dopamine in the central nervous system.[76][77][78] 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.[77][79][80] At therapeutic doses, the adverse effects of amphetamine do not impede athletic performance;[25][76] however, at much higher doses, amphetamine can induce effects that severely impair performance, such as rapid muscle breakdown and elevated body temperature.[26][76]

Contraindications

According to the International Programme on Chemical Safety (IPCS) and the United States Food and Drug Administration (USFDA),[note 8] amphetamine is contraindicated in people with a history of drug abuse,[note 9] cardiovascular disease, severe agitation, or severe anxiety.[33][26][82] 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.[33][26][82] 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,[33][26][82] although safe concurrent use of amphetamine and monoamine oxidase inhibitors has been documented.[83][84] 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.[26][82] 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.[82] Amphetamine has also been shown to pass into breast milk, so the IPCS and the USFDA advise mothers to avoid breastfeeding when using it.[26][82] Due to the potential for reversible growth impairments,[note 10] the USFDA advises monitoring the height and weight of children and adolescents prescribed an amphetamine pharmaceutical.[26]

Adverse effects

The adverse side effects of amphetamine are many and varied, and the amount of amphetamine used is the primary factor in determining the likelihood and severity of adverse effects.[26][37] Amphetamine products such as Adderall, Dexedrine, and their generic equivalents are currently approved by the USFDA for long-term therapeutic use.[34][26] Recreational use of amphetamine generally involves much larger doses, which have a greater risk of serious adverse drug effects than dosages used for therapeutic purposes.[37]

Physical

Cardiovascular side effects can include hypertension or hypotension from a vasovagal response, Raynaud's phenomenon (reduced blood flow to the hands and feet), and tachycardia (increased heart rate).[26][37][85] Sexual side effects in males may include erectile dysfunction, frequent erections, or prolonged erections.[26] Gastrointestinal side effects may include abdominal pain, constipation, diarrhea, and nausea.[1][26][86] 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 5] Dangerous physical side effects are rare at typical pharmaceutical doses.[37]

Amphetamine stimulates the medullary respiratory centers, producing faster and deeper breaths.[37] In a normal person at therapeutic doses, this effect is usually not noticeable, but when respiration is already compromised, it may be evident.[37] Amphetamine also induces contraction in the urinary bladder sphincter, the muscle which controls urination, which can result in difficulty urinating.[37] This effect can be useful in treating bed wetting and loss of bladder control.[37] The effects of amphetamine on the gastrointestinal tract are unpredictable.[37] If intestinal activity is high, amphetamine may reduce gastrointestinal motility (the rate at which content moves through the digestive system);[37] however, amphetamine may increase motility when the smooth muscle of the tract is relaxed.[37] Amphetamine also has a slight analgesic effect and can enhance the pain relieving effects of opioids.[1][37]

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 6] However, amphetamine pharmaceuticals are contraindicated in individuals with cardiovascular disease.[sources 7]

Psychological

At normal therapeutic doses, the most common psychological side effects of amphetamine include increased alertness, apprehension, concentration, initiative, self-confidence and sociability, mood swings (elated mood followed by mildly depressed mood), insomnia or wakefulness, and decreased sense of fatigue.[26][37] Less common side effects include anxiety, change in libido, grandiosity, irritability, repetitive or obsessive behaviors, and restlessness;[sources 8] these effects depend on the user's personality and current mental state.[37] Amphetamine psychosis (e.g., delusions and paranoia) can occur in heavy users.[26][38][39] Although very rare, this psychosis can also occur at therapeutic doses during long-term therapy.[26][39][40] According to the USFDA, "there is no systematic evidence" that stimulants produce aggressive behavior or hostility.[26]

Amphetamine has also been shown to produce a conditioned place preference in humans taking therapeutic doses,[61][93] meaning that individuals acquire a preference for spending time in places where they have previously used amphetamine.[93][94]

Reinforcement disorders

Addiction

Addiction and dependence glossary[94][95][96][97]
  • 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 that involves emotional–motivational withdrawal symptoms (e.g., dysphoria and anhedonia)
  • 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,[98][99] 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.[98][100] Phosphorylated CREB increases levels of ΔFosB, which in turn represses the c-Fos gene with the help of corepressors;[98][101][102] c-Fos repression acts as a molecular switch that enables the accumulation of ΔFosB in the neuron.[103] 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.[101][102] 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.[101][102]

Addiction is a serious risk with heavy recreational amphetamine use, but is unlikely to occur from long-term medical use at therapeutic doses;[41][42][43] in fact, lifetime stimulant therapy for ADHD that begins during childhood reduces the risk of developing substance use disorders as an adult.[41] 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.[104][105] 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.[95][106][107] 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.[106][108] 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.[109][110] Sustained aerobic exercise on a regular basis also appears to be an effective treatment for amphetamine addiction;[sources 9] exercise therapy improves clinical treatment outcomes and may be used as an adjunct therapy with behavioral therapies for addiction.[109][111]

Biomolecular mechanisms

Chronic use of amphetamine at excessive doses causes alterations in gene expression in the mesocorticolimbic projection, which arise through transcriptional and epigenetic mechanisms.[107][112][113] The most important transcription factors[note 11] 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).[107] 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 12] for many of the neural adaptations and regulates multiple behavioral effects (e.g., reward sensitization and escalating drug self-administration) involved in addiction.[95][106][107] Once ΔFosB is sufficiently overexpressed, it induces an addictive state that becomes increasingly more severe with further increases in ΔFosB expression.[95][106] It has been implicated in addictions to alcohol, cannabinoids, cocaine, methylphenidate, nicotine, opioids, phencyclidine, propofol, and substituted amphetamines, among others.[sources 10]

ΔJunD, a transcription factor, and G9a, a histone methyltransferase enzyme, both oppose the function of ΔFosB and inhibit increases in its expression.[95][107][117] 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).[107] 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 11] which occurs via H3K9me2-mediated repression of transcription factors for ΔFosB and H3K9me2-mediated repression of various ΔFosB transcriptional targets (e.g., CDK5).[107][117][118] ΔFosB also plays an important role in regulating behavioral responses to natural rewards, such as palatable food, sex, and exercise.[108][107][121] 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.[108][107] 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.[108][122][123] These sexual addictions are associated with a dopamine dysregulation syndrome which occurs in some patients taking dopaminergic drugs.[108][121]

The effects of amphetamine on gene regulation are both dose- and route-dependent.[113] Most of the research on gene regulation and addiction is based upon animal studies with intravenous amphetamine administration at very high doses.[113] 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.[113] This suggests that medical use of amphetamine does not significantly affect gene regulation.[113]

Pharmacological treatments

As of December 2019, there is no effective pharmacotherapy for amphetamine addiction.[124][125][126] Reviews from 2015 and 2016 indicated that TAAR1-selective agonists have significant therapeutic potential as a treatment for psychostimulant addictions;[36][127] however, as of February 2016, the only compounds which are known to function as TAAR1-selective agonists are experimental drugs.[36][127] Amphetamine addiction is largely mediated through increased activation of dopamine receptors and co-localized NMDA receptors[note 13] in the nucleus accumbens;[105] magnesium ions inhibit NMDA receptors by blocking the receptor calcium channel.[105][128] One review suggested that, based upon animal testing, pathological (addiction-inducing) psychostimulant use significantly reduces the level of intracellular magnesium throughout the brain.[105] Supplemental magnesium[note 14] 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.[105]

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;[125] it found only low-strength evidence that methylphenidate might reduce amphetamine or methamphetamine self-administration.[125] 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.[125]

Behavioral treatments

A 2018 systematic review and network meta-analysis of 50 trials involving 12 different psychosocial interventions for amphetamine, methamphetamine, or cocaine addiction found that combination therapy with both contingency management and community reinforcement approach had the highest efficacy (i.e., abstinence rate) and acceptability (i.e., lowest dropout rate).[129] 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.[129]

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 9] Exercise leads to better treatment outcomes when used as an adjunct treatment, particularly for psychostimulant addictions.[109][111][130] 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.[108][130] This is the opposite of pathological stimulant use, which induces decreased striatal DRD2 density.[108] 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.[110]

Summary of addiction-related plasticity
Form of neuroplasticity
or behavioral plasticity
Type of reinforcer Sources
Opiates Psychostimulants High fat or sugar food Sexual intercourse Physical exercise
(aerobic)
Environmental
enrichment
ΔFosB expression in
nucleus accumbens D1-type MSNs
[108]
Behavioral plasticity
Escalation of intake Yes Yes Yes [108]
Psychostimulant
cross-sensitization
Yes Not applicable Yes Yes Attenuated Attenuated [108]
Psychostimulant
self-administration
[108]
Psychostimulant
conditioned place preference
[108]
Reinstatement of drug-seeking behavior [108]
Neurochemical plasticity
CREB phosphorylation
in the nucleus accumbens
[108]
Sensitized dopamine response
in the nucleus accumbens
No Yes No Yes [108]
Altered striatal dopamine signaling DRD2, ↑DRD3 DRD1, ↓DRD2, ↑DRD3 DRD1, ↓DRD2, ↑DRD3 DRD2 DRD2 [108]
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 [108]
Changes in striatal opioid peptides dynorphin
No change: enkephalin
dynorphin enkephalin dynorphin dynorphin [108]
Mesocorticolimbic synaptic plasticity
Number of dendrites in the nucleus accumbens [108]
Dendritic spine density in
the nucleus accumbens
[108]

Dependence and withdrawal

Drug tolerance develops rapidly in amphetamine abuse (i.e., recreational amphetamine use), so periods of extended abuse require increasingly larger doses of the drug in order to achieve the same effect.[131][132] 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."[133] 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.[133] 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.[133] The review indicated that the severity of withdrawal symptoms is positively correlated with the age of the individual and the extent of their dependence.[133] Mild withdrawal symptoms from the discontinuation of amphetamine treatment at therapeutic doses can be avoided by tapering the dose.[1]

Overdose

An amphetamine overdose can lead to many different symptoms, but is rarely fatal with appropriate care.[1][82][134] The severity of overdose symptoms increases with dosage and decreases with drug tolerance to amphetamine.[37][82] 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.[82] Symptoms of a moderate and extremely large overdose are listed below; fatal amphetamine poisoning usually also involves convulsions and coma.[26][37] 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 15][135]

Overdose symptoms by system
System Minor or moderate overdose[26][37][82] Severe overdose[sources 12]
Cardiovascular
Central nervous
system
Musculoskeletal
Respiratory
  • Rapid breathing
Urinary
Other

Toxicity

In rodents and primates, sufficiently high doses of amphetamine cause dopaminergic neurotoxicity, or damage to dopamine neurons, which is characterized by dopamine terminal degeneration and reduced transporter and receptor function.[137][138] There is no evidence that amphetamine is directly neurotoxic in humans.[139][140] However, large doses of amphetamine may indirectly cause dopaminergic neurotoxicity as a result of hyperpyrexia, the excessive formation of reactive oxygen species, and increased autoxidation of dopamine.[sources 13] Animal models of neurotoxicity from high-dose amphetamine exposure indicate that the occurrence of hyperpyrexia (i.e., core body temperature ≥ 40 °C) is necessary for the development of amphetamine-induced neurotoxicity.[138] Prolonged elevations of brain temperature above 40 °C likely promote the development of amphetamine-induced neurotoxicity in laboratory animals by facilitating the production of reactive oxygen species, disrupting cellular protein function, and transiently increasing blood–brain barrier permeability.[138]

Psychosis

An amphetamine overdose can result in a stimulant psychosis that may involve a variety of symptoms, such as delusions and paranoia.[38][39] A Cochrane review on treatment for amphetamine, dextroamphetamine, and methamphetamine psychosis states that about 5–15% of users fail to recover completely.[38][143] According to the same review, there is at least one trial that shows antipsychotic medications effectively resolve the symptoms of acute amphetamine psychosis.[38] Psychosis rarely arises from therapeutic use.[26][39][40]

Drug interactions

Many types of substances are known to interact with amphetamine, resulting in altered drug action or metabolism of amphetamine, the interacting substance, or both.[26] Inhibitors of enzymes that metabolize amphetamine (e.g., CYP2D6 and FMO3) will prolong its elimination half-life, meaning that its effects will last longer.[15][26] Amphetamine also interacts with MAOIs, particularly monoamine oxidase A inhibitors, since both MAOIs and amphetamine increase plasma catecholamines (i.e., norepinephrine and dopamine);[26] therefore, concurrent use of both is dangerous.[26] Amphetamine modulates the activity of most psychoactive drugs. In particular, amphetamine may decrease the effects of sedatives and depressants and increase the effects of stimulants and antidepressants.[26] Amphetamine may also decrease the effects of antihypertensives and antipsychotics due to its effects on blood pressure and dopamine respectively.[26] Zinc supplementation may reduce the minimum effective dose of amphetamine when it is used for the treatment of ADHD.[note 16][148]

In general, there is no significant interaction when consuming amphetamine with food, but the pH of gastrointestinal content and urine affects the absorption and excretion of amphetamine, respectively.[26] Acidic substances reduce the absorption of amphetamine and increase urinary excretion, and alkaline substances do the opposite.[26] Due to the effect pH has on absorption, amphetamine also interacts with gastric acid reducers such as proton pump inhibitors and H2 antihistamines, which increase gastrointestinal pH (i.e., make it less acidic).[26]

