HOME
The Info List - Benzedrine


--- Advertisement ---



Amphetamine[note 1] (contracted from alpha-methylphenethylamine) is a potent central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity. Amphetamine
Amphetamine
was discovered in 1887 and exists as two enantiomers:[note 2] levoamphetamine and dextroamphetamine. Amphetamine
Amphetamine
properly refers to a specific chemical, the racemic free base, which is equal parts of the two enantiomers, levoamphetamine and dextroamphetamine, 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
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] 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 3] dextroamphetamine, or the inactive prodrug lisdexamfetamine. Amphetamine, through activation of a trace amine receptor, increases monoamine and excitatory neurotransmitter activity in the brain, with its most pronounced effects targeting the catecholamine neurotransmitters norepinephrine and dopamine.[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. Drug addiction is a serious risk with large recreational doses but is unlikely to arise from typical 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
Amphetamine
belongs to the phenethylamine class. It is also the parent compound of its own structural class, the substituted amphetamines,[note 4] 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
Phenethylamine
is the parent compound of amphetamine, while N-methylphenethylamine
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 Side effects

3.1 Physical 3.2 Psychological

4 Overdose

4.1 Addiction

4.1.1 Biomolecular mechanisms 4.1.2 Pharmacological treatments 4.1.3 Behavioral treatments

4.2 Dependence and withdrawal 4.3 Toxicity 4.4 Psychosis

5 Interactions 6 Pharmacology

6.1 Pharmacodynamics

6.1.1 Dopamine 6.1.2 Norepinephrine 6.1.3 Serotonin 6.1.4 Other neurotransmitters, peptides, and hormones

6.2 Pharmacokinetics 6.3 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 links

Uses Medical Amphetamine
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.[2][35][49] Long-term amphetamine exposure at sufficiently high doses in some animal species is known to produce abnormal dopamine system development or nerve damage,[50][51] but, in humans with ADHD, pharmaceutical amphetamines appear to improve brain development and nerve growth.[52][53][54] 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.[52][53][54] Reviews of clinical stimulant research have established the safety and effectiveness of long-term continuous amphetamine use for the treatment of ADHD.[55][56][57] Randomized controlled trials of continuous stimulant therapy for the treatment of ADHD spanning 2 years have demonstrated treatment effectiveness and safety.[55][57] 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 5] 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.[56][57] 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.[55] 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.[57] Current models of ADHD suggest that it is associated with functional impairments in some of the brain's neurotransmitter systems;[58] 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.[58] Psychostimulants like methylphenidate and amphetamine are effective in treating ADHD because they increase neurotransmitter activity in these systems.[26][58][59] Approximately 80% of those who use these stimulants see improvements in ADHD symptoms.[60] 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.[61][62] The Cochrane Collaboration's reviews[note 6] on the treatment of ADHD in children, adolescents, and adults with pharmaceutical amphetamines stated that while these drugs improve short-term symptoms, they have higher discontinuation rates than non-stimulant medications due to their adverse side effects.[64][65] A Cochrane Collaboration
Cochrane Collaboration
review on the treatment of ADHD in children with tic disorders such as Tourette syndrome indicated that stimulants in general do not make tics worse, but high doses of dextroamphetamine could exacerbate tics in some individuals.[66] 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;[67][68] 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.[26][67] A systematic review from 2014 found that low doses of amphetamine also improve memory consolidation, in turn leading to improved recall of information.[69] Therapeutic doses of amphetamine also enhance cortical network efficiency, an effect which mediates improvements in working memory in all individuals.[26][70] Amphetamine and other ADHD stimulants also improve task saliency (motivation to perform a task) and increase arousal (wakefulness), in turn promoting goal-directed behavior.[26][71][72] Stimulants
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.[26][72][73] Based upon studies of self-reported illicit stimulant use, 5–35% of college students use diverted ADHD stimulants, which are primarily used for performance enhancement rather than as recreational drugs.[74][75][76] However, high amphetamine doses that are above the therapeutic range can interfere with working memory and other aspects of cognitive control.[26][72] Physical performance Amphetamine
Amphetamine
is used by some athletes for its psychological and athletic performance-enhancing effects, such as increased endurance and alertness;[27][40] however, non-medical amphetamine use is prohibited at sporting events that are regulated by collegiate, national, and international anti-doping agencies.[77][78] 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.[27][79][80] Amphetamine improves endurance and reaction time primarily through reuptake inhibition and effluxion of dopamine in the central nervous system.[79][80][81] Amphetamine
Amphetamine
and other dopaminergic drugs also increase power output at fixed levels of perceived exertion by overriding a "safety switch" that allows the core temperature limit to increase in order to access a reserve capacity that is normally off-limits.[80][82][83] At therapeutic doses, the adverse effects of amphetamine do not impede athletic performance;[27][79] however, at much higher doses, amphetamine can induce effects that severely impair performance, such as rapid muscle breakdown and elevated body temperature.[28][39][79] Contraindications See also: Amphetamine
Amphetamine
§ Interactions According to the International Programme on Chemical Safety (IPCS) and United States Food and Drug Administration
United States Food and Drug Administration
(USFDA),[note 7] amphetamine is contraindicated in people with a history of drug abuse,[note 8] cardiovascular disease, severe agitation, or severe anxiety.[35][85][86] It is also contraindicated in people currently experiencing advanced arteriosclerosis (hardening of the arteries), glaucoma (increased eye pressure), hyperthyroidism (excessive production of thyroid hormone), or moderate to severe hypertension.[35][85][86] People who have experienced allergic reactions to other stimulants in the past or who are taking monoamine oxidase inhibitors (MAOIs) are advised not to take amphetamine,[35][85][86] although safe concurrent use of amphetamine and monoamine oxidase inhibitors has been documented.[87][88] 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
Tourette syndrome
should monitor their symptoms while taking amphetamine.[85][86] 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.[86] Amphetamine
Amphetamine
has also been shown to pass into breast milk, so the IPCS and USFDA advise mothers to avoid breastfeeding when using it.[85][86] Due to the potential for reversible growth impairments,[note 9] the USFDA advises monitoring the height and weight of children and adolescents prescribed an amphetamine pharmaceutical.[85] Side effects The 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 side effects.[28][39][40] Amphetamine
Amphetamine
products such as Adderall, Dexedrine, and their generic equivalents are currently approved by the USFDA for long-term therapeutic use.[36][39] Recreational use of amphetamine generally involves much larger doses, which have a greater risk of serious side effects than dosages used for therapeutic reasons.[40] Physical At normal therapeutic doses, the physical side effects of amphetamine vary widely by age and from person to person.[39] Cardiovascular
Cardiovascular
side effects can include hypertension or hypotension from a vasovagal response, Raynaud's phenomenon
Raynaud's phenomenon
(reduced blood flow to the hands and feet), and tachycardia (increased heart rate).[39][40][89] Sexual side effects in males may include erectile dysfunction, frequent erections, or prolonged erections.[39] Abdominal side effects may include abdominal pain, appetite loss, nausea, and weight loss.[2][39][90] Other potential side effects include blurred vision, dry mouth, excessive grinding of the teeth, nosebleed, profuse sweating, rhinitis medicamentosa (drug-induced nasal congestion), reduced seizure threshold, and tics (a type of movement disorder).[sources 5] Dangerous physical side effects are rare at typical pharmaceutical doses.[40] Amphetamine
Amphetamine
stimulates the medullary respiratory centers, producing faster and deeper breaths.[40] In a normal person at therapeutic doses, this effect is usually not noticeable, but when respiration is already compromised, it may be evident.[40] Amphetamine
Amphetamine
also induces contraction in the urinary bladder sphincter, the muscle which controls urination, which can result in difficulty urinating.[40] This effect can be useful in treating bed wetting and loss of bladder control.[40] The effects of amphetamine on the gastrointestinal tract are unpredictable.[40] If intestinal activity is high, amphetamine may reduce gastrointestinal motility (the rate at which content moves through the digestive system);[40] however, amphetamine may increase motility when the smooth muscle of the tract is relaxed.[40] Amphetamine
Amphetamine
also has a slight analgesic effect and can enhance the pain relieving effects of opioids.[2][40] 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.[39][40] 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.[40] Amphetamine psychosis (e.g., delusions and paranoia) can occur in heavy users.[28][39][41] Although very rare, this psychosis can also occur at therapeutic doses during long-term therapy.[28][39][42] According to the USFDA, "there is no systematic evidence" that stimulants produce aggressive behavior or hostility.[39] Amphetamine
Amphetamine
has also been shown to produce a conditioned place preference in humans taking therapeutic doses,[64][97] meaning that individuals acquire a preference for spending time in places where they have previously used amphetamine.[97][98] Overdose An amphetamine overdose can lead to many different symptoms, but is rarely fatal with appropriate care.[2][86][99] The severity of overdose symptoms increases with dosage and decreases with drug tolerance to amphetamine.[40][86] 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.[86] Symptoms of a moderate and extremely large overdose are listed below; fatal amphetamine poisoning usually also involves convulsions and coma.[28][40] 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 10][100] 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.[101][102] Individuals who frequently overdose on amphetamine during recreational use have a high risk of developing an amphetamine addiction, since repeated overdoses gradually increase the level of accumbal ΔFosB, a "molecular switch" and "master control protein" for addiction.[103][104][105] Once nucleus accumbens ΔFosB
ΔFosB
is sufficiently overexpressed, it begins to increase the severity of addictive behavior (i.e., compulsive drug-seeking) with further increases in its expression.[103][106] 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.[107][108] 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 a combination therapy with cognitive behavioral therapy, which is currently the best clinical treatment available.[107][109][110]