Pharmacology

Pharmacodynamics

Pharmacodynamics of amphetamine in a dopamine neuron
 
via AADC
 
Amphetamine enters the presynaptic neuron across the neuronal membrane or through DAT.[35] Once inside, it binds to TAAR1 or enters synaptic vesicles through VMAT2.[35][149] 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.[149][150] When amphetamine binds to TAAR1, it reduces the firing rate of the dopamine neuron via potassium channels and activates protein kinase A (PKA) and protein kinase C (PKC), which subsequently phosphorylates DAT.[35][151][152] PKA-phosphorylation causes DAT to withdraw into the presynaptic neuron (internalize) and cease transport.[35] PKC-phosphorylated DAT may either operate in reverse or, like PKA-phosphorylated DAT, internalize and cease transport.[35] 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.[153][154]

Amphetamine exerts its behavioral effects by altering the use of monoamines as neuronal signals in the brain, primarily in catecholamine neurons in the reward and executive function pathways of the brain.[35][56] The concentrations of the main neurotransmitters involved in reward circuitry and executive functioning, dopamine and norepinephrine, increase dramatically in a dose-dependent manner by amphetamine because of its effects on monoamine transporters.[35][56][149] The reinforcing and motivational salience-promoting effects of amphetamine are due mostly to enhanced dopaminergic activity in the mesolimbic pathway.[24] The euphoric and locomotor-stimulating effects of amphetamine are dependent upon the magnitude and speed by which it increases synaptic dopamine and norepinephrine concentrations in the striatum.[2]

Amphetamine has been identified as a potent full agonist of trace amine-associated receptor 1 (TAAR1), a Gs-coupled and Gq-coupled G protein-coupled receptor (GPCR) discovered in 2001, which is important for regulation of brain monoamines.[35][155] Activation of TAAR1 increases cAMP production via adenylyl cyclase activation and inhibits monoamine transporter function.[35][156] Monoamine autoreceptors (e.g., D2 short, presynaptic α2, and presynaptic 5-HT1A) have the opposite effect of TAAR1, and together these receptors provide a regulatory system for monoamines.[35][36] Notably, amphetamine and trace amines possess high binding affinities for TAAR1, but not for monoamine autoreceptors.[35][36] Imaging studies indicate that monoamine reuptake inhibition by amphetamine and trace amines is site specific and depends upon the presence of TAAR1 co-localization in the associated monoamine neurons.[35]

In addition to the neuronal monoamine transporters, amphetamine also inhibits both vesicular monoamine transporters, VMAT1 and VMAT2, as well as SLC1A1, SLC22A3, and SLC22A5.[sources 14] SLC1A1 is excitatory amino acid transporter 3 (EAAT3), a glutamate transporter located in neurons, SLC22A3 is an extraneuronal monoamine transporter that is present in astrocytes, and SLC22A5 is a high-affinity carnitine transporter.[sources 14] Amphetamine is known to strongly induce cocaine- and amphetamine-regulated transcript (CART) gene expression,[4][162] a neuropeptide involved in feeding behavior, stress, and reward, which induces observable increases in neuronal development and survival in vitro.[4][163][164] The CART receptor has yet to be identified, but there is significant evidence that CART binds to a unique Gi/Go-coupled GPCR.[164][165] Amphetamine also inhibits monoamine oxidases at very high doses, resulting in less monoamine and trace amine metabolism and consequently higher concentrations of synaptic monoamines.[21][166] In humans, the only post-synaptic receptor at which amphetamine is known to bind is the 5-HT1A receptor, where it acts as an agonist with low micromolar affinity.[167][168]

The full profile of amphetamine's short-term drug effects in humans is mostly derived through increased cellular communication or neurotransmission of dopamine,[35] serotonin,[35] norepinephrine,[35] epinephrine,[149] histamine,[149] CART peptides,[4][162] endogenous opioids,[169][170][171] adrenocorticotropic hormone,[172][173] corticosteroids,[172][173] and glutamate,[153][158] which it affects through interactions with CART, 5-HT1A, EAAT3, TAAR1, VMAT1, VMAT2, and possibly other biological targets.[sources 15] Amphetamine also activates seven human carbonic anhydrase enzymes, several of which are expressed in the human brain.[174]

Dextroamphetamine is a more potent agonist of TAAR1 than levoamphetamine.[175] Consequently, dextroamphetamine produces greater CNS stimulation than levoamphetamine, roughly three to four times more, but levoamphetamine has slightly stronger cardiovascular and peripheral effects.[37][175]

Dopamine

In certain brain regions, amphetamine increases the concentration of dopamine in the synaptic cleft.[35] Amphetamine can enter the presynaptic neuron either through DAT or by diffusing across the neuronal membrane directly.[35] As a consequence of DAT uptake, amphetamine produces competitive reuptake inhibition at the transporter.[35] Upon entering the presynaptic neuron, amphetamine activates TAAR1 which, through protein kinase A (PKA) and protein kinase C (PKC) signaling, causes DAT phosphorylation.[35] Phosphorylation by either protein kinase can result in DAT internalization (non-competitive reuptake inhibition), but PKC-mediated phosphorylation alone induces the reversal of dopamine transport through DAT (i.e., dopamine efflux).[note 16][35][176] Amphetamine is also known to increase intracellular calcium, an effect which is associated with DAT phosphorylation through an unidentified Ca2+/calmodulin-dependent protein kinase (CAMK)-dependent pathway, in turn producing dopamine efflux.[155][153][154] Through direct activation of G protein-coupled inwardly-rectifying potassium channels, TAAR1 reduces the firing rate of dopamine neurons, preventing a hyper-dopaminergic state.[151][152][177]

Amphetamine is also a substrate for the presynaptic vesicular monoamine transporter, VMAT2.[149][150] Following amphetamine uptake at VMAT2, amphetamine induces the collapse of the vesicular pH gradient, which results in the release of dopamine molecules from synaptic vesicles into the cytosol via dopamine efflux through VMAT2.[149][150] Subsequently, the cytosolic dopamine molecules are released from the presynaptic neuron into the synaptic cleft via reverse transport at DAT.[35][149][150]

Norepinephrine

Similar to dopamine, amphetamine dose-dependently increases the level of synaptic norepinephrine, the direct precursor of epinephrine.[44][56] Based upon neuronal TAAR1 mRNA expression, amphetamine is thought to affect norepinephrine analogously to dopamine.[35][149][176] In other words, amphetamine induces TAAR1-mediated efflux and non-competitive reuptake inhibition at phosphorylated NET, competitive NET reuptake inhibition, and norepinephrine release from VMAT2.[35][149]

Serotonin

Amphetamine exerts analogous, yet less pronounced, effects on serotonin as on dopamine and norepinephrine.[35][56] Amphetamine affects serotonin via VMAT2 and, like norepinephrine, is thought to phosphorylate SERT via TAAR1.[35][149] Like dopamine, amphetamine has low, micromolar affinity at the human 5-HT1A receptor.[167][168]

Other neurotransmitters, peptides, hormones, and enzymes

Human carbonic anhydrase
activation potency
Enzyme KA (nM) Sources
hCA4 94 [174]
hCA5A 810 [174][178]
hCA5B 2560 [174]
hCA7 910 [174][178]
hCA12 640 [174]
hCA13 24100 [174]
hCA14 9150 [174]

Acute amphetamine administration in humans increases endogenous opioid release in several brain structures in the reward system.[169][170][171] Extracellular levels of glutamate, the primary excitatory neurotransmitter in the brain, have been shown to increase in the striatum following exposure to amphetamine.[153] This increase in extracellular glutamate presumably occurs via the amphetamine-induced internalization of EAAT3, a glutamate reuptake transporter, in dopamine neurons.[153][158] Amphetamine also induces the selective release of histamine from mast cells and efflux from histaminergic neurons through VMAT2.[149] Acute amphetamine administration can also increase adrenocorticotropic hormone and corticosteroid levels in blood plasma by stimulating the hypothalamic–pituitary–adrenal axis.[33][172][173]

In December 2017, the first study assessing the interaction between amphetamine and human carbonic anhydrase enzymes was published;[174] of the eleven carbonic anhydrase enzymes it examined, it found that amphetamine potently activates seven, four of which are highly expressed in the human brain, with low nanomolar through low micromolar activating effects.[174] Based upon preclinical research, cerebral carbonic anhydrase activation has cognition-enhancing effects;[179] but, based upon the clinical use of carbonic anhydrase inhibitors, carbonic anhydrase activation in other tissues may be associated with adverse effects, such as ocular activation exacerbating glaucoma.[179]

Pharmacokinetics

The oral bioavailability of amphetamine varies with gastrointestinal pH;[26] it is well absorbed from the gut, and bioavailability is typically over 75% for dextroamphetamine.[3] Amphetamine is a weak base with a pKa of 9.9;[5] 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.[5][26] Conversely, an acidic pH means the drug is predominantly in a water-soluble cationic (salt) form, and less is absorbed.[5] Approximately 20% of amphetamine circulating in the bloodstream is bound to plasma proteins.[4] Following absorption, amphetamine readily distributes into most tissues in the body, with high concentrations occurring in cerebrospinal fluid and brain tissue.[11]

The half-lives of amphetamine enantiomers differ and vary with urine pH.[5] At normal urine pH, the half-lives of dextroamphetamine and levoamphetamine are 9–11 hours and 11–14 hours, respectively.[5] Highly acidic urine will reduce the enantiomer half-lives to 7 hours;[11] highly alkaline urine will increase the half-lives up to 34 hours.[11] 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.[5] Amphetamine is eliminated via the kidneys, with 30–40% of the drug being excreted unchanged at normal urinary pH.[5] When the urinary pH is basic, amphetamine is in its free base form, so less is excreted.[5] 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.[5] Following oral administration, amphetamine appears in urine within 3 hours.[11] Roughly 90% of ingested amphetamine is eliminated 3 days after the last oral dose.[11] 

Lisdexamfetamine is a prodrug of dextroamphetamine.[180][181] It is not as sensitive to pH as amphetamine when being absorbed in the gastrointestinal tract.[181] Following absorption into the blood stream, lisdexamfetamine is completely converted by red blood cells to dextroamphetamine and the amino acid L-lysine by hydrolysis via undetermined aminopeptidase enzymes.[181][180][182] This is the rate-limiting step in the bioactivation of lisdexamfetamine.[180] The elimination half-life of lisdexamfetamine is generally less than 1 hour.[181][180] Due to the necessary conversion of lisdexamfetamine into dextroamphetamine, levels of dextroamphetamine with lisdexamfetamine peak about one hour later than with an equivalent dose of immediate-release dextroamphetamine.[180][182] Presumably due to its rate-limited activation by red blood cells, intravenous administration of lisdexamfetamine shows greatly delayed time to peak and reduced peak levels compared to intravenous administration of an equivalent dose of dextroamphetamine.[180] The pharmacokinetics of lisdexamfetamine are similar regardless of whether it is administered orally, intranasally, or intravenously.[180][182] Hence, in contrast to dextroamphetamine, parenteral use does not enhance the subjective effects of lisdexamfetamine.[180][182] Because of its behavior as a prodrug and its pharmacokinetic differences, lisdexamfetamine has a longer duration of therapeutic effect than immediate-release dextroamphetamine and shows reduced misuse potential.[180][182]

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 16] Amphetamine has a variety of excreted metabolic products, including 4-hydroxyamphetamine, 4-hydroxynorephedrine, 4-hydroxyphenylacetone, benzoic acid, hippuric acid, norephedrine, and phenylacetone.[5][6] Among these metabolites, the active sympathomimetics are 4-hydroxyamphetamine,[183] 4-hydroxynorephedrine,[184] and norephedrine.[185] The main metabolic pathways involve aromatic para-hydroxylation, aliphatic alpha- and beta-hydroxylation, N-oxidation, N-dealkylation, and deamination.[5][186] The known metabolic pathways, detectable metabolites, and metabolizing enzymes in humans include the following:

Metabolic pathways of amphetamine in humans[sources 16]
 
Amphetamine
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;[6] at normal urine pH, about 30–40% of amphetamine is excreted unchanged and roughly 50% is excreted as the inactive metabolites (bottom row).[5] The remaining 10–20% is excreted as the active metabolites.[5] Benzoic acid is metabolized by XM-ligase into an intermediate product, benzoyl-CoA, which is then metabolized by GLYAT into hippuric acid.[188]

Pharmacomicrobiomics

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.[192][193] Since the total number of microbial and viral cells in the human body (over 100 trillion) greatly outnumbers human cells (tens of trillions),[note 18][192][194] 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.[192][193][195] The field that studies these interactions is known as pharmacomicrobiomics.[192]

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.[195] The first amphetamine-metabolizing microbial enzyme, tyramine oxidase from a strain of E. coli commonly found in the human gut, was identified in 2019.[195] This enzyme was found to metabolize amphetamine, tyramine, and phenethylamine with roughly the same binding affinity for all three compounds.[195]