Overdose symptoms by system

System Minor or moderate overdose[28][40][86] Severe overdose[sources 10]

Cardiovascular

Abnormal heartbeat High or low blood pressure

Cardiogenic shock (heart not pumping enough blood) Cerebral hemorrhage
Cerebral hemorrhage
(bleeding in the brain) Circulatory collapse
Circulatory collapse
(partial or complete failure of the circulatory system)

Central nervous system

Confusion Abnormally fast reflexes Severe agitation Tremor
Tremor
(involuntary muscle twitching)

Acute amphetamine psychosis (e.g., delusions and paranoia) Compulsive and repetitive movement Serotonin syndrome
Serotonin syndrome
(excessive serotonergic nerve activity) Sympathomimetic toxidrome (excessive adrenergic nerve activity)

Musculoskeletal

Muscle pain

Rhabdomyolysis
Rhabdomyolysis
(rapid muscle breakdown)

Respiratory

Rapid breathing

Pulmonary edema
Pulmonary edema
(fluid accumulation in the lungs) Pulmonary hypertension
Pulmonary hypertension
(high blood pressure in the arteries of the lung) Respiratory alkalosis
Respiratory alkalosis
(reduced blood CO2)

Urinary

Painful urination Urinary retention
Urinary retention
(inability to urinate)

No urine production Kidney
Kidney
failure

Other

Elevated body temperature Mydriasis
Mydriasis
(dilated pupils)

Elevated or low blood potassium Hyperpyrexia
Hyperpyrexia
(extremely elevated core body temperature) Metabolic acidosis
Metabolic acidosis
(excessively acidic bodily fluids)

Addiction

Addiction
Addiction
and dependence glossary[98][104][112][113]

addiction – a brain disorder characterized by compulsive engagement in rewarding stimuli despite adverse consequences addictive behavior – a behavior that is both rewarding and reinforcing addictive drug – a drug that is both rewarding and reinforcing 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

v t e

Signaling cascade
Signaling cascade
in the nucleus accumbens that results in amphetamine addiction This box:

view talk edit

Note: colored text contains article links. Nuclear pore Nuclear membrane Plasma membrane Cav1.2 NMDAR AMPAR DRD1 DRD5 DRD2 DRD3 DRD4 Gs Gi/o AC cAMP cAMP PKA CaM CaMKII DARPP-32 PP1 PP2B CREB ΔFosB JunD c-Fos SIRT1 HDAC1 [Color legend 1]

This diagram depicts the signaling events in the brain's reward center that are induced by chronic high-dose exposure to psychostimulants that increase the concentration of synaptic dopamine, like amphetamine, methamphetamine, and phenethylamine. Following presynaptic dopamine and glutamate co-release by such psychostimulants,[114][115] 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.[114][116] Phosphorylated CREB increases levels of ΔFosB, which in turn represses the c-Fos gene with the help of corepressors;[114][117][118] c-Fos repression acts as a molecular switch that enables the accumulation of ΔFosB
ΔFosB
in the neuron.[119] 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.[117][118] ΔFosB
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.[117][118]

Addiction
Addiction
is a serious risk with heavy recreational amphetamine use but is unlikely to arise from typical long-term medical use at therapeutic doses.[43][44][45] Drug tolerance develops rapidly in amphetamine abuse (i.e., a recreational amphetamine overdose), so periods of extended use require increasingly larger doses of the drug in order to achieve the same effect.[120][121] 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.[122][123][124] The most important transcription factors[note 11] that produce these alterations are ΔFosB, cAMP response element binding protein (CREB), and nuclear factor kappa B (NF-κB).[123] ΔFosB
ΔFosB
is the most significant biomolecular mechanism in addiction because the overexpression of ΔFosB
ΔFosB
in the D1-type medium spiny neurons in the nucleus accumbens is necessary and sufficient[note 12] for many of the neural adaptations and behavioral effects (e.g., expression-dependent increases in drug self-administration and reward sensitization) seen in drug addiction.[103][104][123] Once ΔFosB
ΔFosB
is sufficiently overexpressed, it induces an addictive state that becomes increasingly more severe with further increases in ΔFosB
ΔFosB
expression.[103][104] It has been implicated in addictions to alcohol, cannabinoids, cocaine, methylphenidate, nicotine, opioids, phencyclidine, propofol, and substituted amphetamines, among others.[sources 11] ΔJunD, a transcription factor, and G9a, a histone methyltransferase enzyme, both oppose the function of ΔFosB
ΔFosB
and inhibit increases in its expression.[104][123][128] Sufficiently overexpressing Δ JunD
JunD
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).[123] ΔFosB
ΔFosB
also plays an important role in regulating behavioral responses to natural rewards, such as palatable food, sex, and exercise.[106][123][129] Since both natural rewards and addictive drugs induce expression of ΔFosB
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.[106][123] Consequently, ΔFosB
ΔFosB
is the most significant factor involved in both amphetamine addiction and amphetamine-induced sex addictions, which are compulsive sexual behaviors that result from excessive sexual activity and amphetamine use.[106][130][131] These sex addictions are associated with a dopamine dysregulation syndrome which occurs in some patients taking dopaminergic drugs.[106][129] The effects of amphetamine on gene regulation are both dose- and route-dependent.[124] Most of the research on gene regulation and addiction is based upon animal studies with intravenous amphetamine administration at very high doses.[124] 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.[124] This suggests that medical use of amphetamine does not significantly affect gene regulation.[124] Pharmacological treatments Further information: Addiction
Addiction
§ Research As of 2015,[update] there is no effective pharmacotherapy for amphetamine addiction.[1][120][132] Reviews from 2015 and 2016 indicated that TAAR1-selective agonists have significant therapeutic potential as a treatment for psychostimulant addictions;[38][133] however, as of February 2016,[update] the only compounds which are known to function as TAAR1-selective agonists are experimental drugs.[38][133] Amphetamine
Amphetamine
addiction is largely mediated through increased activation of dopamine receptors and co-localized NMDA receptors[note 13] in the nucleus accumbens;[102] magnesium ions inhibit NMDA receptors by blocking the receptor calcium channel.[102][134] One review suggested that, based upon animal testing, pathological (addiction-inducing) psychostimulant use significantly reduces the level of intracellular magnesium throughout the brain.[102] 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.[102] Behavioral treatments Cognitive behavioral therapy
Cognitive behavioral therapy
is currently the most effective clinical treatment for psychostimulant addictions.[110] 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.[107][109][135] 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.[106][135] This is the opposite of pathological stimulant use, which induces decreased striatal DRD2
DRD2
density.[106] One review noted that exercise may also prevent the development of a drug addiction by altering ΔFosB
ΔFosB
or c-Fos immunoreactivity in the striatum or other parts of the reward system.[108]

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
ΔFosB
expression in nucleus accumbens D1-type MSNs ↑ ↑ ↑ ↑ ↑ ↑ [106]

Behavioral plasticity

Escalation of intake Yes Yes Yes

[106]

Psychostimulant cross-sensitization Yes Not applicable Yes Yes Attenuated Attenuated [106]

Psychostimulant self-administration ↑ ↑ ↓

↓ ↓ [106]

Psychostimulant conditioned place preference ↑ ↑ ↓ ↑ ↓ ↑ [106]

Reinstatement
Reinstatement
of drug-seeking behavior ↑ ↑

↓ ↓ [106]

Neurochemical plasticity

CREB phosphorylation in the nucleus accumbens ↓ ↓ ↓

↓ ↓ [106]

Sensitized dopamine response in the nucleus accumbens No Yes No Yes

[106]

Altered striatal dopamine signaling ↓DRD2, ↑DRD3 ↑DRD1, ↓DRD2, ↑DRD3 ↑DRD1, ↓DRD2, ↑DRD3

↑DRD2 ↑DRD2 [106]

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 [106]

Changes in striatal opioid peptides ↑dynorphin No change: enkephalin ↑dynorphin ↓enkephalin

↑dynorphin ↑dynorphin [106]

Mesocorticolimbic synaptic plasticity

Number of dendrites in the nucleus accumbens ↓ ↑

[106]

Dendritic spine
Dendritic spine
density in the nucleus accumbens ↓ ↑

[106]

Dependence and withdrawal According to another Cochrane Collaboration
Cochrane Collaboration
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."[136] 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.[136] Amphetamine
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.[136] The review indicated that the severity of withdrawal symptoms is positively correlated with the age of the individual and the extent of their dependence.[136] Mild withdrawal symptoms from the discontinuation of amphetamine treatment at therapeutic doses can be avoided by tapering the dose.[2] 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 12] 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
Stimulant
psychosis A severe amphetamine overdose can result in a stimulant psychosis that may involve a variety of symptoms, such as delusions and paranoia.[41] A Cochrane Collaboration
Cochrane Collaboration
review on treatment for amphetamine, dextroamphetamine, and methamphetamine psychosis states that about 5–15% of users fail to recover completely.[41][143] According to the same review, there is at least one trial that shows antipsychotic medications effectively resolve the symptoms of acute amphetamine psychosis.[41] Psychosis
Psychosis
very rarely arises from therapeutic use.[42][85] Interactions See also: Amphetamine
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.[4][144] Inhibitors of enzymes that metabolize amphetamine (e.g., CYP2D6
CYP2D6
and FMO3) will prolong its elimination half-life, meaning that its effects will last longer.[7][144] Amphetamine
Amphetamine
also interacts with MAOIs, particularly monoamine oxidase A inhibitors, since both MAOIs and amphetamine increase plasma catecholamines (i.e., norepinephrine and dopamine);[144] therefore, concurrent use of both is dangerous.[144] Amphetamine
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.[144] Amphetamine
Amphetamine
may also decrease the effects of antihypertensives and antipsychotics due to its effects on blood pressure and dopamine respectively.[144] Zinc supplementation
Zinc supplementation
may reduce the minimum effective dose of amphetamine when it is used for the treatment of ADHD.[note 15][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.[144] Acidic substances reduce the absorption of amphetamine and increase urinary excretion, and alkaline substances do the opposite.[144] 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).[144] Pharmacology Pharmacodynamics For a simpler and less technical explanation of amphetamine's mechanism of action, see Adderall
Adderall
§ Mechanism of action.