Related endogenous compounds

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.[35][44][196] Among this group, the most closely related compounds are phenethylamine, the parent compound of amphetamine, and N-methylphenethylamine, an isomer of amphetamine (i.e., it has an identical molecular formula).[35][44][197] 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.[44][197] In turn, N-methylphenethylamine is metabolized from phenethylamine by phenylethanolamine N-methyltransferase, the same enzyme that metabolizes norepinephrine into epinephrine.[44][197] Like amphetamine, both phenethylamine and N-methylphenethylamine regulate monoamine neurotransmission via TAAR1;[35][196][197] unlike amphetamine, both of these substances are broken down by monoamine oxidase B, and therefore have a shorter half-life than amphetamine.[44][197]

Chemistry

Racemic amphetamine
 
The skeletal structures of L-amph and D-amph
 
A vial of the colorless amphetamine free base
 
Amphetamine hydrochloride (left bowl)
Phenyl-2-nitropropene (right cups)

Amphetamine is a methyl homolog of the mammalian neurotransmitter phenethylamine with the chemical formula C9H13N. The carbon atom adjacent to the primary amine is a stereogenic center, and amphetamine is composed of a racemic 1:1 mixture of two enantiomers.[4] This racemic mixture can be separated into its optical isomers:[note 19] levoamphetamine and dextroamphetamine.[4] At room temperature, the pure free base of amphetamine is a mobile, colorless, and volatile liquid with a characteristically strong amine odor, and acrid, burning taste.[20] Frequently prepared solid salts of amphetamine include amphetamine adipate,[198] aspartate,[26] hydrochloride,[199] phosphate,[200] saccharate,[26] sulfate,[26] and tannate.[201] Dextroamphetamine sulfate is the most common enantiopure salt.[45] Amphetamine is also the parent compound of its own structural class, which includes a number of psychoactive derivatives.[13][4] In organic chemistry, amphetamine is an excellent chiral ligand for the stereoselective synthesis of 1,1'-bi-2-naphthol.[202]

Substituted derivatives

The substituted derivatives of amphetamine, or "substituted amphetamines", are a broad range of chemicals that contain amphetamine as a "backbone";[13][46][203] specifically, this chemical class includes derivative compounds that are formed by replacing one or more hydrogen atoms in the amphetamine core structure with substituents.[13][46][204] The class includes amphetamine itself, stimulants like methamphetamine, serotonergic empathogens like MDMA, and decongestants like ephedrine, among other subgroups.[13][46][203]

Synthesis

Since the first preparation was reported in 1887,[205] numerous synthetic routes to amphetamine have been developed.[206][207] The most common route of both legal and illicit amphetamine synthesis employs a non-metal reduction known as the Leuckart reaction (method 1).[45][208] In the first step, a reaction between phenylacetone and formamide, either using additional formic acid or formamide itself as a reducing agent, yields N-formylamphetamine. This intermediate is then hydrolyzed using hydrochloric acid, and subsequently basified, extracted with organic solvent, concentrated, and distilled to yield the free base. The free base is then dissolved in an organic solvent, sulfuric acid added, and amphetamine precipitates out as the sulfate salt.[208][209]

A number of chiral resolutions have been developed to separate the two enantiomers of amphetamine.[206] For example, racemic amphetamine can be treated with d-tartaric acid to form a diastereoisomeric salt which is fractionally crystallized to yield dextroamphetamine.[210] Chiral resolution remains the most economical method for obtaining optically pure amphetamine on a large scale.[211] In addition, several enantioselective syntheses of amphetamine have been developed. In one example, optically pure (R)-1-phenyl-ethanamine is condensed with phenylacetone to yield a chiral Schiff base. In the key step, this intermediate is reduced by catalytic hydrogenation with a transfer of chirality to the carbon atom alpha to the amino group. Cleavage of the benzylic amine bond by hydrogenation yields optically pure dextroamphetamine.[211]

A large number of alternative synthetic routes to amphetamine have been developed based on classic organic reactions.[206][207] One example is the Friedel–Crafts alkylation of benzene by allyl chloride to yield beta chloropropylbenzene which is then reacted with ammonia to produce racemic amphetamine (method 2).[212] Another example employs the Ritter reaction (method 3). In this route, allylbenzene is reacted acetonitrile in sulfuric acid to yield an organosulfate which in turn is treated with sodium hydroxide to give amphetamine via an acetamide intermediate.[213][214] A third route starts with ethyl 3-oxobutanoate which through a double alkylation with methyl iodide followed by benzyl chloride can be converted into 2-methyl-3-phenyl-propanoic acid. This synthetic intermediate can be transformed into amphetamine using either a Hofmann or Curtius rearrangement (method 4).[215]

A significant number of amphetamine syntheses feature a reduction of a nitro, imine, oxime, or other nitrogen-containing functional groups.[207] In one such example, a Knoevenagel condensation of benzaldehyde with nitroethane yields phenyl-2-nitropropene. The double bond and nitro group of this intermediate is reduced using either catalytic hydrogenation or by treatment with lithium aluminium hydride (method 5).[208][216] Another method is the reaction of phenylacetone with ammonia, producing an imine intermediate that is reduced to the primary amine using hydrogen over a palladium catalyst or lithium aluminum hydride (method 6).[208]

Amphetamine synthetic routes
 
Method 1: Synthesis by the Leuckart reaction 
 
Top: Chiral resolution of amphetamine 
Bottom: Stereoselective synthesis of amphetamine 
 
Method 2: Synthesis by Friedel–Crafts alkylation 
 
Method 3: Ritter synthesis
 
Method 4: Synthesis via Hofmann and Curtius rearrangements
 
Method 5: Synthesis by Knoevenagel condensation
 
Method 6: Synthesis using phenylacetone and ammonia

Detection in body fluids

Amphetamine is frequently measured in urine or blood as part of a drug test for sports, employment, poisoning diagnostics, and forensics.[sources 17] Techniques such as immunoassay, which is the most common form of amphetamine test, may cross-react with a number of sympathomimetic drugs.[220] Chromatographic methods specific for amphetamine are employed to prevent false positive results.[221] Chiral separation techniques may be employed to help distinguish the source of the drug, whether prescription amphetamine, prescription amphetamine prodrugs, (e.g., selegiline), over-the-counter drug products that contain levomethamphetamine,[note 20] or illicitly obtained substituted amphetamines.[221][224][225] Several prescription drugs produce amphetamine as a metabolite, including benzphetamine, clobenzorex, famprofazone, fenproporex, lisdexamfetamine, mesocarb, methamphetamine, prenylamine, and selegiline, among others.[2][226][227] These compounds may produce positive results for amphetamine on drug tests.[226][227] Amphetamine is generally only detectable by a standard drug test for approximately 24 hours, although a high dose may be detectable for 2–4 days.[220]

For the assays, a study noted that an enzyme multiplied immunoassay technique (EMIT) assay for amphetamine and methamphetamine may produce more false positives than liquid chromatography–tandem mass spectrometry.[224] Gas chromatography–mass spectrometry (GC–MS) of amphetamine and methamphetamine with the derivatizing agent (S)-(−)-trifluoroacetylprolyl chloride allows for the detection of methamphetamine in urine.[221] GC–MS of amphetamine and methamphetamine with the chiral derivatizing agent Mosher's acid chloride allows for the detection of both dextroamphetamine and dextromethamphetamine in urine.[221] Hence, the latter method may be used on samples that test positive using other methods to help distinguish between the various sources of the drug.[221]

History, society, and culture

Global estimates of drug users in 2016
(in millions of users)[228]
Substance Best
estimate
Low
estimate
High
estimate
Amphetamine-
type stimulants
34.16 13.42 55.24
Cannabis 192.15 165.76 234.06
Cocaine 18.20 13.87 22.85
Ecstasy 20.57 8.99 32.34
Opiates 19.38 13.80 26.15
Opioids 34.26 27.01 44.54

Amphetamine-type stimulants were originally derived from the plant Ephedra, which contains the amphetamine-like stimulant ephedrine and had been used for its effects in China dating back an estimated 5,000 years.[229][230] Ephedrine was isolated from Ephedra vulgaris in Japan in 1885 and was studied for its medicinal properties through the 1920s.[229] The scarce amounts of ephedrine in the Ephedra plant led to investigations of synthetic analogues of ephedrine.[229]

Amphetamine was first synthesized in 1887 in Germany by Romanian chemist Lazăr Edeleanu who named it phenylisopropylamine;[205][231][232] its stimulant effects remained unknown until 1927, when it was independently resynthesized by Gordon Alles and reported to have sympathomimetic properties.[232] Amphetamine had no medical use until late 1933, when Smith, Kline and French began selling it as an inhaler under the brand name Benzedrine as a decongestant.[27] Benzedrine sulfate was introduced 3 years later and was used to treat a wide variety of medical conditions, including narcolepsy, obesity, low blood pressure, low libido, and chronic pain, among others.[47][27] The beneficial effect of Benzedrine in children with hyperactivity was discovered serendipitously in 1937 when it was given against a low intracranial pressure headache. It did not improve the headache, but improved school performance and behavior of some.[233] During World War II, amphetamine and methamphetamine were used extensively by both the Allied and Axis forces for their stimulant and performance-enhancing effects.[205][234][235] As the addictive properties of the drug became known, governments began to place strict controls on the sale of amphetamine.[205] For example, during the early 1970s in the United States, amphetamine became a schedule II controlled substance under the Controlled Substances Act.[236][237] In spite of strict government controls, amphetamine has been used legally or illicitly by people from a variety of backgrounds, including authors,[238] musicians,[239] mathematicians,[240] and athletes.[25]

Amphetamine is still illegally synthesized today in clandestine labs and sold on the black market, primarily in European countries.[241] Among European Union (EU) member states in 2018, 11.9 million adults of ages 15–64 have used amphetamine or methamphetamine at least once in their lives and 1.7 million have used either in the last year.[242] During 2012, approximately 5.9 metric tons of illicit amphetamine were seized within EU member states;[243] the "street price" of illicit amphetamine within the EU ranged from 6–38 per gram during the same period.[243] Outside Europe, the illicit market for amphetamine is much smaller than the market for methamphetamine and MDMA.[241]

Legal status

As a result of the United Nations 1971 Convention on Psychotropic Substances, amphetamine became a schedule II controlled substance, as defined in the treaty, in all 183 state parties.[28] Consequently, it is heavily regulated in most countries.[244][245] Some countries, such as South Korea and Japan, have banned substituted amphetamines even for medical use.[246][247] In other nations, such as Canada (schedule I drug),[248] the Netherlands (List I drug),[249] the United States (schedule II drug),[26] Australia (schedule 8),[250] Thailand (category 1 narcotic),[251] and United Kingdom (class B drug),[252] amphetamine is in a restrictive national drug schedule that allows for its use as a medical treatment.[241][29]

Pharmaceutical products

Several currently marketed amphetamine formulations contain both enantiomers, including those marketed under the brand names Adderall, Adderall XR, Mydayis,[note 1] Adzenys ER, Adzenys XR-ODT, Dyanavel XR, Evekeo, and Evekeo ODT. Of those, Evekeo (including Evekeo ODT) is the only product containing only racemic amphetamine (as amphetamine sulfate), and is therefore the only one whose active moiety can be accurately referred to simply as "amphetamine".[1][33][86] Dextroamphetamine, marketed under the brand names Dexedrine and Zenzedi, is the only enantiopure amphetamine product currently available. A prodrug form of dextroamphetamine, lisdexamfetamine, is also available and is marketed under the brand name Vyvanse. As it is a prodrug, lisdexamfetamine is structurally different from dextroamphetamine, and is inactive until it metabolizes into dextroamphetamine.[34][181] The free base of racemic amphetamine was previously available as Benzedrine, Psychedrine, and Sympatedrine.[2] Levoamphetamine was previously available as Cydril.[2] Many current amphetamine pharmaceuticals are salts due to the comparatively high volatility of the free base.[2][34][45] However, oral suspension and orally disintegrating tablet (ODT) dosage forms composed of the free base were introduced in 2015 and 2016, respectively.[86][253][254] Some of the current brands and their generic equivalents are listed below.