Pharmacodynamics of amphetamine in a dopamine neuron v · t · e

via AADC

Amphetamine
Amphetamine
enters the presynaptic neuron across the neuronal membrane or through DAT.[37] Once inside, it binds to TAAR1
TAAR1
or enters synaptic vesicles through VMAT2.[37][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 phosphorylate DAT.[37][151][152] PKA-phosphorylation causes DAT to withdraw into the presynaptic neuron (internalize) and cease transport.[37] PKC-phosphorylated DAT may either operate in reverse or, like PKA-phosphorylated DAT, internalize and cease transport.[37] Amphetamine
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
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.[37][59] 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 due to its effects on monoamine transporters.[37][59][149] The reinforcing and motivational salience-promoting effects of amphetamine are mostly due to enhanced dopaminergic activity in the mesolimbic pathway.[26] 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.[3] Amphetamine
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.[37][155] Activation of TAAR1 increases cAMP production via adenylyl cyclase activation and inhibits monoamine transporter function.[37][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.[37][38] Notably, amphetamine and trace amines possess high binding affinities for TAAR1, but not for monoamine autoreceptors.[37][38] Imaging studies indicate that monoamine reuptake inhibition by amphetamine and trace amines is site specific and depends upon the presence of TAAR1
TAAR1
co-localization in the associated monoamine neurons.[37] As of 2010,[update] co-localization of TAAR1
TAAR1
and the dopamine transporter (DAT) has been visualized in rhesus monkeys, but co-localization of TAAR1
TAAR1
with the norepinephrine transporter (NET) and the serotonin transporter (SERT) has only been evidenced by messenger RNA (mRNA) expression.[37] In addition to the neuronal monoamine transporters, amphetamine also inhibits both vesicular monoamine transporters, VMAT1
VMAT1
and VMAT2, as well as SLC1A1, SLC22A3, and SLC22A5.[sources 13] SLC1A1
SLC1A1
is excitatory amino acid transporter 3 (EAAT3), a glutamate transporter located in neurons, SLC22A3
SLC22A3
is an extraneuronal monoamine transporter that is present in astrocytes, and SLC22A5
SLC22A5
is a high-affinity carnitine transporter.[sources 13] Amphetamine
Amphetamine
is known to strongly induce cocaine- and amphetamine-regulated transcript (CART) gene expression,[10][162] a neuropeptide involved in feeding behavior, stress, and reward, which induces observable increases in neuronal development and survival in vitro.[10][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
Amphetamine
also inhibits monoamine oxidases at very high doses, resulting in less monoamine and trace amine metabolism and consequently higher concentrations of synaptic monoamines.[18][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 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,[37] serotonin,[37] norepinephrine,[37] epinephrine,[149] histamine,[149] CART peptides,[10][162] endogenous opioids,[169][170][171] adrenocorticotropic hormone,[172][173] corticosteroids,[172][173] and glutamate,[153][158] which it effects through interactions with CART, 5-HT1A, EAAT3, TAAR1, VMAT1, VMAT2, and possibly other biological targets.[sources 14] Dextroamphetamine
Dextroamphetamine
is a more potent agonist of TAAR1
TAAR1
than levoamphetamine.[174] Consequently, dextroamphetamine produces greater CNS stimulation than levoamphetamine, roughly three to four times more, but levoamphetamine has slightly stronger cardiovascular and peripheral effects.[40][174] Dopamine In certain brain regions, amphetamine increases the concentration of dopamine in the synaptic cleft.[37] Amphetamine
Amphetamine
can enter the presynaptic neuron either through DAT or by diffusing across the neuronal membrane directly.[37] As a consequence of DAT uptake, amphetamine produces competitive reuptake inhibition at the transporter.[37] Upon entering the presynaptic neuron, amphetamine activates TAAR1
TAAR1
which, through protein kinase A (PKA) and protein kinase C (PKC) signaling, causes DAT phosphorylation.[37] Phosphorylation
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).[37][175] Amphetamine
Amphetamine
is also known to increase intracellular calcium, an effect which is associated with DAT phosphorylation through an unidentified Ca2+/calmodulin-dependent protein kinase
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
TAAR1
reduces the firing rate of dopamine neurons, preventing a hyper-dopaminergic state.[151][152][176] Amphetamine
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.[37][149][150] Norepinephrine Similar to dopamine, amphetamine dose-dependently increases the level of synaptic norepinephrine, the direct precursor of epinephrine.[46][59] Based upon neuronal TAAR1
TAAR1
mRNA expression, amphetamine is thought to affect norepinephrine analogously to dopamine.[37][149][175] 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.[37][149] Serotonin Amphetamine
Amphetamine
exerts analogous, yet less pronounced, effects on serotonin as on dopamine and norepinephrine.[37][59] Amphetamine affects serotonin via VMAT2
VMAT2
and, like norepinephrine, is thought to phosphorylate SERT via TAAR1.[37][149] Like dopamine, amphetamine has low, micromolar affinity at the human 5-HT1A receptor.[167][168] Other neurotransmitters, peptides, and hormones 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
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.[35][172][173] Pharmacokinetics The oral bioavailability of amphetamine varies with gastrointestinal pH;[144] it is well absorbed from the gut, and bioavailability is typically over 75% for dextroamphetamine.[9] Amphetamine
Amphetamine
is a weak base with a pKa of 9.9;[4] 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.[4][144] Conversely, an acidic pH means the drug is predominantly in a water-soluble cationic (salt) form, and less is absorbed.[4] Approximately 15–40% of amphetamine circulating in the bloodstream is bound to plasma proteins.[10] Following absorption, amphetamine readily distributes into most tissues in the body, with high concentrations occurring in cerebrospinal fluid and brain tissue.[16] The half-life of amphetamine enantiomers differ and vary with urine pH.[4] At normal urine pH, the half-lives of dextroamphetamine and levoamphetamine are 9–11 hours and 11–14 hours, respectively.[4] Highly acidic urine will reduce the enantiomer half-lives to 7 hours;[16] highly alkaline urine will increase the half-lives up to 34 hours.[16] 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.[4] Amphetamine
Amphetamine
is eliminated via the kidneys, with 30–40% of the drug being excreted unchanged at normal urinary pH.[4] When the urinary pH is basic, amphetamine is in its free base form, so less is excreted.[4] 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.[4] Following oral administration, amphetamine appears in urine within 3 hours.[16] Roughly 90% of ingested amphetamine is eliminated 3 days after the last oral dose.[16]  The prodrug lisdexamfetamine is not as sensitive to pH as amphetamine when being absorbed in the gastrointestinal tract;[177] following absorption into the blood stream, it is converted by red blood cell-associated enzymes to dextroamphetamine via hydrolysis.[177] The elimination half-life of lisdexamfetamine is generally less than 1 hour.[177] 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 15] Amphetamine
Amphetamine
has a variety of excreted metabolic products, including 4-hydroxyamphetamine, 4-hydroxynorephedrine, 4-hydroxyphenylacetone, benzoic acid, hippuric acid, norephedrine, and phenylacetone.[4][11] Among these metabolites, the active sympathomimetics are 4-hydroxyamphetamine,[178] 4-hydroxynorephedrine,[179] and norephedrine.[180] The main metabolic pathways involve aromatic para-hydroxylation, aliphatic alpha- and beta-hydroxylation, N-oxidation, N-dealkylation, and deamination.[4][181] The known metabolic pathways, detectable metabolites, and metabolizing enzymes in humans include the following:

Metabolic pathways of amphetamine in humans[sources 15]

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 16] Oxidative Deamination FMO3 Oxidation unidentified Glycine Conjugation XM-ligase GLYAT

The primary active metabolites of amphetamine are 4-hydroxyamphetamine and norephedrine;[11] at normal urine pH, about 30–40% of amphetamine is excreted unchanged and roughly 50% is excreted as the inactive metabolites (bottom row).[4] The remaining 10–20% is excreted as the active metabolites.[4] Benzoic acid
Benzoic acid
is metabolized by XM-ligase into an intermediate product, benzoyl-CoA, which is then metabolized by GLYAT into hippuric acid.[183]

Related endogenous compounds Further information on related compounds: Trace amine Amphetamine
Amphetamine
has a very similar structure and function to the endogenous trace amines, which are naturally occurring neurotransmitter molecules produced in the human body and brain.[37][46][187] 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).[37][46][188] In humans, phenethylamine is produced directly from L-phenylalanine
L-phenylalanine
by the aromatic amino acid decarboxylase (AADC) enzyme, which converts L-DOPA
L-DOPA
into dopamine as well.[46][188] In turn, N-methylphenethylamine
N-methylphenethylamine
is metabolized from phenethylamine by phenylethanolamine N-methyltransferase, the same enzyme that metabolizes norepinephrine into epinephrine.[46][188] Like amphetamine, both phenethylamine and N-methylphenethylamine
N-methylphenethylamine
regulate monoamine neurotransmission via TAAR1;[37][187][188] unlike amphetamine, both of these substances are broken down by monoamine oxidase B, and therefore have a shorter half-life than amphetamine.[46][188] Chemistry

Racemic amphetamine

Levoamphetamine Dextroamphetamine

The skeletal structures of L-amph and D-amph

A vial of the colorless amphetamine free base

Amphetamine
Amphetamine
hydrochloride (left bowl) Phenyl-2-nitropropene
Phenyl-2-nitropropene
(right cups)

Amphetamine
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 enantiomeric mirror images.[23] This racemic mixture can be separated into its optical isomers:[note 17] levoamphetamine and dextroamphetamine.[23] 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.[22] Frequently prepared solid salts of amphetamine include amphetamine aspartate,[28] hydrochloride,[189] phosphate,[190] saccharate,[28] and sulfate,[28] the last of which is the most common amphetamine salt.[47] Amphetamine
Amphetamine
is also the parent compound of its own structural class, which includes a number of psychoactive derivatives.[5][23] In organic chemistry, amphetamine is an excellent chiral ligand for the stereoselective synthesis of 1,1'-bi-2-naphthol.[191] 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";[5][48][192] specifically, this chemical class includes derivative compounds that are formed by replacing one or more hydrogen atoms in the amphetamine core structure with substituents.[5][48][193] The class includes amphetamine itself, stimulants like methamphetamine, serotonergic empathogens like MDMA, and decongestants like ephedrine, among other subgroups.[5][48][192] Synthesis Further information on illicit amphetamine synthesis: History and culture of substituted amphetamines § Illegal synthesis Since the first preparation was reported in 1887,[194] numerous synthetic routes to amphetamine have been developed.[195][196] The most common route of both legal and illicit amphetamine synthesis employs a non-metal reduction known as the Leuckart reaction (method 1).[47][197] 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.[197][198] A number of chiral resolutions have been developed to separate the two enantiomers of amphetamine.[195] For example, racemic amphetamine can be treated with d-tartaric acid to form a diastereoisomeric salt which is fractionally crystallized to yield dextroamphetamine.[199] Chiral resolution remains the most economical method for obtaining optically pure amphetamine on a large scale.[200] 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.[200] A large number of alternative synthetic routes to amphetamine have been developed based on classic organic reactions.[195][196] 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).[201] Another example employs the Ritter reaction
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.[202][203] 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).[204] A significant number of amphetamine syntheses feature a reduction of a nitro, imine, oxime or other nitrogen-containing functional groups.[196] In one such example, a Knoevenagel condensation
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).[197][205] 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).[197]

Amphetamine
Amphetamine
synthetic routes

Method 1: Synthesis by the Leuckart reaction 

Top: Chiral resolution
Chiral resolution
of amphetamine  Bottom: Stereoselective synthesis
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
Amphetamine
is frequently measured in urine or blood as part of a drug test for sports, employment, poisoning diagnostics, and forensics.[sources 16] Techniques such as immunoassay, which is the most common form of amphetamine test, may cross-react with a number of sympathomimetic drugs.[209] Chromatographic methods specific for amphetamine are employed to prevent false positive results.[210] 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 18] or illicitly obtained substituted amphetamines.[210][213][214] Several prescription drugs produce amphetamine as a metabolite, including benzphetamine, clobenzorex, famprofazone, fenproporex, lisdexamfetamine, mesocarb, methamphetamine, prenylamine, and selegiline, among others.[3][215][216] These compounds may produce positive results for amphetamine on drug tests.[215][216] Amphetamine
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.[209] 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.[213] Gas chromatography–mass spectrometry
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.[210] 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.[210] 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.[210] History, society, and culture Main article: History and culture of substituted amphetamines

Global estimates of illegal drug users in 2014 (in millions of users)[217]

Substance Best estimate Low estimate High estimate

Amphetamine- type stimulants 35.65 15.34 55.90

Cannabis 182.50 127.54 233.65

Cocaine 18.26 14.88 22.08

Ecstasy 19.40 9.89 29.01

Opiates 17.44 13.74 21.59

Opioids 33.12 28.57 38.52

Amphetamine
Amphetamine
was first synthesized in 1887 in Germany by Romanian chemist Lazăr Edeleanu who named it phenylisopropylamine;[194][218][219] its stimulant effects remained unknown until 1927, when it was independently resynthesized by Gordon Alles and reported to have sympathomimetic properties.[219] Amphetamine
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.[29] 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.[49][29] During World War II, amphetamine and methamphetamine were used extensively by both the Allied and Axis forces for their stimulant and performance-enhancing effects.[194][220][221] As the addictive properties of the drug became known, governments began to place strict controls on the sale of amphetamine.[194] For example, during the early 1970s in the United States, amphetamine became a schedule II controlled substance under the Controlled Substances Act.[222] In spite of strict government controls, amphetamine has been used legally or illicitly by people from a variety of backgrounds, including authors,[223] musicians,[224] mathematicians,[225] and athletes.[27] Amphetamine
Amphetamine
is still illegally synthesized today in clandestine labs and sold on the black market, primarily in European countries.[226] Among European Union (EU) member states, 1.2 million young adults used illicit amphetamine or methamphetamine in 2013.[227] During 2012, approximately 5.9 metric tons of illicit amphetamine were seized within EU member states;[227] the "street price" of illicit amphetamine within the EU ranged from €6–38 per gram during the same period.[227] Outside Europe, the illicit market for amphetamine is much smaller than the market for methamphetamine and MDMA.[226] Legal status As a result of the United Nations
United Nations
1971 Convention on Psychotropic Substances, amphetamine became a schedule II controlled substance, as defined in the treaty, in all 183 state parties.[30] Consequently, it is heavily regulated in most countries.[228][229] Some countries, such as South Korea and Japan, have banned substituted amphetamines even for medical use.[230][231] In other nations, such as Canada (schedule I drug),[232] the Netherlands (List I drug),[233] the United States (schedule II drug),[28] Australia (schedule 8),[234] Thailand (category 1 narcotic),[235] and United Kingdom (class B drug),[236] amphetamine is in a restrictive national drug schedule that allows for its use as a medical treatment.[226][31] Pharmaceutical products Several currently prescribed amphetamine formulations contain both enantiomers, including Adderall, Adderall XR, Mydayis, Adzenys XR-ODT, Dyanavel XR, and Evekeo, the last of which contains racemic amphetamine sulfate.[2][35][90] Amphetamine
Amphetamine
is also prescribed in enantiopure and prodrug form as dextroamphetamine and lisdexamfetamine respectively.[36][177] Lisdexamfetamine
Lisdexamfetamine
is structurally different from amphetamine, and is inactive until it metabolizes into dextroamphetamine.[177] The free base of racemic amphetamine was previously available as Benzedrine, Psychedrine, and Sympatedrine.[3] Levoamphetamine
Levoamphetamine
was previously available as Cydril.[3] Many current amphetamine pharmaceuticals are salts due to the comparatively high volatility of the free base.[3][36][47] However, oral suspension and orally disintegrating tablet (ODT) dosage forms composed of the free base were introduced in 2015 and 2016, respectively.[90][237][238] Some of the current brands and their generic equivalents are listed below.