Amphetamine pharmaceuticals
Brand
name
United States
Adopted Name
(D:L) ratio
Dosage
form
Marketing
start date
US consumer
price data
Sources
Adderall 3:1 (salts) tablet 1996 GoodRx [2][34]
Adderall XR 3:1 (salts) capsule 2001 GoodRx [2][34]
Mydayis 3:1 (salts) capsule 2017 GoodRx [255][256]
Adzenys ER amphetamine 3:1 (base) suspension 2017 GoodRx [257]
Adzenys XR-ODT amphetamine 3:1 (base) ODT 2016 GoodRx [254][258]
Dyanavel XR amphetamine 3.2:1 (base) suspension 2015 GoodRx [86][253]
Evekeo amphetamine sulfate 1:1 (salts) tablet 2012 GoodRx [33][259]
Evekeo ODT amphetamine sulfate 1:1 (salts) ODT 2019 GoodRx [260]
Dexedrine dextroamphetamine sulfate 1:0 (salts) capsule 1976 GoodRx [2][34]
Zenzedi dextroamphetamine sulfate 1:0 (salts) tablet 2013 GoodRx [34][261]
Vyvanse lisdexamfetamine dimesylate 1:0 (prodrug) capsule 2007 GoodRx [2][181][262]
tablet
Xelstrym dextroamphetamine 1:0 (base) patch 2022 GoodRx [263]
Amphetamine base in marketed amphetamine medications
drug formula molar mass
[note 21]
amphetamine base
[note 22]
amphetamine base
in equal doses
doses with
equal base
content
[note 23]
(g/mol) (percent) (30 mg dose)
total base total dextro- levo- dextro- levo-
dextroamphetamine sulfate[265][266] (C9H13N)2•H2SO4
368.49
270.41
73.38%
73.38%
22.0 mg
30.0 mg
amphetamine sulfate[267] (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[265][266] (C9H13N)2•H2SO4
368.49
270.41
73.38%
73.38%
25% amphetamine sulfate[267] (C9H13N)2•H2SO4
368.49
270.41
73.38%
36.69%
36.69%
25% dextroamphetamine saccharate[268] (C9H13N)2•C6H10O8
480.55
270.41
56.27%
56.27%
25% amphetamine aspartate monohydrate[269] (C9H13N)•C4H7NO4•H2O
286.32
135.21
47.22%
23.61%
23.61%
lisdexamfetamine dimesylate[181] C15H25N3O•(CH4O3S)2
455.49
135.21
29.68%
29.68%
8.9 mg
74.2 mg
amphetamine base suspension[86] C9H13N
135.21
135.21
100%
76.19%
23.81%
22.9 mg
7.1 mg
22.0 mg

Notes

  1. ^ a b Adderall and other mixed amphetamine salts products such as Mydayis are not racemic amphetamine - they are a mixture composed of equal parts racemate and dextroamphetamine.
    See Mixed amphetamine salts for more information about the mixture, and this section for information about the various mixtures of amphetamine enantiomers currently marketed.
  2. ^ Synonyms and alternate spellings include: 1-phenylpropan-2-amine (IUPAC name), α-methylphenethylamine, amfetamine (International Nonproprietary Name [INN]), β-phenylisopropylamine, and speed.[21][4][22]
  3. ^ Enantiomers are molecules that are mirror images of one another; they are structurally identical, but of the opposite orientation.[23]
    Levoamphetamine and dextroamphetamine are also known as L-amph or levamfetamine (INN) and D-amph or dexamfetamine (INN) respectively.[21]
  4. ^ The brand name Adderall is used throughout this article to refer to the amphetamine four-salt mixture it contains (dextroamphetamine sulfate 25%, dextroamphetamine saccharate 25%, amphetamine sulfate 25%, and amphetamine aspartate 25%). The nonproprietary name, which lists all four active constituent chemicals, is excessively lengthy.[34]
  5. ^ The term "amphetamines" also refers to a chemical class, but, unlike the class of substituted amphetamines,[13] the "amphetamines" class does not have a standardized definition in academic literature.[17] One of the more restrictive definitions of this class includes only the racemate and enantiomers of amphetamine and methamphetamine.[17] The most general definition of the class encompasses a broad range of pharmacologically and structurally related compounds.[17]
    Due to confusion that may arise from use of the plural form, this article will only use the terms "amphetamine" and "amphetamines" to refer to racemic amphetamine, levoamphetamine, and dextroamphetamine and reserve the term "substituted amphetamines" for its structural class.
  6. ^ 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).[54]

    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).[54]

    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.[54]
  7. ^ Cochrane reviews are high quality meta-analytic systematic reviews of randomized controlled trials.[60]
  8. ^ 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.[81]
  9. ^ 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.[2]
  10. ^ 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.[41][53][85] The average reduction in final adult height from 3 years of continuous stimulant therapy is 2 cm.[85]
  11. ^ Transcription factors are proteins that increase or decrease the expression of specific genes.[114]
  12. ^ 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.
  13. ^ 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.[128]
  14. ^ The review indicated that magnesium L-aspartate and magnesium chloride produce significant changes in addictive behavior;[105] other forms of magnesium were not mentioned.
  15. ^ The 95% confidence interval indicates that there is a 95% probability that the true number of deaths lies between 3,425 and 4,145.
  16. ^ a b The human dopamine transporter (hDAT) contains a high-affinity, extracellular, and allosteric Zn2+ (zinc ion) binding site which, upon zinc binding, inhibits dopamine reuptake, inhibits amphetamine-induced hDAT internalization, and amplifies amphetamine-induced dopamine efflux.[144][145][146][147] The human serotonin transporter and norepinephrine transporter do not contain zinc binding sites.[146]
  17. ^ 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.[13][187] 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;[187][189] however, other evidence from animal studies suggests that this reaction is catalyzed by DBH in synaptic vesicles within noradrenergic neurons in the brain.[190][191]
  18. ^ There is substantial variation in microbiome composition and microbial concentrations by anatomical site.[192][193] 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.[192]
  19. ^ Enantiomers are molecules that are mirror images of one another; they are structurally identical, but of the opposite orientation.[23]
  20. ^ The active ingredient in some OTC inhalers in the United States is listed as levmetamfetamine, the INN and USAN of levomethamphetamine.[222][223]
  21. ^ For uniformity, molar masses were calculated using the Lenntech Molecular Weight Calculator[264] and were within 0.01 g/mol of published pharmaceutical values.
  22. ^ Amphetamine base percentage = molecular massbase / molecular masstotal. Amphetamine base percentage for Adderall = sum of component percentages / 4.
  23. ^ 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.
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Reference notes