Amphetamine
Amphetamine
pharmaceuticals

Brand name United States Adopted Name (D:L) ratio Dosage form Marketing start date Sources

Adderall – 3:1 (salts) tablet 1996 [3][36]

Adderall XR – 3:1 (salts) capsule 2001 [3][36]

Mydayis – 3:1 (salts) capsule 2017 [239]

Adzenys XR-ODT amphetamine 3:1 (base) ODT 2016 [238][240]

Dyanavel XR amphetamine 3.2:1 (base) suspension 2015 [90][237]

Evekeo amphetamine sulfate 1:1 (salts) tablet 2012 [35][241]

Dexedrine dextroamphetamine sulfate 1:0 (salts) capsule 1976 [3][36]

ProCentra dextroamphetamine sulfate 1:0 (salts) liquid 2010 [36]

Zenzedi dextroamphetamine sulfate 1:0 (salts) tablet 2013 [36]

Vyvanse lisdexamfetamine dimesylate 1:0 (prodrug) capsule 2007 [3][177]

tablet

 

The skeletal structure of lisdexamfetamine

Amphetamine
Amphetamine
base in marketed amphetamine medications

drug formula molecular mass [note 19] amphetamine base [note 20] amphetamine base in equal doses doses with equal base content [note 21]

(g/mol) (percent) (30 mg dose)

total base total dextro- levo- dextro- levo-

dextroamphetamine sulfate[243][244] (C9H13N)2•H2SO4

368.49

270.41

73.38%

73.38%

22.0 mg

30.0 mg

amphetamine sulfate[245] (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[243][244] (C9H13N)2•H2SO4

368.49

270.41

73.38%

73.38%

25% amphetamine sulfate[245] (C9H13N)2•H2SO4

368.49

270.41

73.38%

36.69%

36.69%

25% dextroamphetamine saccharate[246] (C9H13N)2•C6H10O8

480.55

270.41

56.27%

56.27%

25% amphetamine aspartate monohydrate[247] (C9H13N)•C4H7NO4•H2O

286.32

135.21

47.22%

23.61%

23.61%

lisdexamfetamine dimesylate[177] C15H25N3O•(CH4O3S)2

455.49

135.21

29.68%

29.68%

8.9 mg

74.2 mg

amphetamine base suspension[note 22][90] C9H13N

135.21

135.21

100%

76.19%

23.81%

22.9 mg

7.1 mg

22.0 mg

Notes

^ Synonyms and alternate spellings include: 1-phenylpropan-2-amine (IUPAC name), α-methylphenethylamine, amfetamine (International Nonproprietary Name [INN]), β-phenylisopropylamine, and speed.[18][23][24] ^ Enantiomers are molecules that are mirror images of one another; they are structurally identical, but of the opposite orientation.[25] Levoamphetamine
Levoamphetamine
and dextroamphetamine are also known as L-amph or levamfetamine (INN) and D-amph or dexamfetamine (INN) respectively.[18] ^ "Adderall" is a brand name as opposed to a nonproprietary name; because the latter ("dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine sulfate, and amphetamine aspartate"[36]) is excessively long, this article exclusively refers to this amphetamine mixture by the brand name. ^ The term "amphetamines" also refers to a chemical class, but, unlike the class of substituted amphetamines,[5] the "amphetamines" class does not have a standardized definition in academic literature.[19] One of the more restrictive definitions of this class includes only the racemate and enantiomers of amphetamine and methamphetamine.[19] The most general definition of the class encompasses a broad range of pharmacologically and structurally related compounds.[19] 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).[56]

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).[56]

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.[56] ^ Cochrane Collaboration
Cochrane Collaboration
reviews are high quality meta-analytic systematic reviews of randomized controlled trials.[63] ^ 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.[84] ^ 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.[3] ^ 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.[55][57][89] The average reduction in final adult height from 3 years of continuous stimulant therapy is 2 cm.[89] ^ The 95% confidence interval indicates that there is a 95% probability that the true number of deaths lies between 3,425 and 4,145. ^ Transcription factors are proteins that increase or decrease the expression of specific genes.[125] ^ In simpler terms, this necessary and sufficient relationship means that ΔFosB
ΔFosB
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.[134] ^ The review indicated that magnesium L-aspartate and magnesium chloride produce significant changes in addictive behavior;[102] other forms of magnesium were not mentioned. ^ The human dopamine transporter contains a high affinity extracellular zinc binding site which, upon zinc binding, inhibits dopamine reuptake and amplifies amphetamine-induced dopamine efflux in vitro.[145][146][147] The human serotonin transporter and norepinephrine transporter do not contain zinc binding sites.[147] ^ 4-Hydroxyamphetamine
4-Hydroxyamphetamine
has been shown to be metabolized into 4-hydroxynorephedrine
4-hydroxynorephedrine
by dopamine beta-hydroxylase (DBH) in vitro and it is presumed to be metabolized similarly in vivo.[5][182] Evidence from studies that measured the effect of serum DBH concentrations on 4-hydroxyamphetamine
4-hydroxyamphetamine
metabolism in humans suggests that a different enzyme may mediate the conversion of 4-hydroxyamphetamine
4-hydroxyamphetamine
to 4-hydroxynorephedrine;[182][184] however, other evidence from animal studies suggests that this reaction is catalyzed by DBH in synaptic vesicles within noradrenergic neurons in the brain.[185][186] ^ Enantiomers are molecules that are mirror images of one another; they are structurally identical, but of the opposite orientation.[25] ^ The active ingredient in some OTC inhalers in the United States is listed as levmetamfetamine, the INN and USAN of levomethamphetamine.[211][212] ^ For uniformity, molecular masses were calculated using the Lenntech Molecular Weight Calculator[242] and were within 0.01g/mol of published pharmaceutical values. ^ Amphetamine
Amphetamine
base percentage = molecular massbase / molecular masstotal. Amphetamine
Amphetamine
base percentage for Adderall
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. ^ This product (Dyanavel XR) is an oral suspension (i.e., a drug that is suspended in a liquid and taken by mouth) that contains 2.5 mg/mL of amphetamine base.[90] The product uses an ion exchange resin to achieve extended release of the amphetamine base.[90]

Image legend

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

Reference notes

^ [3][19][26][27][28][29][30][31][32][33][34][35] ^ [3][15][26][29][35][37][38] ^ [15][26][27][28][32][39][40][41][42][43][44][45] ^ [46][47][48] ^ [2][39][40][89][90][91] ^ [92][93][94][95] ^ [85][86][92][94] ^ [32][39][40][96] ^ a b [106][107][108][109][135] ^ [24][28][40][99][111] ^ [103][106][123][126][127] ^ [50][138][141][142] ^ a b [149][153][157][158][159][160][161] ^ [37][149][157][158][162][167] ^ a b [4][5][6][7][8][11][182][183] ^ [27][206][207][208]

References

^ a b Malenka RC, Nestler EJ, Hyman SE, Holtzman DM (2015). "Chapter 16: Reinforcement
Reinforcement
and Addictive Disorders". Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (3rd ed.). New York: McGraw-Hill Medical. ISBN 9780071827706. Pharmacologic treatment for psychostimulant addiction is generally unsatisfactory. As previously discussed, cessation of cocaine use and the use of other psychostimulants in dependent individuals does not produce a physical withdrawal syndrome but may produce dysphoria, anhedonia, and an intense desire to reinitiate drug use.  ^ a b c d e f g h i j Stahl SM (March 2017). " Amphetamine
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". J. Psychopharmacol. 27 (6): 479–496. doi:10.1177/0269881113482532. PMC 3666194 . PMID 23539642. The intravenous use of d-amphetamine and other stimulants still pose major safety risks to the individuals indulging in this practice. Some of this intravenous abuse is derived from the diversion of ampoules of d-amphetamine, which are still occasionally prescribed in the UK for the control of severe narcolepsy and other disorders of excessive sedation. ... For these reasons, observations of dependence and abuse of prescription d-amphetamine are rare in clinical practice, and this stimulant can even be prescribed to people with a history of drug abuse provided certain controls, such as daily pick-ups of prescriptions, are put in place (Jasinski and Krishnan, 2009b).  ^ a b c d e f g h i j k l m n o p q r s t " Adderall
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 e f g h i Glennon RA (2013). "Phenylisopropylamine stimulants: amphetamine-related agents". In Lemke TL, Williams DA, Roche VF, Zito W. Foye's principles of medicinal chemistry (7th ed.). Philadelphia, USA: Wolters Kluwer Health/Lippincott Williams & Wilkins. pp. 646–648. ISBN 9781609133450. The simplest unsubstituted phenylisopropylamine, 1-phenyl-2-aminopropane, or amphetamine, serves as a common structural template for hallucinogens and psychostimulants. Amphetamine
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
Amphetamine
can also undergo aromatic hydroxylation to p-hydroxyamphetamine. ... Subsequent oxidation at the benzylic position by DA β-hydroxylase affords p-hydroxynorephedrine. Alternatively, direct oxidation of amphetamine by DA β-hydroxylase can afford norephedrine.  ^ a b Taylor KB (January 1974). "Dopamine-beta-hydroxylase. Stereochemical course of the reaction" (PDF). J. Biol. Chem. 249 (2): 454–458. PMID 4809526. Retrieved 6 November 2014. Dopamine-β-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". Pharmacol. Ther. 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". J. Pharmacol. Exp. Ther. 288 (3): 1251–1260. PMID 10027866.  ^ a b "Pharmacology". Dextroamphetamine. DrugBank. University of Alberta. 8 February 2013. Retrieved 5 November 2013.  ^ a b c d e "Pharmacology". Amphetamine. DrugBank. University of Alberta. 8 February 2013. Retrieved 5 November 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". J. Pharm. Biomed. Anal. 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. Attention Deficit Hyperactivity Disorder Handbook: A Physician's Guide to ADHD (2nd ed.). New York, USA: Springer. p. 112. ISBN 9781441913968. Table 9.2 Dextroamphetamine
Dextroamphetamine
formulations of stimulant medication Dexedrine [Peak:2–3 h] [Duration:5–6 h] ... Adderall
Adderall
[Peak:2–3 h] [Duration:5–7 h] Dexedrine spansules [Peak:7–8 h] [Duration:12 h] ... Adderall
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". Postgrad. Med. 120 (3): 69–88. doi:10.3810/pgm.2008.09.1909. PMID 18824827.  ^ a b c d " Adderall
Adderall
IR Prescribing Information" (PDF). United States Food and Drug Administration. Teva Pharmaceuticals USA, Inc. October 2015. pp. 1–6. Retrieved 18 May 2016.  ^ 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
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
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 "Compound Summary". Amphetamine. PubChem Compound. United States National Library of Medicine – National Center for Biotechnology Information. 11 April 2015. Retrieved 17 April 2015.  ^ a b c d e Yoshida T (1997). "Chapter 1: Use and Misuse of Amphetamines: An International Overview". In Klee H. Amphetamine Misuse: International Perspectives on Current Trends. Amsterdam, Netherlands: Harwood Academic Publishers. p. 2. ISBN 9789057020810. Retrieved 1 December 2014. 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. United States National Library of Medicine – National Center for Biotechnology Information. 5 November 2016. Retrieved 9 November 2016.  ^ "Properties: Predicted – EPISuite". Amphetamine. ChemSpider. Royal Society of Chemistry. Retrieved 6 November 2013.  ^ a b "Chemical and Physical Properties". Amphetamine. PubChem Compound. United States National Library of Medicine – National Center for Biotechnology Information. Retrieved 13 October 2013.  ^ a b c d "Identification". Amphetamine. DrugBank. University of Alberta. 8 February 2013. Retrieved 13 October 2013.  ^ a b Greene SL, Kerr F, Braitberg G (October 2008). "Review article: amphetamines and related drugs of abuse". Emerg. Med. Australas. 20 (5): 391–402. doi:10.1111/j.1742-6723.2008.01114.x. PMID 18973636.  ^ a b "Enantiomer". IUPAC Goldbook. International Union of Pure and Applied Chemistry. doi:10.1351/goldbook.E02069. 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. 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". Prim. Care. 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 " Adderall
Adderall
XR Prescribing Information" (PDF). United States Food and Drug Administration. Shire US Inc. December 2013. p. 11. Retrieved 30 December 2013.  ^ a b c d Rasmussen N (July 2006). "Making the first anti-depressant: amphetamine in American medicine, 1929–1950". J. Hist. Med. Allied Sci. 61 (3): 288–323. doi:10.1093/jhmas/jrj039. PMID 16492800. 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
Inhaler
as a decongestant in late 1933.  ^ a b "Convention on psychotropic substances". United Nations
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". J. Am. Acad. Child Adolesc. Psychiatry. 47 (1): 21–31. doi:10.1097/chi.0b013e31815a56f1. PMID 18174822. Stimulant
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 (Edgmont). 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. 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 Prescribing Information" (PDF). Arbor Pharmaceuticals LLC. April 2014. pp. 1–2. Retrieved 11 August 2015.  ^ a b c d e f g h i "National Drug Code Amphetamine
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 ae Miller GM (January 2011). "The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity". J. Neurochem. 116 (2): 164–176. 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 Alcohol Depend. 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 " Adderall
Adderall
XR Prescribing Information" (PDF). United States Food and Drug Administration. Shire US Inc. December 2013. pp. 4–8. Retrieved 30 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 Westfall DP, Westfall TC (2010). "Miscellaneous Sympathomimetic
Sympathomimetic
Agonists". In Brunton LL, Chabner BA, Knollmann BC. Goodman & 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 Syst. Rev. (1): CD003026. doi:10.1002/14651858.CD003026.pub3. 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.  ^ a b c Greydanus D. " Stimulant
Stimulant
Misuse: Strategies to Manage a Growing Problem" (PDF). American College Health Association (Review Article). ACHA Professional Development Program. p. 20. Archived from the original (PDF) on 3 November 2013. Retrieved 2 November 2013.  ^ a b Malenka RC, Nestler EJ, Hyman SE, Holtzman DM (2015). "Chapter 16: Reinforcement
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". Curr. Med. Res. Opin. 24 (5): 1345–1357. doi:10.1185/030079908X280707. PMID 18384709. 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 Stolerman IP (2010). Stolerman IP, ed. Encyclopedia of Psychopharmacology. Berlin, Germany; London, England: Springer. p. 78. ISBN 9783540686989.  ^ a b c d e f g Broadley KJ (March 2010). "The vascular effects of trace amines and amphetamines". Pharmacol. Ther. 125 (3): 363–375. doi:10.1016/j.pharmthera.2009.11.005. PMID 19948186.  ^ 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 Plant Sci. 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 α-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". Postgrad. Med. J. 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, Remião F, Carvalho F, Bastos Mde L (August 2012). "Toxicity of amphetamines: an update". Arch. Toxicol. 86 (8): 1167–1231. doi:10.1007/s00204-012-0815-5. PMID 22392347.  ^ Berman S, O'Neill J, Fears S, Bartzokis G, London ED (October 2008). "Abuse of amphetamines and structural abnormalities in the brain". Ann. N. Y. Acad. Sci. 1141: 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
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". J. Clin. Psychiatry. 74 (9): 902–917. doi:10.4088/JCP.12r08287. PMC 3801446 . PMID 24107764.  ^ a b Frodl T, Skokauskas N (February 2012). " Meta-analysis
Meta-analysis
of structural MRI studies in children and adults with attention deficit hyperactivity disorder indicates treatment effects". Acta psychiatrica Scand. 125 (2): 114–126. doi:10.1111/j.1600-0447.2011.01786.x. PMID 22118249. Basal ganglia
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. 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 d e 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. 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. ... In the longest follow-up study (of more than 10 years), lifetime stimulant treatment for ADHD was effective and protective against the development of adverse psychiatric disorders.  ^ a b c Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York, USA: McGraw-Hill Medical. pp. 154–157. ISBN 9780071481274.  ^ a b c d e Bidwell LC, McClernon FJ, Kollins SH (August 2011). "Cognitive enhancers for the treatment of ADHD". Pharmacol. Biochem. Behav. 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". Psychol. Res. Behav. Manag. 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. Attention Deficit Hyperactivity Disorder Handbook: A Physician's Guide to ADHD (2nd ed.). New York, USA: Springer. pp. 111–113. ISBN 9781441913968.  ^ " Stimulants