References

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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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    Table 5: N-containing drugs and xenobiotics oxygenated by FMO
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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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    Although useful in the treatment of ADHD, stimulants are controlled II substances with a history of preclinical and human studies showing potential abuse liability.
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    About 5–15% of the users who develop an amphetamine psychosis fail to recover completely (Hofmann 1983) ...
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    [Figure 4](b) Examples of synthetic, pharmaceutically important substituted amphetamines.
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    Figure 3: Treatment benefit by treatment type and outcome group
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  78. ^ 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.
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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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     – Sympathomimetic:
       • Amphetamine
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  95. ^ 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.
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    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.
  98. ^ a b c Renthal W, Nestler EJ (September 2009). "Chromatin regulation in drug addiction and depression". Dialogues in Clinical Neuroscience. 11 (3): 257–268. 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
  99. ^ 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.
  100. ^ 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.
  101. ^ 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
  102. ^ 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
  103. ^ 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
  104. ^ Kanehisa Laboratories (10 October 2014). "Amphetamine – Homo sapiens (human)". KEGG Pathway. Retrieved 31 October 2014.
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  107. ^ 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.
  108. ^ 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).
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This article is about mixtures of levoamphetamine and dextroamphetamine For other uses see Amphetamine disambiguation Amphetamine note 2 contracted from alpha methylphenethylamine is a strong central nervous system CNS stimulant that is used in the treatment of attention deficit hyperactivity disorder ADHD narcolepsy and obesity It is also commonly used as a recreational drug Amphetamine was discovered in 1887 and exists as two enantiomers note 3 levoamphetamine and dextroamphetamine Amphetamine properly refers to a specific chemical the racemic free base which is equal parts of the two enantiomers in their pure amine forms The term is frequently used informally to refer to any combination of the enantiomers or to either of them alone Historically it has been used to treat nasal congestion and depression Amphetamine is also used as an athletic performance enhancer and cognitive enhancer and recreationally as an aphrodisiac and euphoriant It is a prescription drug in many countries and unauthorized possession and distribution of amphetamine are often tightly controlled due to the significant health risks associated with recreational use sources 1 AmphetamineINN AmfetamineClinical dataPronunciation ae m ˈ f ɛ t e m iː n listen Trade namesEvekeo Adderall note 1 othersOther namesa methylphenethylamineAHFS Drugs comMonographMedlinePlusa616004License dataUS DailyMed AmphetamineDependenceliabilityModerate 1 AddictionliabilityModerateRoutes ofadministrationMedical oral intravenous 2 Recreational oral insufflation rectal intravenous intramuscularDrug classCNS stimulant anorecticATC codeN06BA01 WHO N06BA02 WHO N06BA12 WHO Legal statusLegal statusAU S8 Controlled drug BR Class A3 Psychoactive drugs CA Schedule I DE Anlage III Special prescription form required NZ Class B UK Class B US Schedule II UN Psychotropic Schedule IIPharmacokinetic dataBioavailabilityOral 75 100 3 Protein binding20 4 MetabolismCYP2D6 5 DBH 13 14 FMO3 13 15 16 Metabolites4 hydroxyamphetamine 4 hydroxynorephedrine 4 hydroxyphenylacetone benzoic acid hippuric acid norephedrine phenylacetone 5 6 Onset of actionIR dosing 30 60 minutes 7 XR dosing 1 5 2 hours 8 9 Elimination half lifeD amph 9 11 hours 5 10 L amph 11 14 hours 5 10 pH dependent 7 34 hours 11 Duration of actionIR dosing 3 6 hours 1 8 12 XR dosing 8 12 hours 1 8 12 ExcretionPrimarily renal pH dependent range 1 75 5 IdentifiersIUPAC name RS 1 phenylpropan 2 amineCAS Number300 62 9 YPubChem CID3007IUPHAR BPS4804DrugBankDB00182 YChemSpider13852819 YUNIICK833KGX7EKEGGD07445 YChEBICHEBI 2679 YChEMBLChEMBL405 YNIAID ChemDB018564CompTox Dashboard EPA DTXSID4022600ECHA InfoCard100 005 543Chemical and physical dataFormulaC 9H 13NMolar mass135 210 g mol 13D model JSmol Interactive imageChiralityRacemic mixture 17 Density 936 g cm3 at 25 C 18 Melting point146 C 295 F 19 Boiling point203 C 397 F at 760 mmHg 20 SMILES NC C Cc1ccccc1InChI InChI 1S C9H13N c1 8 10 7 9 5 3 2 4 6 9 h2 6 8H 7 10H2 1H3 YKey KWTSXDURSIMDCE UHFFFAOYSA N Y verify The first amphetamine pharmaceutical was Benzedrine a brand which was used to treat a variety of conditions Currently pharmaceutical amphetamine is prescribed as racemic amphetamine Adderall note 4 dextroamphetamine or the inactive prodrug lisdexamfetamine Amphetamine increases monoamine and excitatory neurotransmission in the brain with its most pronounced effects targeting the norepinephrine and dopamine neurotransmitter systems sources 2 At therapeutic doses amphetamine causes emotional and cognitive effects such as euphoria change in desire for sex increased wakefulness and improved cognitive control It induces physical effects such as improved reaction time fatigue resistance and increased muscle strength Larger doses of amphetamine may impair cognitive function and induce rapid muscle breakdown Addiction is a serious risk with heavy recreational amphetamine use but is unlikely to occur from long term medical use at therapeutic doses Very high doses can result in psychosis e g delusions and paranoia which rarely occurs at therapeutic doses even during long term use Recreational doses are generally much larger than prescribed therapeutic doses and carry a far greater risk of serious side effects sources 3 Amphetamine belongs to the phenethylamine class It is also the parent compound of its own structural class the substituted amphetamines note 5 which includes prominent substances such as bupropion cathinone MDMA and methamphetamine As a member of the phenethylamine class amphetamine is also chemically related to the naturally occurring trace amine neuromodulators specifically phenethylamine and N methylphenethylamine both of which are produced within the human body Phenethylamine is the parent compound of amphetamine while N methylphenethylamine is a positional isomer of amphetamine that differs only in the placement of the methyl group sources 4 Contents 1 Uses 1 1 Medical 1 2 Enhancing performance 1 2 1 Cognitive performance 1 2 2 Physical performance 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 4 1 Toxicity 4 2 Psychosis 5 Drug interactions 6 Pharmacology 6 1 Pharmacodynamics 6 1 1 Dopamine 6 1 2 Norepinephrine 6 1 3 Serotonin 6 1 4 Other neurotransmitters peptides hormones and enzymes 6 2 Pharmacokinetics 6 3 Pharmacomicrobiomics 6 4 Related endogenous compounds 7 Chemistry 7 1 Substituted derivatives 7 2 Synthesis 7 3 Detection in body fluids 8 History society and culture 8 1 Legal status 8 2 Pharmaceutical products 9 Notes 10 Reference notes 11 References 12 External linksUsesMedical Amphetamine is used to treat attention deficit hyperactivity disorder ADHD narcolepsy a sleep disorder and obesity and is sometimes prescribed off label for its past medical indications particularly for depression and chronic pain 1 33 47 Long term amphetamine exposure at sufficiently high doses in some animal species is known to produce abnormal dopamine system development or nerve damage 48 49 but in humans with ADHD pharmaceutical amphetamines at therapeutic dosages appear to improve brain development and nerve growth 50 51 52 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 50 51 52 Reviews of clinical stimulant research have established the safety and effectiveness of long term continuous amphetamine use for the treatment of ADHD 41 53 54 Randomized controlled trials of continuous stimulant therapy for the treatment of ADHD spanning 2 years have demonstrated treatment effectiveness and safety 41 53 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 6 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 41 54 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 53 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 41 Current models of ADHD suggest that it is associated with functional impairments in some of the brain s neurotransmitter systems 55 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 55 Psychostimulants like methylphenidate and amphetamine are effective in treating ADHD because they increase neurotransmitter activity in these systems 24 55 56 Approximately 80 of those who use these stimulants see improvements in ADHD symptoms 57 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 58 59 The Cochrane reviews note 7 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 61 62 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 63 Enhancing performance Cognitive performance In 2015 a systematic review and a meta analysis of high quality clinical trials found that when used at low therapeutic doses amphetamine produces modest yet unambiguous improvements in cognition including working memory long term episodic memory inhibitory control and some aspects of attention in normal healthy adults 64 65 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 24 64 A systematic review from 2014 found that low doses of amphetamine also improve memory consolidation in turn leading to improved recall of information 66 Therapeutic doses of amphetamine also enhance cortical network efficiency an effect which mediates improvements in working memory in all individuals 24 67 Amphetamine and other ADHD stimulants also improve task saliency motivation to perform a task and increase arousal wakefulness in turn promoting goal directed behavior 24 68 69 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 24 69 70 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 71 72 73 However high amphetamine doses that are above the therapeutic range can interfere with working memory and other aspects of cognitive control 24 69 Physical performance Amphetamine is used by some athletes for its psychological and athletic performance enhancing effects such as increased endurance and alertness 25 37 however non medical amphetamine use is prohibited at sporting events that are regulated by collegiate national and international anti doping agencies 74 75 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 25 76 77 Amphetamine improves endurance and reaction time primarily through reuptake inhibition and release of dopamine in the central nervous system 76 77 78 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 77 79 80 At therapeutic doses the adverse effects of amphetamine do not impede athletic performance 25 76 however at much higher doses amphetamine can induce effects that severely impair performance such as rapid muscle breakdown and elevated body temperature 26 76 ContraindicationsSee also Amphetamine Drug interactions According to the International Programme on Chemical Safety IPCS and the United States Food and Drug Administration USFDA note 8 amphetamine is contraindicated in people with a history of drug abuse note 9 cardiovascular disease severe agitation or severe anxiety 33 26 82 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 33 26 82 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 33 26 82 although safe concurrent use of amphetamine and monoamine oxidase inhibitors has been documented 83 84 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 26 82 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 82 Amphetamine has also been shown to pass into breast milk so the IPCS and the USFDA advise mothers to avoid breastfeeding when using it 26 82 Due to the potential for reversible growth impairments note 10 the USFDA advises monitoring the height and weight of children and adolescents prescribed an amphetamine pharmaceutical 26 Adverse effectsThe adverse side effects of amphetamine are many and varied and the amount of amphetamine used is the primary factor in determining the likelihood and severity of adverse effects 26 37 Amphetamine products such as Adderall Dexedrine and their generic equivalents are currently approved by the USFDA for long term therapeutic use 34 26 Recreational use of amphetamine generally involves much larger doses which have a greater risk of serious adverse drug effects than dosages used for therapeutic purposes 37 Physical Cardiovascular side effects can include hypertension or hypotension from a vasovagal response Raynaud s phenomenon reduced blood flow to the hands and feet and tachycardia increased heart rate 26 37 85 Sexual side effects in males may include erectile dysfunction frequent erections or prolonged erections 26 Gastrointestinal side effects may include abdominal pain constipation diarrhea and nausea 1 26 86 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 5 Dangerous physical side effects are rare at typical pharmaceutical doses 37 Amphetamine stimulates the medullary respiratory centers producing faster and deeper breaths 37 In a normal person at therapeutic doses this effect is usually not noticeable but when respiration is already compromised it may be evident 37 Amphetamine also induces contraction in the urinary bladder sphincter the muscle which controls urination which can result in difficulty urinating 37 This effect can be useful in treating bed wetting and loss of bladder control 37 The effects of amphetamine on the gastrointestinal tract are unpredictable 37 If intestinal activity is high amphetamine may reduce gastrointestinal motility the rate at which content moves through the digestive system 37 however amphetamine may increase motility when the smooth muscle of the tract is relaxed 37 Amphetamine also has a slight analgesic effect and can enhance the pain relieving effects of opioids 1 37 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 6 However amphetamine pharmaceuticals are contraindicated in individuals with cardiovascular disease sources 7 Psychological At normal therapeutic doses the most common psychological side effects of amphetamine include increased alertness apprehension concentration initiative self confidence and sociability mood swings elated mood followed by mildly depressed mood insomnia or wakefulness and decreased sense of fatigue 26 37 Less common side effects include anxiety change in libido grandiosity irritability repetitive or obsessive behaviors and restlessness sources 8 these effects depend on the user s personality and current mental state 37 Amphetamine psychosis e g delusions and paranoia can occur in heavy users 26 38 39 Although very rare this psychosis can also occur at therapeutic doses during long term therapy 26 39 40 According to the USFDA there is no systematic evidence that stimulants produce aggressive behavior or hostility 26 Amphetamine has also been shown to produce a conditioned place preference in humans taking therapeutic doses 61 93 meaning that individuals acquire a preference for spending time in places where they have previously used amphetamine 93 94 Reinforcement disorders Addiction Addiction and dependence glossary 94 95 96 97 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 that involves emotional motivational withdrawal symptoms e g dysphoria and anhedonia 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 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 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 98 99 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 98 100 Phosphorylated CREB increases levels of DFosB which in turn represses the c Fos gene with the help of corepressors 98 101 102 c Fos repression acts as a molecular switch that enables the accumulation of DFosB in the neuron 103 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 101 102 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 101 102 Addiction is a serious risk with heavy recreational amphetamine use but is unlikely to occur from long term medical use at therapeutic doses 41 42 43 in fact lifetime stimulant therapy for ADHD that begins during childhood reduces the risk of developing substance use disorders as an adult 41 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 104 105 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 95 106 107 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 106 108 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 109 110 Sustained aerobic exercise on a regular basis also appears to be an effective treatment for amphetamine addiction sources 9 exercise therapy improves clinical treatment outcomes and may be used as an adjunct therapy with behavioral therapies for addiction 109 111 Biomolecular mechanisms Chronic use of amphetamine at excessive doses causes alterations in gene expression in the mesocorticolimbic projection which arise through transcriptional and epigenetic mechanisms 107 112 113 The most important transcription factors note 11 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 107 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 12 for many of the neural adaptations and regulates multiple behavioral effects e g reward sensitization and escalating drug self administration involved in addiction 95 106 