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". Eur. J. Clin. Nutr. 59 Suppl 1: S147–S149; discussion S195–S196. doi:10.1038/sj.ejcn.1602188. PMID 16052183.  ^ a b Castells X, Ramos-Quiroga JA, Bosch R, Nogueira M, Casas M (June 2011). Castells X, ed. "Amphetamines for Attention Deficit Hyperactivity Disorder (ADHD) in adults". Cochrane Database Syst. Rev. (6): CD007813. doi:10.1002/14651858.CD007813.pub2. PMID 21678370.  ^ 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 Syst. Rev. 2: CD009996. doi:10.1002/14651858.CD009996.pub2. PMID 26844979.  ^ Pringsheim T, Steeves T (April 2011). Pringsheim T, ed. "Pharmacological treatment for Attention Deficit Hyperactivity Disorder (ADHD) in children with comorbid tic disorders". Cochrane Database Syst. Rev. (4): CD007990. doi:10.1002/14651858.CD007990.pub2. PMID 21491404.  ^ a b Spencer RC, Devilbiss DM, Berridge CW (June 2015). "The Cognition-Enhancing Effects of Psychostimulants Involve Direct Action in the Prefrontal Cortex". Biol. Psychiatry. 77 (11): 940–950. doi:10.1016/j.biopsych.2014.09.013. PMC 4377121 . PMID 25499957. The procognitive actions of psychostimulants are only associated with low doses. Surprisingly, despite nearly 80 years of clinical use, the neurobiology of the procognitive actions of psychostimulants has only recently been systematically investigated. Findings from this research unambiguously demonstrate that the cognition-enhancing effects of psychostimulants involve the preferential elevation of catecholamines in the PFC and the subsequent activation of norepinephrine α2 and dopamine D1 receptors. ... This differential modulation of PFC-dependent processes across dose appears to be associated with the differential involvement of noradrenergic α2 versus α1 receptors. Collectively, this evidence indicates that at low, clinically relevant doses, psychostimulants are devoid of the behavioral and neurochemical actions that define this class of drugs and instead act largely as cognitive enhancers (improving PFC-dependent function). ... In particular, in both animals and humans, lower doses maximally improve performance in tests of working memory and response inhibition, whereas maximal suppression of overt behavior and facilitation of attentional processes occurs at higher doses.  ^ Ilieva IP, Hook CJ, Farah MJ (June 2015). "Prescription Stimulants' Effects on Healthy Inhibitory Control, Working Memory, and Episodic Memory: A Meta-analysis". J. Cogn. Neurosci. 27 (6): 1–21. doi:10.1162/jocn_a_00776. PMID 25591060. 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
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". J. Nucl. Med. 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. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York, USA: McGraw-Hill Medical. p. 266. ISBN 9780071481274. Dopamine
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". Pharmacol. Rev. 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". Psychol. Res. Behav. Manag. 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". Postgrad. Med. 126 (5): 64–81. doi:10.3810/pgm.2014.09.2801. PMID 25295651. 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. Retrieved 8 October 2013.  ^ Docherty JR (June 2008). "Pharmacology of stimulants prohibited by the World Anti-Doping Agency (WADA)". Br. J. Pharmacol. 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". Clin. Sports Med. 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 Med. 43 (5): 301–311. doi:10.1007/s40279-013-0030-4. PMID 23456493. 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". Front. Integr. Neurosci. 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?". Front. Physiol. 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
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". Scand. J. Med. Sci. Sports. 25 Suppl 1: 65–78. doi:10.1111/sms.12350. PMID 25943657. 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". South. Med. J. 89 (1): 33–38. doi:10.1097/00007611-199601000-00005. PMID 8545689. 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 " Adderall
Adderall
XR Prescribing Information" (PDF). United States Food and Drug Administration. Shire US Inc. December 2013. pp. 4–6. Retrieved 30 December 2013.  ^ a b c d e f g h i j k Heedes G, Ailakis J. " Amphetamine
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". J. Clin. 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?". J. Affect. Disord. 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 Adolesc. Psychiatr. Clin. N. Am. 17 (2): 459–474. doi:10.1016/j.chc.2007.11.010. PMC 2408826 . PMID 18295156.  ^ a b c d e f g h "Dyanavel XR Prescribing Information" (PDF). United States Food and Drug Administration. Tris Pharma, Inc. May 2017. pp. 1–14. Retrieved 4 August 2017. 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 6–12 years) were: epistaxis, allergic rhinitis and upper abdominal pain. ... DOSAGE FORMS AND STRENGTHS Extended-release oral suspension contains 2.5 mg amphetamine base per mL.  ^ Ramey JT, Bailen E, Lockey RF (2006). "Rhinitis medicamentosa" (PDF). J. Investig. Allergol. Clin. Immunol. 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. 20 December 2011. Retrieved 4 November 2013.  ^ 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". N. Engl. J. Med. 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. 15 December 2011. Retrieved 4 November 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". Biol. 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
Reinforcement
and Addictive Disorders". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 364–375. ISBN 9780071481274.  ^ a b Spiller HA, Hays HL, Aleguas A (June 2013). "Overdose of drugs for attention-deficit hyperactivity disorder: clinical presentation, mechanisms of toxicity, and management". CNS Drugs. 27 (7): 531–543. doi:10.1007/s40263-013-0084-8. PMID 23757186. Amphetamine, dextroamphetamine, and methylphenidate act as substrates for the cellular monoamine transporter, especially the dopamine transporter (DAT) and less so the norepinephrine (NET) and serotonin transporter. The mechanism of toxicity is primarily related to excessive extracellular dopamine, norepinephrine, and serotonin.  ^ Collaborators (2015). "Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013" (PDF). Lancet. 385 (9963): 117–171. doi:10.1016/S0140-6736(14)61682-2. PMC 4340604 . PMID 25530442. Retrieved 3 March 2015. Amphetamine
Amphetamine
use disorders ... 3,788 (3,425–4,145)  ^ Kanehisa Laboratories (10 October 2014). " Amphetamine
Amphetamine
– Homo sapiens (human)". KEGG
KEGG
Pathway. Retrieved 31 October 2014.  ^ a b c d e f Nechifor M (March 2008). " Magnesium
Magnesium
in drug dependences". Magnes. Res. 21 (1): 5–15. PMID 18557129.  ^ a b c d e Ruffle JK (November 2014). "Molecular neurobiology of addiction: what's all the (Δ)FosB about?". Am. J. Drug Alcohol Abuse. 40 (6): 428–437. doi:10.3109/00952990.2014.933840. PMID 25083822. ΔFosB
ΔFosB
is an essential transcription factor implicated in the molecular and behavioral pathways of addiction following repeated drug exposure.  ^ a b c d e Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues Clin. Neurosci. 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
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
ΔFosB
target is cFos: as ΔFosB
ΔFosB
accumulates with repeated drug exposure it represses c-Fos and contributes to the molecular switch whereby ΔFosB
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.  ^ Robison AJ, Nestler EJ (November 2011). " Transcriptional
Transcriptional
and epigenetic mechanisms of addiction". Nat. Rev. Neurosci. 12 (11): 623–637. doi:10.1038/nrn3111. PMC 3272277 . PMID 21989194. ΔFosB
ΔFosB
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". Neurosci. Biobehav. Rev. 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". Front. Neuroendocrinol. 40: 24–41. doi:10.1016/j.yfrne.2015.07.001. PMC 4712120 . PMID 26182835. Collectively, these findings demonstrate that exercise may serve as a substitute or competition for drug abuse by changing ΔFosB
ΔFosB
or cFos immunoreactivity in the reward system to protect against later or previous drug use. ... The postulate that exercise serves as an ideal intervention for drug addiction has been widely recognized and used in human and animal rehabilitation.  ^ a b c Linke SE, Ussher M (January 2015). "Exercise-based treatments for substance use disorders: evidence, theory, and practicality". Am. J. Drug 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.  ^ a b Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement
Reinforcement
and Addictive Disorders". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York, USA: McGraw-Hill Medical. p. 386. ISBN 9780071481274. Currently, cognitive–behavioral therapies are the most successful treatment available for preventing the relapse of psychostimulant use.  ^ Albertson TE (2011). "Amphetamines". In Olson KR, Anderson IB, Benowitz NL, Blanc PD, Kearney TE, Kim-Katz SY, Wu AH. Poisoning & Drug Overdose (6th ed.). New York: McGraw-Hill Medical. pp. 77–79. ISBN 9780071668330.  ^ "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". N. Engl. J. Med. 374 (4): 363–371. doi:10.1056/NEJMra1511480. 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 Clin. Neurosci. 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
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 ^ Broussard JI (January 2012). "Co-transmission of dopamine and glutamate". J. Gen. Physiol. 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
Amphetamine
– Homo sapiens (human)". KEGG
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
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
Transcriptional
and epigenetic mechanisms of addiction". Nat. Rev. Neurosci. 12 (11): 623–637. doi:10.1038/nrn3111. PMC 3272277 . PMID 21989194. ΔFosB
ΔFosB
serves as one of the master control proteins governing this structural plasticity. ... ΔFosB
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
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
Epigenetic
basis of drug regulation of gene expression ^ a b c Nestler EJ (December 2012). " Transcriptional
Transcriptional
mechanisms of drug addiction". Clin. Psychopharmacol. Neurosci. 10 (3): 136–143. doi:10.9758/cpn.2012.10.3.136. PMC 3569166 . PMID 23430970. The 35-37 kD ΔFosB
ΔFosB
isoforms accumulate with chronic drug exposure due to their extraordinarily long half-lives. ... As a result of its stability, the ΔFosB
ΔFosB
protein persists in neurons for at least several weeks after cessation of drug exposure. ... ΔFosB
ΔFosB
overexpression in nucleus accumbens induces NFκB ... In contrast, the ability of ΔFosB
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  ^ Nestler EJ (October 2008). "Review. Transcriptional
Transcriptional
mechanisms of addiction: role of DeltaFosB". Philos. Trans. R. Soc. Lond., B, Biol. Sci. 363 (1507): 3245–3255. doi:10.1098/rstb.2008.0067. PMC 2607320 . PMID 18640924. Recent evidence has shown that ΔFosB