107 Once DFosB is sufficiently overexpressed it induces an addictive state that becomes increasingly more severe with further increases in DFosB expression 95 106 It has been implicated in addictions to alcohol cannabinoids cocaine methylphenidate nicotine opioids phencyclidine propofol and substituted amphetamines among others sources 10 DJunD a transcription factor and G9a a histone methyltransferase enzyme both oppose the function of DFosB and inhibit increases in its expression 95 107 117 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 107 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 11 which occurs via H3K9me2 mediated repression of transcription factors for DFosB and H3K9me2 mediated repression of various DFosB transcriptional targets e g CDK5 107 117 118 DFosB also plays an important role in regulating behavioral responses to natural rewards such as palatable food sex and exercise 108 107 121 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 108 107 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 108 122 123 These sexual addictions are associated with a dopamine dysregulation syndrome which occurs in some patients taking dopaminergic drugs 108 121 The effects of amphetamine on gene regulation are both dose and route dependent 113 Most of the research on gene regulation and addiction is based upon animal studies with intravenous amphetamine administration at very high doses 113 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 113 This suggests that medical use of amphetamine does not significantly affect gene regulation 113 Pharmacological treatments Further information Addiction Research As of December 2019 update there is no effective pharmacotherapy for amphetamine addiction 124 125 126 Reviews from 2015 and 2016 indicated that TAAR1 selective agonists have significant therapeutic potential as a treatment for psychostimulant addictions 36 127 however as of February 2016 update the only compounds which are known to function as TAAR1 selective agonists are experimental drugs 36 127 Amphetamine addiction is largely mediated through increased activation of dopamine receptors and co localized NMDA receptors note 13 in the nucleus accumbens 105 magnesium ions inhibit NMDA receptors by blocking the receptor calcium channel 105 128 One review suggested that based upon animal testing pathological addiction inducing psychostimulant use significantly reduces the level of intracellular magnesium throughout the brain 105 Supplemental magnesium note 14 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 105 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 125 it found only low strength evidence that methylphenidate might reduce amphetamine or methamphetamine self administration 125 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 125 Behavioral treatments A 2018 systematic review and network meta analysis of 50 trials involving 12 different psychosocial interventions for amphetamine methamphetamine or cocaine addiction found that combination therapy with both contingency management and community reinforcement approach had the highest efficacy i e abstinence rate and acceptability i e lowest dropout rate 129 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 129 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 9 Exercise leads to better treatment outcomes when used as an adjunct treatment particularly for psychostimulant addictions 109 111 130 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 108 130 This is the opposite of pathological stimulant use which induces decreased striatal DRD2 density 108 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 110 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 MSNs 108 Behavioral plasticityEscalation of intake Yes Yes Yes 108 Psychostimulantcross sensitization Yes Not applicable Yes Yes Attenuated Attenuated 108 Psychostimulantself administration 108 Psychostimulantconditioned place preference 108 Reinstatement of drug seeking behavior 108 Neurochemical plasticityCREB phosphorylationin the nucleus accumbens 108 Sensitized dopamine responsein the nucleus accumbens No Yes No Yes 108 Altered striatal dopamine signaling DRD2 DRD3 DRD1 DRD2 DRD3 DRD1 DRD2 DRD3 DRD2 DRD2 108 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 108 Changes in striatal opioid peptides dynorphinNo change enkephalin dynorphin enkephalin dynorphin dynorphin 108 Mesocorticolimbic synaptic plasticityNumber of dendrites in the nucleus accumbens 108 Dendritic spine density inthe nucleus accumbens 108 Dependence and withdrawal Drug tolerance develops rapidly in amphetamine abuse i e recreational amphetamine use so periods of extended abuse require increasingly larger doses of the drug in order to achieve the same effect 131 132 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 133 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 133 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 133 The review indicated that the severity of withdrawal symptoms is positively correlated with the age of the individual and the extent of their dependence 133 Mild withdrawal symptoms from the discontinuation of amphetamine treatment at therapeutic doses can be avoided by tapering the dose 1 OverdoseAn amphetamine overdose can lead to many different symptoms but is rarely fatal with appropriate care 1 82 134 The severity of overdose symptoms increases with dosage and decreases with drug tolerance to amphetamine 37 82 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 82 Symptoms of a moderate and extremely large overdose are listed below fatal amphetamine poisoning usually also involves convulsions and coma 26 37 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 15 135 Overdose symptoms by system System Minor or moderate overdose 26 37 82 Severe overdose sources 12 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 Toxicity In rodents and primates sufficiently high doses of amphetamine cause dopaminergic neurotoxicity or damage to dopamine neurons which is characterized by dopamine terminal degeneration and reduced transporter and receptor function 137 138 There is no evidence that amphetamine is directly neurotoxic in humans 139 140 However large doses of amphetamine may indirectly cause dopaminergic neurotoxicity as a result of hyperpyrexia the excessive formation of reactive oxygen species and increased autoxidation of dopamine sources 13 Animal models of neurotoxicity from high dose amphetamine exposure indicate that the occurrence of hyperpyrexia i e core body temperature 40 C is necessary for the development of amphetamine induced neurotoxicity 138 Prolonged elevations of brain temperature above 40 C likely promote the development of amphetamine induced neurotoxicity in laboratory animals by facilitating the production of reactive oxygen species disrupting cellular protein function and transiently increasing blood brain barrier permeability 138 Psychosis See also Stimulant psychosis An amphetamine overdose can result in a stimulant psychosis that may involve a variety of symptoms such as delusions and paranoia 38 39 A Cochrane review on treatment for amphetamine dextroamphetamine and methamphetamine psychosis states that about 5 15 of users fail to recover completely 38 143 According to the same review there is at least one trial that shows antipsychotic medications effectively resolve the symptoms of acute amphetamine psychosis 38 Psychosis rarely arises from therapeutic use 26 39 40 Drug interactionsSee also Amphetamine Contraindications and Amphetamine Pharmacokinetics Many types of substances are known to interact with amphetamine resulting in altered drug action or metabolism of amphetamine the interacting substance or both 26 Inhibitors of enzymes that metabolize amphetamine e g CYP2D6 and FMO3 will prolong its elimination half life meaning that its effects will last longer 15 26 Amphetamine also interacts with MAOIs particularly monoamine oxidase A inhibitors since both MAOIs and amphetamine increase plasma catecholamines i e norepinephrine and dopamine 26 therefore concurrent use of both is dangerous 26 Amphetamine modulates the activity of most psychoactive drugs In particular amphetamine may decrease the effects of sedatives and depressants and increase the effects of stimulants and antidepressants 26 Amphetamine may also decrease the effects of antihypertensives and antipsychotics due to its effects on blood pressure and dopamine respectively 26 Zinc supplementation may reduce the minimum effective dose of amphetamine when it is used for the treatment of ADHD note 16 148 In general there is no significant interaction when consuming amphetamine with food but the pH of gastrointestinal content and urine affects the absorption and excretion of amphetamine respectively 26 Acidic substances reduce the absorption of amphetamine and increase urinary excretion and alkaline substances do the opposite 26 Due to the effect pH has on absorption amphetamine also interacts with gastric acid reducers such as proton pump inhibitors and H2 antihistamines which increase gastrointestinal pH i e make it less acidic 26 PharmacologyPharmacodynamics For a simpler and less technical explanation of amphetamine s mechanism of action see Adderall Mechanism of action Pharmacodynamics of amphetamine in a dopamine neuronvte via AADC Amphetamine enters the presynaptic neuron across the neuronal membrane or through DAT 35 Once inside it binds to TAAR1 or enters synaptic vesicles through VMAT2 35 149 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 149 150 When amphetamine binds to TAAR1 it reduces the firing rate of the dopamine neuron via potassium channels and activates protein kinase A PKA and protein kinase C PKC which subsequently phosphorylates DAT 35 151 152 PKA phosphorylation causes DAT to withdraw into the presynaptic neuron internalize and cease transport 35 PKC phosphorylated DAT may either operate in reverse or like PKA phosphorylated DAT internalize and cease transport 35 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 153 154 Amphetamine exerts its behavioral effects by altering the use of monoamines as neuronal signals in the brain primarily in catecholamine neurons in the reward and executive function pathways of the brain 35 56 The concentrations of the main neurotransmitters involved in reward circuitry and executive functioning dopamine and norepinephrine increase dramatically in a dose dependent manner by amphetamine because of its effects on monoamine transporters 35 56 149 The reinforcing and motivational salience promoting effects of amphetamine are due mostly to enhanced dopaminergic activity in the mesolimbic pathway 24 The euphoric and locomotor stimulating effects of amphetamine are dependent upon the magnitude and speed by which it increases synaptic dopamine and norepinephrine concentrations in the striatum 2 Amphetamine has been identified as a potent full agonist of trace amine associated receptor 1 TAAR1 a Gs coupled and Gq coupled G protein coupled receptor GPCR discovered in 2001 which is important for regulation of brain monoamines 35 155 Activation of TAAR1 increases cAMP production via adenylyl cyclase activation and inhibits monoamine transporter function 35 156 Monoamine autoreceptors e g D2 short presynaptic a2 and presynaptic 5 HT1A have the opposite effect of TAAR1 and together these receptors provide a regulatory system for monoamines 35 36 Notably amphetamine and trace amines possess high binding affinities for TAAR1 but not for monoamine autoreceptors 35 36 Imaging studies indicate that monoamine reuptake inhibition by amphetamine and trace amines is site specific and depends upon the presence of TAAR1 co localization in the associated monoamine neurons 35 In addition to the neuronal monoamine transporters amphetamine also inhibits both vesicular monoamine transporters VMAT1 and VMAT2 as well as SLC1A1 SLC22A3 and SLC22A5 sources 14 SLC1A1 is excitatory amino acid transporter 3 EAAT3 a glutamate transporter located in neurons SLC22A3 is an extraneuronal monoamine transporter that is present in astrocytes and SLC22A5 is a high affinity carnitine transporter sources 14 Amphetamine is known to strongly induce cocaine and amphetamine regulated transcript CART gene expression 4 162 a neuropeptide involved in feeding behavior stress and reward which induces observable increases in neuronal development and survival in vitro 4 163 164 The CART receptor has yet to be identified but there is significant evidence that CART binds to a unique Gi Go coupled GPCR 164 165 Amphetamine also inhibits monoamine oxidases at very high doses resulting in less monoamine and trace amine metabolism and consequently higher concentrations of synaptic monoamines 21 166 In humans the only post synaptic receptor at which amphetamine is known to bind is the 5 HT1A receptor where it acts as an agonist with low micromolar affinity 167 168 The full profile of amphetamine s short term drug effects in humans is mostly derived through increased cellular communication or neurotransmission of dopamine 35 serotonin 35 norepinephrine 35 epinephrine 149 histamine 149 CART peptides 4 162 endogenous opioids 169 170 171 adrenocorticotropic hormone 172 173 corticosteroids 172 173 and glutamate 153 158 which it affects through interactions with CART 5 HT1A EAAT3 TAAR1 VMAT1 VMAT2 and possibly other biological targets sources 15 Amphetamine also activates seven human carbonic anhydrase enzymes several of which are expressed in the human brain 174 Dextroamphetamine is a more potent agonist of TAAR1 than levoamphetamine 175 Consequently dextroamphetamine produces greater CNS stimulation than levoamphetamine roughly three to four times more but levoamphetamine has slightly stronger cardiovascular and peripheral effects 37 175 Dopamine In certain brain regions amphetamine increases the concentration of dopamine in the synaptic cleft 35 Amphetamine can enter the presynaptic neuron either through DAT or by diffusing across the neuronal membrane directly 35 As a consequence of DAT uptake amphetamine produces competitive reuptake inhibition at the transporter 35 Upon entering the presynaptic neuron amphetamine activates TAAR1 which through protein kinase A PKA and protein kinase C PKC signaling causes DAT phosphorylation 35 Phosphorylation by either protein kinase can result in DAT internalization non competitive reuptake inhibition but PKC mediated phosphorylation alone induces the reversal of dopamine transport through DAT i e dopamine efflux note 16 35 176 Amphetamine is also known to increase intracellular calcium an effect which is associated with DAT phosphorylation through an unidentified Ca2 calmodulin dependent protein kinase CAMK dependent pathway in turn producing dopamine efflux 155 153 154 Through direct activation of G protein coupled inwardly rectifying potassium channels TAAR1 reduces the firing rate of dopamine neurons preventing a hyper dopaminergic state 151 152 177 Amphetamine is also a substrate for the presynaptic vesicular monoamine transporter VMAT2 149 150 Following amphetamine uptake at VMAT2 amphetamine induces the collapse of the vesicular pH gradient which results in the release of dopamine molecules from synaptic vesicles into the cytosol via dopamine efflux through VMAT2 149 150 Subsequently the cytosolic dopamine molecules are released from the presynaptic neuron into the synaptic cleft via reverse transport at DAT 35 149 150 Norepinephrine Similar to dopamine amphetamine dose dependently increases the level of synaptic norepinephrine the direct precursor of epinephrine 44 56 Based upon neuronal TAAR1 mRNA expression amphetamine is thought to affect norepinephrine analogously to dopamine 35 149 176 In other words amphetamine induces TAAR1 mediated efflux and non competitive reuptake inhibition at phosphorylated NET competitive NET reuptake inhibition and norepinephrine release from VMAT2 35 149 Serotonin Amphetamine exerts analogous yet less pronounced effects on serotonin as on dopamine and norepinephrine 35 56 Amphetamine affects serotonin via VMAT2 and like norepinephrine is thought to phosphorylate SERT via TAAR1 35 149 Like dopamine amphetamine has low micromolar affinity at the human 5 HT1A receptor 167 168 Other neurotransmitters peptides hormones and enzymes Human carbonic anhydraseactivation potency Enzyme KA nM SourceshCA4 94 174 hCA5A 810 174 178 hCA5B 2560 174 hCA7 910 174 178 hCA12 640 174 hCA13 24100 174 hCA14 9150 174 Acute amphetamine administration in humans increases endogenous opioid release in several brain structures in the reward system 169 170 171 Extracellular levels of glutamate the primary excitatory neurotransmitter in the brain have been shown to increase in the striatum following exposure to amphetamine 153 This increase in extracellular glutamate presumably occurs via the amphetamine induced internalization of EAAT3 a glutamate reuptake transporter in dopamine neurons 153 158 Amphetamine also induces the selective release of histamine from mast cells and efflux from histaminergic neurons through VMAT2 149 Acute amphetamine administration can also increase adrenocorticotropic hormone and corticosteroid levels in blood plasma by stimulating the hypothalamic pituitary adrenal axis 33 172 173 In December 2017 the first study assessing the interaction between amphetamine and human carbonic anhydrase enzymes was published 174 of the eleven carbonic anhydrase enzymes it examined it found that amphetamine potently activates seven four of which are highly expressed in the human brain with low nanomolar through low micromolar activating effects 174 Based upon preclinical research cerebral carbonic anhydrase activation has cognition enhancing effects 179 but based upon the clinical use of carbonic anhydrase inhibitors carbonic anhydrase activation in other tissues may be associated with adverse effects such as ocular activation exacerbating glaucoma 179 Pharmacokinetics The oral bioavailability of amphetamine varies with gastrointestinal pH 26 it is well absorbed from the gut and bioavailability is typically over 75 for dextroamphetamine 3 Amphetamine is a weak base with a pKa of 9 9 5 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 5 26 Conversely an acidic pH means the drug is predominantly in a water soluble cationic salt form and less is absorbed 5 Approximately 20 of amphetamine circulating in the bloodstream is bound to plasma proteins 4 Following absorption amphetamine readily distributes into most tissues in the body with high concentrations occurring in cerebrospinal fluid and brain tissue 11 The half lives of amphetamine enantiomers differ and vary with urine pH 5 At normal urine pH the half lives of dextroamphetamine and levoamphetamine are 9 11 hours and 11 14 hours respectively 5 Highly acidic urine will reduce the enantiomer half lives to 7 hours 11 highly alkaline urine will increase the half lives up to 34 hours 11 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 5 Amphetamine is eliminated via the kidneys with 30 40 of the drug being excreted unchanged at normal urinary pH 5 When the urinary pH is basic amphetamine is in its free base form so less is excreted 5 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 5 Following oral administration amphetamine appears in urine within 3 hours 11 Roughly 90 of ingested amphetamine is eliminated 3 days after the last oral dose 11 Lisdexamfetamine is a prodrug of dextroamphetamine 180 181 It is not as sensitive to pH as amphetamine when being absorbed in the gastrointestinal tract 181 Following absorption into the blood stream lisdexamfetamine is completely converted by red blood cells to dextroamphetamine and the amino acid L lysine by hydrolysis via undetermined aminopeptidase enzymes 181 180 182 This is the rate limiting step in the bioactivation of lisdexamfetamine 180 The elimination half life of lisdexamfetamine is generally less than 1 hour 181 180 Due to the necessary conversion of lisdexamfetamine into dextroamphetamine levels of dextroamphetamine with lisdexamfetamine peak about one hour later than with an equivalent dose of immediate release dextroamphetamine 180 182 Presumably due to its rate limited activation by red blood cells intravenous administration of lisdexamfetamine shows greatly delayed time to peak and reduced peak levels compared to intravenous administration of an equivalent dose of dextroamphetamine 180 The pharmacokinetics of lisdexamfetamine are similar regardless of whether it is administered orally intranasally or intravenously 180 182 Hence in contrast to dextroamphetamine parenteral use does not enhance the subjective effects of lisdexamfetamine 180 182 Because of its behavior as a prodrug and its pharmacokinetic differences lisdexamfetamine has a longer duration of therapeutic effect than immediate release dextroamphetamine and shows reduced misuse potential 180 182 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 16 Amphetamine has a variety of excreted metabolic products including 4 hydroxyamphetamine 4 hydroxynorephedrine 4 hydroxyphenylacetone benzoic acid hippuric acid norephedrine and phenylacetone 5 6 Among these metabolites the active sympathomimetics are 4 hydroxyamphetamine 183 4 hydroxynorephedrine 184 and norephedrine 185 The main metabolic pathways involve aromatic para hydroxylation aliphatic alpha and beta hydroxylation N oxidation N dealkylation and deamination 5 186 The known metabolic pathways detectable metabolites and metabolizing enzymes in humans include the following Metabolic pathways of amphetamine in humans sources 16 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 17 OxidativeDeamination FMO3 Oxidation unidentified GlycineConjugation XM ligaseGLYAT The primary active metabolites of amphetamine are 4 hydroxyamphetamine and norephedrine 6 at normal urine pH about 30 40 of amphetamine is excreted unchanged and roughly 50 is excreted as the inactive metabolites bottom row 5 The remaining 10 20 is excreted as the active metabolites 5 Benzoic acid is metabolized by XM ligase into an intermediate product benzoyl CoA which is then metabolized by GLYAT into hippuric acid 188 Pharmacomicrobiomics 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 192 193 Since the total number of microbial and viral cells in the human body over 100 trillion greatly outnumbers human cells tens of trillions note 18 192 194 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 192 193 195 The field that studies these interactions is known as pharmacomicrobiomics 192 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 195 The first amphetamine metabolizing microbial enzyme tyramine oxidase from a strain of E coli commonly found in the human gut was identified in 2019 195 This enzyme was found to metabolize amphetamine tyramine and phenethylamine with roughly the same binding affinity for all three compounds 195 Related endogenous compounds 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 35 44 196 Among this group the most closely related compounds are phenethylamine the parent compound of amphetamine and N methylphenethylamine an isomer of amphetamine i e it has an identical molecular formula 35 44 197 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 44 197 In turn N methylphenethylamine is metabolized from phenethylamine by phenylethanolamine N methyltransferase the same enzyme that metabolizes norepinephrine into epinephrine 44 197 Like amphetamine both phenethylamine and N methylphenethylamine regulate monoamine neurotransmission via TAAR1 35 196 197 unlike amphetamine both of these substances are broken down by monoamine oxidase B and therefore have a shorter half life than amphetamine 44 197 ChemistryRacemic amphetamine Levoamphetamine Dextroamphetamine The skeletal structures of L amph and D amph A vial of the colorless amphetamine free base Amphetamine hydrochloride left bowl Phenyl 2 nitropropene right cups Amphetamine is a methyl homolog of the mammalian neurotransmitter phenethylamine with the chemical formula C9H13N The carbon atom adjacent to the primary amine is a stereogenic center and amphetamine is composed of a racemic 1 1 mixture of two enantiomers 4 This racemic mixture can be separated into its optical isomers note 19 levoamphetamine and dextroamphetamine 4 At room temperature the pure free base of amphetamine is a mobile colorless and volatile liquid with a characteristically strong amine odor and acrid burning taste 20 Frequently prepared solid salts of amphetamine include amphetamine adipate 198 aspartate 26 hydrochloride 199 phosphate 200 saccharate 26 sulfate 26 and tannate 201 Dextroamphetamine sulfate is the most common enantiopure salt 45 Amphetamine is also the parent compound of its own structural class which includes a number of psychoactive derivatives 13 4 In organic chemistry amphetamine is an excellent chiral ligand for the stereoselective synthesis of 1 1 bi 2 naphthol 202 Substituted derivatives For a more comprehensive list see Substituted amphetamine The substituted derivatives of amphetamine or substituted amphetamines are a broad range of chemicals that contain amphetamine as a backbone 13 46 203 specifically this chemical class includes derivative compounds that are formed by replacing one or more hydrogen atoms in the amphetamine core structure with substituents 13 46 204 The class includes amphetamine itself stimulants like methamphetamine serotonergic empathogens like MDMA and decongestants like ephedrine among other subgroups 13 46 203 Synthesis Further information on illicit amphetamine synthesis History and culture of substituted amphetamines Illegal synthesis Since the first preparation was reported in 1887 205 numerous synthetic routes to amphetamine have been developed 206 207 The most common route of both legal and illicit amphetamine synthesis employs a non metal reduction known as the Leuckart reaction method 1 45 208 In the first step a reaction between phenylacetone and formamide either using additional formic acid or formamide itself as a reducing agent yields N formylamphetamine This intermediate is then hydrolyzed using hydrochloric acid and subsequently basified extracted with organic solvent concentrated and distilled to yield the free base The free base is then dissolved in an organic solvent sulfuric acid added and amphetamine precipitates out as the sulfate salt 208 209 A number of chiral resolutions have been developed to separate the two enantiomers of amphetamine 206 For example racemic amphetamine can be treated with d tartaric acid to form a diastereoisomeric salt which is fractionally crystallized to yield dextroamphetamine 210 Chiral resolution remains the most economical method for obtaining optically pure amphetamine on a large scale 211 In addition several enantioselective syntheses of amphetamine have been developed In one example optically pure R 1 phenyl ethanamine is condensed with phenylacetone to yield a chiral Schiff base In the key step this intermediate is reduced by catalytic hydrogenation with a transfer of chirality to the carbon atom alpha to the amino group Cleavage of the benzylic amine bond by hydrogenation yields optically pure dextroamphetamine 211 A large number of alternative synthetic routes to amphetamine have been developed based on classic organic reactions 206 207 One example is the Friedel Crafts alkylation of benzene by allyl chloride to yield beta chloropropylbenzene which is then reacted with ammonia to produce racemic amphetamine method 2 212 Another example employs the Ritter reaction method 3 In this route allylbenzene is reacted acetonitrile in sulfuric acid to yield an organosulfate which in turn is treated with sodium hydroxide to give amphetamine via an acetamide intermediate 213 214 A third route starts with ethyl 3 oxobutanoate which through a double alkylation with methyl iodide followed by benzyl chloride can be converted into 2 methyl 3 phenyl propanoic acid This synthetic intermediate can be transformed into amphetamine using either a Hofmann or Curtius rearrangement method 4 215 A significant number of amphetamine syntheses feature a reduction of a nitro imine oxime or other nitrogen containing functional groups 207 In one such example a Knoevenagel condensation of benzaldehyde with nitroethane yields phenyl 2 nitropropene The double bond and nitro group of this intermediate is reduced using either catalytic hydrogenation or by treatment with lithium aluminium hydride method 5 208 216 Another method is the reaction of phenylacetone with ammonia producing an imine intermediate that is reduced to the primary amine using hydrogen over a palladium catalyst or lithium aluminum hydride method 6 208 Amphetamine synthetic routes Method 1 Synthesis by the Leuckart reaction Top Chiral resolution of amphetamine Bottom Stereoselective synthesis of amphetamine Method 2 Synthesis by Friedel Crafts alkylation Method 3 Ritter synthesis Method 4 Synthesis via Hofmann and Curtius rearrangements Method 5 Synthesis by Knoevenagel condensation Method 6 Synthesis using phenylacetone and ammonia Detection in body fluids Amphetamine is frequently measured in urine or blood as part of a drug test for sports employment poisoning diagnostics and forensics sources 17 Techniques such as immunoassay which is the most common form of amphetamine test may cross react with a number of sympathomimetic drugs 220 Chromatographic methods specific for amphetamine are employed to prevent false positive results 221 Chiral separation techniques may be employed to help distinguish the source of the drug whether prescription amphetamine prescription amphetamine prodrugs e g selegiline over the counter drug products that contain levomethamphetamine note 20 or illicitly obtained substituted amphetamines 221 224 225 Several prescription drugs produce amphetamine as a metabolite including benzphetamine clobenzorex famprofazone fenproporex lisdexamfetamine mesocarb methamphetamine prenylamine and selegiline among others 2 226 227 These compounds may produce positive results for amphetamine on drug tests 226 227 Amphetamine is generally only detectable by a standard drug test for approximately 24 hours although a high dose may be detectable for 2 4 days 220 For the assays a study noted that an enzyme multiplied immunoassay technique EMIT assay for amphetamine and methamphetamine may produce more false positives than liquid chromatography tandem mass spectrometry 224 Gas chromatography mass spectrometry GC MS of amphetamine and methamphetamine with the derivatizing agent S trifluoroacetylprolyl chloride allows for the detection of methamphetamine in urine 221 GC MS of amphetamine and methamphetamine with the chiral derivatizing agent Mosher s acid chloride allows for the detection of both dextroamphetamine and dextromethamphetamine in urine 221 Hence the latter method may be used on samples that test positive using other methods to help distinguish between the various sources of the drug 221 History society and cultureMain article History and culture of substituted amphetamines Global estimates of drug users in 2016 in millions of users 228 Substance Bestestimate Lowestimate HighestimateAmphetamine type stimulants 34 16 13 42 55 24Cannabis 192 15 165 76 234 06Cocaine 18 20 13 87 22 85Ecstasy 20 57 8 99 32 34Opiates 19 38 13 80 26 15Opioids 34 26 27 01 44 54Amphetamine type stimulants were originally derived from the plant Ephedra which contains the amphetamine like stimulant ephedrine and had been used for its effects in China dating back an estimated 5 000 years 229 230 Ephedrine was isolated from Ephedra vulgaris in Japan in 1885 and was studied for its medicinal properties through the 1920s 229 The scarce amounts of ephedrine in the Ephedra plant led to investigations of synthetic analogues of ephedrine 229 Amphetamine was first synthesized in 1887 in Germany by Romanian chemist Lazăr Edeleanu who named it phenylisopropylamine 205 231 232 its stimulant effects remained unknown until 1927 when it was independently resynthesized by Gordon Alles and reported to have sympathomimetic properties 232 Amphetamine had no medical use until late 1933 when Smith Kline and French began selling it as an inhaler under the brand name Benzedrine as a decongestant 27 Benzedrine sulfate was introduced 3 years later and was used to treat a wide variety of medical conditions including narcolepsy obesity low blood pressure low libido and chronic pain among others 47 27 The beneficial effect of Benzedrine in children with hyperactivity was discovered serendipitously in 1937 when it was given against a low intracranial pressure headache It did not improve the headache but improved school performance and behavior of some 233 During World War II amphetamine and methamphetamine were used extensively by both the Allied and Axis forces for their stimulant and performance enhancing effects 205 234 235 As the addictive properties of the drug became known governments began to place strict controls on the sale of amphetamine 205 For example during the early 1970s in the United States amphetamine became a schedule II controlled substance under the Controlled Substances Act 236 237 In spite of strict government controls amphetamine has been used legally or illicitly by people from a variety of backgrounds including authors 238 musicians 239 mathematicians 240 and athletes 25 Amphetamine is still illegally synthesized today in clandestine labs and sold on the black market primarily in European countries 241 Among European Union EU member states in 2018 update 11 9 million adults of ages 15 64 have used amphetamine or methamphetamine at least once in their lives and 1 7 million have used either in the last year 242 During 2012 approximately 5 9 metric tons of illicit amphetamine were seized within EU member states 243 the street price of illicit amphetamine within the EU ranged from 6 38 per gram during the same period 243 Outside Europe the illicit market for amphetamine is much smaller than the market for methamphetamine and MDMA 241 Legal status As a result of the United Nations 1971 Convention on Psychotropic Substances amphetamine became a schedule II controlled substance as defined in the treaty in all 183 state parties 28 Consequently it is heavily regulated in most countries 244 245 Some countries such as South Korea and Japan have banned substituted amphetamines even for medical use 246 247 In other nations such as Canada schedule I drug 248 the Netherlands List I drug 249 the United States schedule II drug 26 Australia schedule 8 250 Thailand category 1 narcotic 251 and United Kingdom class B drug 252 amphetamine is in a restrictive national drug schedule that allows for its use as a medical treatment 241 29 Pharmaceutical products Several currently marketed amphetamine formulations contain both enantiomers including those marketed under the brand names Adderall Adderall XR Mydayis note 1 Adzenys ER Adzenys XR ODT Dyanavel XR Evekeo and Evekeo ODT Of those Evekeo including Evekeo ODT is the only product containing only racemic amphetamine as amphetamine sulfate and is therefore the only one whose active moiety can be accurately referred to simply as amphetamine 1 33 86 Dextroamphetamine marketed under the brand names Dexedrine and Zenzedi is the only enantiopure amphetamine product currently available A prodrug form of dextroamphetamine lisdexamfetamine is also available and is marketed under the brand name Vyvanse As it is a prodrug lisdexamfetamine is structurally different from dextroamphetamine and is inactive until it metabolizes into dextroamphetamine 34 181 The free base of racemic amphetamine was previously available as Benzedrine Psychedrine and Sympatedrine 2 Levoamphetamine was previously available as Cydril 2 Many current amphetamine pharmaceuticals are salts due to the comparatively high volatility of the free base 2 34 45 However oral suspension and orally disintegrating tablet ODT dosage forms composed of the free base were introduced in 2015 and 2016 respectively 86 253 254 Some of the current brands and their generic equivalents are listed below Amphetamine pharmaceuticals Brandname United StatesAdopted Name D L ratio Dosageform Marketingstart date US consumerprice data SourcesAdderall 3 1 salts tablet 1996 GoodRx 2 34 Adderall XR 3 1 salts capsule 2001 GoodRx 2 34 Mydayis 3 1 salts capsule 2017 GoodRx 255 256 Adzenys ER amphetamine 3 1 base suspension 2017 GoodRx 257 Adzenys XR ODT amphetamine 3 1 base ODT 2016 GoodRx 254 258 Dyanavel XR amphetamine 3 2 1 base suspension 2015 GoodRx 86 253 Evekeo amphetamine sulfate 1 1 salts tablet 2012 GoodRx 33 259 Evekeo ODT amphetamine sulfate 1 1 salts ODT 2019 GoodRx 260 Dexedrine dextroamphetamine sulfate 1 0 salts capsule 1976 GoodRx 2 34 Zenzedi dextroamphetamine sulfate 1 0 salts tablet 2013 GoodRx 34 261 Vyvanse lisdexamfetamine dimesylate 1 0 prodrug capsule 2007 GoodRx 2 181 262 tabletXelstrym dextroamphetamine 1 0 base patch 2022 GoodRx 263 Amphetamine base in marketed amphetamine medications drug formula molar mass note 21 amphetamine base note 22 amphetamine basein equal doses doses withequal basecontent note 23 g mol percent 30 mg dose total base total dextro levo dextro levo dextroamphetamine sulfate 265 266 C9H13N 2 H2SO4 368 49 270 41 73 38 73 38 22 0 mg 30 0 mgamphetamine sulfate 267 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 265 266 C9H13N 2 H2SO4 368 49 270 41 73 38 73 38 25 amphetamine sulfate 267 C9H13N 2 H2SO4 368 49 270 41 73 38 36 69 36 69 25 dextroamphetamine saccharate 268 C9H13N 2 C6H10O8 480 55 270 41 56 27 56 27 25 amphetamine aspartate monohydrate 269 C9H13N C4H7NO4 H2O 286 32 135 21 47 22 23 61 23 61 lisdexamfetamine dimesylate 181 C15H25N3O CH4O3S 2 455 49 135 21 29 68 29 68 8 9 mg 74 2 mgamphetamine base suspension 86 C9H13N 135 21 135 21 100 76 19 23 81 22 9 mg 7 1 mg 22 0 mgNotes a b Adderall and other mixed amphetamine salts products such as Mydayis are not racemic amphetamine they are a mixture composed of equal parts racemate and dextroamphetamine See Mixed amphetamine salts for more information about the mixture and this section for information about the various mixtures of amphetamine enantiomers currently marketed Synonyms and alternate spellings include 1 phenylpropan 2 amine IUPAC name a methylphenethylamine amfetamine International Nonproprietary Name INN b phenylisopropylamine and speed 21 4 22 Enantiomers are molecules that are mirror images of one another they are structurally identical but of the opposite orientation 23 Levoamphetamine and dextroamphetamine are also known as L amph or levamfetamine INN and D amph or dexamfetamine INN respectively 21 The brand name Adderall is used throughout this article to refer to the amphetamine four salt mixture it contains dextroamphetamine sulfate 25 dextroamphetamine saccharate 25 amphetamine sulfate 25 and amphetamine aspartate 25 The nonproprietary name which lists all four active constituent chemicals is excessively lengthy 34 The term amphetamines also refers to a chemical class but unlike the class of substituted amphetamines 13 the amphetamines class does not have a standardized definition in academic literature 17 One of the more restrictive definitions of this class includes only the racemate and enantiomers of amphetamine and methamphetamine 17 The most general definition of the class encompasses a broad range of pharmacologically and structurally related compounds 17 Due to confusion that may arise from use of the plural form this article will only use the terms amphetamine and amphetamines to refer to racemic amphetamine levoamphetamine and dextroamphetamine and reserve the term substituted amphetamines for its structural class 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 54 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 54 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 54 Cochrane reviews are high quality meta analytic systematic reviews of randomized controlled trials 60 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 81 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 2 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 41 53 85 The average reduction in final adult height from 3 years of continuous stimulant therapy is 2 cm 85 Transcription factors are proteins that increase or decrease the expression of specific genes 114 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 128 The review indicated that magnesium L aspartate and magnesium chloride produce significant changes in addictive behavior 105 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 a b The human dopamine transporter hDAT contains a high affinity extracellular and allosteric Zn2 zinc ion binding site which upon zinc binding inhibits dopamine reuptake inhibits amphetamine induced hDAT internalization and amplifies amphetamine induced dopamine efflux 144 145 146 147 The human serotonin transporter and norepinephrine transporter do not contain zinc binding sites 146 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 13 187 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 187 189 however other evidence from animal studies suggests that this reaction is catalyzed by DBH in synaptic vesicles within noradrenergic neurons in the brain 190 191 There is substantial variation in microbiome composition and microbial concentrations by anatomical site 192 193 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 192 Enantiomers are molecules that are mirror images of one another they are structurally identical but of the opposite orientation 23 The active ingredient in some OTC inhalers in the United States is listed as levmetamfetamine the INN and USAN of levomethamphetamine 222 223 For uniformity molar masses were calculated using the Lenntech Molecular Weight Calculator 264 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 2 17 24 25 26 27 28 29 30 31 32 33 2 10 24 27 33 35 36 10 24 25 26 30 37 38 39 40 41 42 43 44 45 46 1 26 37 85 86 87 88 89 90 91 26 82 88 90 30 26 37 92 a b 108 109 110 111 130 106 108 107 115 116 107 118 119 120 22 26 37 134 136 48 138 141 142 a b 149 153 157 158 159 160 161 35 149 157 158 162 167 a b 5 13 14 15 16 6 187 188 25 217 218 219 References a b c d e f g h i j 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 c d e f g h i j k l m 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 Wishart DS Djombou Feunang Y Guo AC Lo EJ Marcu A Grant JR Sajed T Johnson D Li C Sayeeda Z Assempour N Iynkkaran I Liu Y Maciejewski A Gale N Wilson A Chin L Cummings R Le D Pon A Knox C Wilson M Dextroamphetamine DrugBank Online DrugBank 5 0 a b c d e f g h i Wishart DS Djombou Feunang Y Guo AC Lo EJ Marcu A Grant JR Sajed T Johnson D Li C Sayeeda Z Assempour N Iynkkaran I Liu Y Maciejewski A Gale N Wilson A Chin L Cummings R Le D Pon A Knox C Wilson M Amphetamine DrugBank Online DrugBank 5 0 a b c d e f g h i j k l m n o p q r s Adderall XR Prescribing Information PDF United States Food and Drug Administration Shire US Inc December 2013 pp 12 13 Retrieved 30 December 2013 a b c d Santagati NA Ferrara G Marrazzo A Ronsisvalle G September 2002 Simultaneous determination of amphetamine and one of its metabolites by HPLC with electrochemical detection Journal of Pharmaceutical and Biomedical Analysis 30 2 247 255 doi 10 1016 S0731 7085 02 00330 8 PMID 12191709 Pharmacology amphetamine dextroamphetamine Medscape WebMD Retrieved 21 January 2016 Onset of action 30 60 min 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 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 Brams M Mao AR Doyle RL September 2008 Onset of efficacy of long acting psychostimulants in pediatric attention deficit hyperactivity disorder Postgraduate Medicine 120 3 69 88 doi 10 3810 pgm 2008 09 1909 PMID 18824827 S2CID 31791162 a b c d Adderall dextroamphetamine saccharate amphetamine aspartate dextroamphetamine sulfate and amphetamine sulfate tablet DailyMed Teva Pharmaceuticals USA Inc 8 November 2019 Retrieved 22 December 2019 a b c d e f Metabolism Pharmacokinetics Amphetamine United States National Library of Medicine Toxicology Data Network Hazardous Substances Data Bank Archived from the original on 2 October 2017 Retrieved 2 October 2017 Duration of effect varies depending on agent and urine pH Excretion is enhanced in more acidic urine Half life is 7 to 34 hours and is in part dependent on urine pH half life is longer with alkaline urine Amphetamines are distributed into most body tissues with high concentrations occurring in the brain and CSF Amphetamine appears in the urine within about 3 hours following oral administration Three days after a dose of or amphetamine human subjects had excreted 91 of the 14 C in the urine a b Mignot EJ October 2012 A practical guide to the therapy of narcolepsy and hypersomnia syndromes Neurotherapeutics 9 4 739 752 doi 10 1007 s13311 012 0150 9 PMC 3480574 PMID 23065655 a b c d e f g h i Glennon RA 2013 Phenylisopropylamine stimulants amphetamine related agents In Lemke TL Williams DA Roche VF Zito W eds Foye s principles of medicinal chemistry 7th ed Philadelphia USA Wolters Kluwer Health Lippincott Williams amp Wilkins pp 646 648 ISBN 9781609133450 The simplest unsubstituted phenylisopropylamine 1 phenyl 2 aminopropane or amphetamine serves as a common structural template for hallucinogens and psychostimulants Amphetamine produces central stimulant anorectic and sympathomimetic actions and it is the prototype member of this class 39 The phase 1 metabolism of amphetamine analogs is catalyzed by two systems cytochrome P450 and flavin monooxygenase Amphetamine can also undergo aromatic hydroxylation to p hydroxyamphetamine Subsequent oxidation at the benzylic position by DA b hydroxylase affords p hydroxynorephedrine Alternatively direct oxidation of amphetamine by DA b hydroxylase can afford norephedrine a b Taylor KB January 1974 Dopamine beta hydroxylase Stereochemical course of the reaction PDF Journal of Biological Chemistry 249 2 454 458 PMID 4809526 Retrieved 6 November 2014 Dopamine b hydroxylase catalyzed the removal of the pro R hydrogen atom and the production of 1 norephedrine 2S 1R 2 amino 1 hydroxyl 1 phenylpropane from d amphetamine a b c 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 Cashman JR Xiong YN Xu L Janowsky A March 1999 N oxygenation of amphetamine and methamphetamine by the human flavin containing monooxygenase form 3 role in bioactivation and detoxication Journal of Pharmacology and Experimental Therapeutics 288 3 1251 1260 PMID 10027866 a b c d e Yoshida T 1997 Chapter 1 Use and Misuse of Amphetamines An International Overview In Klee H ed Amphetamine Misuse International Perspectives on Current Trends Amsterdam Netherlands Harwood Academic Publishers p 2 ISBN 9789057020810 Amphetamine in the singular form properly applies to the racemate of 2 amino 1 phenylpropane In its broadest context however the term amphetamines can even embrace a large number of structurally and pharmacologically related substances Density Amphetamine PubChem Compound Database United States National Library of Medicine National Center for Biotechnology Information 5 November 2016 Retrieved 9 November 2016 Amphetamine CAS Common Chemistry American Chemical Society Retrieved 25 October 2022 a b Chemical and Physical Properties Amphetamine PubChem Compound Database United States National Library of Medicine National Center for Biotechnology Information Retrieved 13 October 2013 a b c Compound Summary Amphetamine PubChem Compound Database United States National Library of Medicine National Center for Biotechnology Information 11 April 2015 Retrieved 17 April 2015 a b 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 a b Enantiomer IUPAC Compendium of Chemical Terminology IUPAC Goldbook International Union of Pure and Applied Chemistry 2009 doi 10 1351 goldbook E02069 ISBN 9780967855097 Archived from the original on 17 March 2013 Retrieved 14 March 2014 One of a pair of molecular entities which are mirror images of each other and non superposable a b c d e f g h i j 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 USA 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 e f g 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 q r s t u v w x y z aa ab ac ad ae af ag ah ai aj ak al am an 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 Rasmussen N July 2006 Making the first anti depressant amphetamine in American medicine 1929 1950 Journal of the History of Medicine and Allied Sciences 61 3 288 323 doi 10 1093 jhmas jrj039 PMID 16492800 S2CID 24974454 However the firm happened to discover the drug SKF first packaged it as an inhaler so as to exploit the base s volatility and after sponsoring some trials by East Coast otolaryngological specialists began to advertise the Benzedrine Inhaler as a decongestant in late 1933 a b Convention on psychotropic substances United Nations Treaty Collection United Nations Archived from the original on 31 March 2016 Retrieved 11 November 2013 a b Wilens TE Adler LA Adams J Sgambati S Rotrosen J Sawtelle R Utzinger L Fusillo S January 2008 Misuse and diversion of stimulants prescribed for ADHD a systematic review of the literature Journal of the American Academy of Child amp Adolescent Psychiatry 47 1 21 31 doi 10 1097 chi 0b013e31815a56f1 PMID 18174822 Stimulant misuse appears to occur both for performance enhancement and their euphorogenic effects the latter being related to the intrinsic properties of the stimulants e g IR versus ER profile Although useful in the treatment of ADHD stimulants are controlled II substances with a history of preclinical and human studies showing potential abuse liability a b c Montgomery KA June 2008 Sexual desire disorders Psychiatry 5 6 50 55 PMC 2695750 PMID 19727285 Amphetamine Medical Subject Headings United States National Library of Medicine Retrieved 16 December 2013 Guidelines on the Use of International Nonproprietary Names INNS for Pharmaceutical Substances World Health Organization 1997 Archived from the original on 9 January 2015 Retrieved 1 December 2014 In principle INNs are selected only for the active part of the molecule which is usually the base acid or alcohol In some cases however the active molecules need to be expanded for various reasons such as formulation purposes bioavailability or absorption rate In 1975 the experts designated for the selection of INN decided to adopt a new policy for naming such molecules In future names for different salts or esters of the same active substance should differ only with regard to the inactive moiety of the molecule The latter are called modified INNs INNMs a b c d e f g h i Evekeo amphetamine sulfate tablet DailyMed Arbor Pharmaceuticals LLC 14 August 2019 Retrieved 22 December 2019 a b c d e f g h 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 a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad Miller GM January 2011 The emerging role of trace amine associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity Journal of Neurochemistry 116 2 164 176 doi 10 1111 j 1471 4159 2010 07109 x PMC 3005101 PMID 21073468 a b c d e 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 c d e f g h i j k l m n o p q r s t u v w 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 USA McGraw Hill ISBN 9780071624428 a b c d e 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 c d e 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 c 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 c d e f g h 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 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 a b c d e f g 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 Amphetamine European Monitoring Centre for Drugs and Drug Addiction Retrieved 19 October 2013 a b c d Hagel JM Krizevski R Marsolais F Lewinsohn E Facchini PJ 2012 Biosynthesis of amphetamine analogs in plants Trends in Plant Science 17 7 404 412 doi 10 1016 j tplants 2012 03 004 PMID 22502775 Substituted amphetamines which are also called phenylpropylamino alkaloids are a diverse group of nitrogen containing compounds that feature a phenethylamine backbone with a methyl group at the a position relative to the nitrogen Figure 1 Beyond 1R 2S ephedrine and 1S 2S pseudoephedrine myriad other substituted amphetamines have important pharmaceutical applications For example S amphetamine Figure 4b a key ingredient in Adderall and Dexedrine is used to treat attention deficit hyperactivity disorder ADHD 79 Figure 4 b Examples of synthetic pharmaceutically important substituted amphetamines a b Bett WR August 1946 Benzedrine sulphate in clinical medicine a survey of the literature Postgraduate Medical Journal 22 250 205 218 doi 10 1136 pgmj 22 250 205 PMC 2478360 PMID 20997404 a b 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 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 USA 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 USA McGraw Hill Medical pp 154 157 ISBN 9780071481274 a b c d e 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 USA 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 2 CD009996 doi 10 1002 14651858 CD009996 pub2 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 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 USA 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 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 a b c d e f g h i j k 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 a b c d 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 d e f 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 O Connor PG February 2012 Amphetamines Merck Manual for Health Care Professionals Merck Retrieved 8 May 2012 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 Glossary of Terms Mount Sinai School of Medicine Department of Neuroscience Retrieved 9 February 2015 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 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 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 December 2022 PMID 18557129 a href Template Cite journal html title Template Cite journal cite journal a CS1 maint DOI inactive as of December 2022 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 USA McGraw Hill Medical p 94 ISBN 9780071481274 Kanehisa Laboratories 29 October 2014 Alcoholism Homo sapiens human KEGG Pathway Retrieved 31 October 2014 span, wikipedia, wiki, book, books, library,

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