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
ΔFosB
after chronic drug exposure  ^ a b Perez-Mana C, Castells X, Torrens M, Capella D, Farre M (September 2013). "Efficacy of psychostimulant drugs for amphetamine abuse or dependence". Cochrane Database Syst. Rev. 9 (9): CD009695. doi:10.1002/14651858.CD009695.pub2. PMID 23996457. To date, no pharmacological treatment has been approved for [addiction], and psychotherapy remains the mainstay of treatment. ... Results of this review do not support the use of psychostimulant medications at the tested doses as a replacement therapy  ^ "Amphetamines: Drug Use and Abuse". Merck Manual Home Edition. Merck. February 2003. Archived from the original on 17 February 2007. Retrieved 28 February 2007.  ^ Hyman SE, Malenka RC, Nestler EJ (July 2006). "Neural mechanisms of addiction: the role of reward-related learning and memory". Annu. Rev. Neurosci. 29: 565–598. doi:10.1146/annurev.neuro.29.051605.113009. PMID 16776597.  ^ a b c d e f g h Robison AJ, Nestler EJ (November 2011). " Transcriptional
Transcriptional
and epigenetic mechanisms of addiction". Nat. Rev. Neurosci. 12 (11): 623–637. doi:10.1038/nrn3111. PMC 3272277 . PMID 21989194.  ^ 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". Prog. Neurobiol. 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. 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
Alcoholism
– Homo sapiens (human)". KEGG
KEGG
Pathway. Retrieved 31 October 2014.  ^ Kim Y, Teylan MA, Baron M, Sands A, Nairn AC, Greengard P (February 2009). "Methylphenidate-induced dendritic spine formation and DeltaFosB expression in nucleus accumbens". Proc. Natl. Acad. Sci. U.S.A. 106 (8): 2915–2920. doi:10.1073/pnas.0813179106. PMC 2650365 . PMID 19202072.  ^ Nestler EJ (January 2014). " Epigenetic
Epigenetic
mechanisms of drug addiction". Neuropharmacology. 76 Pt B: 259–268. doi:10.1016/j.neuropharm.2013.04.004. PMC 3766384 . PMID 23643695.  ^ a b Blum K, Werner T, Carnes S, Carnes P, Bowirrat A, Giordano J, Oscar-Berman M, Gold M (March 2012). "Sex, drugs, and rock 'n' roll: hypothesizing common mesolimbic activation as a function of reward gene polymorphisms". J. Psychoactive Drugs. 44 (1): 38–55. doi:10.1080/02791072.2012.662112. PMC 4040958 . PMID 22641964.  ^ Pitchers KK, Vialou V, Nestler EJ, Laviolette SR, Lehman MN, Coolen LM (February 2013). "Natural and drug rewards act on common neural plasticity mechanisms with ΔFosB
ΔFosB
as a key mediator". J. Neurosci. 33 (8): 3434–3442. doi:10.1523/JNEUROSCI.4881-12.2013. PMC 3865508 . PMID 23426671.  ^ Beloate LN, Weems PW, Casey GR, Webb IC, Coolen LM (February 2016). " Nucleus accumbens
Nucleus accumbens
NMDA receptor
NMDA receptor
activation regulates amphetamine cross-sensitization and deltaFosB expression following sexual experience in male rats". Neuropharmacology. 101: 154–164. doi:10.1016/j.neuropharm.2015.09.023. PMID 26391065.  ^ Stoops WW, Rush CR (May 2014). "Combination pharmacotherapies for stimulant use disorder: a review of clinical findings and recommendations for future research". Expert Rev. Clin. Pharmacol. 7 (3): 363–374. doi:10.1586/17512433.2014.909283. PMC 4017926 . PMID 24716825. Despite concerted efforts to identify a pharmacotherapy for managing stimulant use disorders, no widely effective medications have been approved.  ^ a b Jing L, Li JX (August 2015). " Trace amine-associated receptor 1: A promising target for the treatment of psychostimulant addiction". Eur. J. Pharmacol. 761: 345–352. doi:10.1016/j.ejphar.2015.06.019. PMC 4532615 . PMID 26092759. Existing data provided robust preclinical evidence supporting the development of TAAR1
TAAR1
agonists as potential treatment for psychostimulant abuse and addiction.  ^ a b Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 5: Excitatory and Inhibitory Amino Acids". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York, USA: McGraw-Hill Medical. pp. 124–125. ISBN 9780071481274.  ^ a b c Carroll ME, Smethells JR (February 2016). "Sex Differences in Behavioral Dyscontrol: Role in Drug Addiction
Addiction
and Novel Treatments". Front. Psychiatry. 6: 175. doi:10.3389/fpsyt.2015.00175. PMC 4745113 . PMID 26903885. Physical Exercise There is accelerating evidence that physical exercise is a useful treatment for preventing and reducing drug addiction ... In some individuals, exercise has its own rewarding effects, and a behavioral economic interaction may occur, such that physical and social rewards of exercise can substitute for the rewarding effects of drug abuse. ... The value of this form of treatment for drug addiction in laboratory animals and humans is that exercise, if it can substitute for the rewarding effects of drugs, could be self-maintained over an extended period of time. Work to date in [laboratory animals and humans] regarding exercise as a treatment for drug addiction supports this hypothesis. ... Animal and human research on physical exercise as a treatment for stimulant addiction indicates that this is one of the most promising treatments on the horizon.  ^ a b c d Shoptaw SJ, Kao U, Heinzerling K, Ling W (April 2009). Shoptaw SJ, ed. "Treatment for amphetamine withdrawal". Cochrane Database Syst. Rev. (2): CD003021. doi:10.1002/14651858.CD003021.pub2. PMID 19370579.  ^ Advokat C (July 2007). "Update on amphetamine neurotoxicity and its relevance to the treatment of ADHD". J. Atten. Disord. 11 (1): 8–16. doi:10.1177/1087054706295605. PMID 17606768.  ^ a b c d Bowyer JF, Hanig JP (November 2014). "Amphetamine- and methamphetamine-induced hyperthermia: Implications of the effects produced in brain vasculature and peripheral organs to forebrain neurotoxicity". Temperature (Austin). 1 (3): 172–182. doi:10.4161/23328940.2014.982049. PMC 5008711 . PMID 27626044. Hyperthermia
Hyperthermia
alone does not produce amphetamine-like neurotoxicity but AMPH and METH exposures that do not produce hyperthermia (≥40°C) are minimally neurotoxic. Hyperthermia likely enhances AMPH and METH neurotoxicity directly through disruption of protein function, ion channels and enhanced ROS production. ... The hyperthermia and the hypertension produced by high doses amphetamines are a primary cause of transient breakdowns in the blood-brain barrier (BBB) resulting in concomitant regional neurodegeneration and neuroinflammation in laboratory animals. ... In animal models that evaluate the neurotoxicity of AMPH and METH, it is quite clear that hyperthermia is one of the essential components necessary for the production of histological signs of dopamine terminal damage and neurodegeneration in cortex, striatum, thalamus and hippocampus.  ^ "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. Direct toxic damage to vessels seems unlikely because of the dilution that occurs before the drug reaches the cerebral circulation.  ^ Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and addictive disorders". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York, USA: McGraw-Hill Medical. p. 370. ISBN 9780071481274. Unlike cocaine and amphetamine, methamphetamine is directly toxic to midbrain dopamine neurons.  ^ Sulzer D, Zecca L (February 2000). "Intraneuronal dopamine-quinone synthesis: a review". Neurotox. Res. 1 (3): 181–195. doi:10.1007/BF03033289. PMID 12835101.  ^ Miyazaki I, Asanuma M (June 2008). "Dopaminergic neuron-specific oxidative stress caused by dopamine itself" (PDF). Acta Med. Okayama. 62 (3): 141–150. doi:10.18926/AMO/30942. PMID 18596830.  ^ Hofmann FG (1983). A Handbook on Drug and Alcohol Abuse: The Biomedical Aspects (2nd ed.). New York, USA: Oxford University Press. p. 329. ISBN 9780195030570.  ^ a b c d e f g h i j k " Adderall
Adderall
XR Prescribing Information" (PDF). United States Food and Drug Administration. Shire US Inc. December 2013. pp. 8–10. Retrieved 30 December 2013.  ^ Krause J (April 2008). "SPECT and PET of the dopamine transporter in attention-deficit/hyperactivity disorder". Expert Rev. Neurother. 8 (4): 611–625. doi:10.1586/14737175.8.4.611. PMID 18416663. Zinc binds at ... extracellular sites of the DAT [103], serving as a DAT inhibitor. In this context, controlled double-blind studies in children are of interest, which showed positive effects of zinc [supplementation] on symptoms of ADHD [105,106]. It should be stated that at this time [supplementation] with zinc is not integrated in any ADHD treatment algorithm.  ^ Sulzer D (February 2011). "How addictive drugs disrupt presynaptic dopamine neurotransmission". Neuron. 69 (4): 628–649. doi:10.1016/j.neuron.2011.02.010. PMC 3065181 . PMID 21338876. They did not confirm the predicted straightforward relationship between uptake and release, but rather that some compounds including AMPH were better releasers than substrates for uptake. Zinc, moreover, stimulates efflux of intracellular [3H]DA despite its concomitant inhibition of uptake (Scholze et al., 2002).  ^ a b Scholze P, Nørregaard L, Singer EA, Freissmuth M, Gether U, Sitte HH (June 2002). "The role of zinc ions in reverse transport mediated by monoamine transporters". J. Biol. Chem. 277 (24): 21505–21513. doi:10.1074/jbc.M112265200. PMID 11940571. The human dopamine transporter (hDAT) contains an endogenous high affinity Zn2+ binding site with three coordinating residues on its extracellular face (His193, His375, and Glu396). ... Although Zn2+ inhibited uptake, Zn2+ facilitated [3H]MPP+ release induced by amphetamine, MPP+, or K+-induced depolarization specifically at hDAT but not at the human serotonin and the norepinephrine transporter (hNET).  ^ Scassellati C, Bonvicini C, Faraone SV, Gennarelli M (October 2012). "Biomarkers and attention-deficit/hyperactivity disorder: a systematic review and meta-analyses". J. Am. Acad. Child Adolesc. Psychiatry. 51 (10): 1003–1019.e20. doi:10.1016/j.jaac.2012.08.015. PMID 23021477. With regard to zinc supplementation, a placebo controlled trial reported that doses up to 30 mg/day of zinc were safe for at least 8 weeks, but the clinical effect was equivocal except for the finding of a 37% reduction in amphetamine optimal dose with 30 mg per day of zinc.110  ^ a b c d e f g h i j k l m n Eiden LE, Weihe E (January 2011). "VMAT2: a dynamic regulator of brain monoaminergic neuronal function interacting with drugs of abuse". Ann. N. Y. Acad. Sci. 1216: 86–98. doi:10.1111/j.1749-6632.2010.05906.x. PMC 4183197 . PMID 21272013. VMAT2
VMAT2
is the CNS vesicular transporter for not only the biogenic amines DA, NE, EPI, 5-HT, and HIS, but likely also for the trace amines TYR, PEA, and thyronamine (THYR) ... [Trace aminergic] neurons in mammalian CNS would be identifiable as neurons expressing VMAT2
VMAT2
for storage, and the biosynthetic enzyme aromatic amino acid decarboxylase (AADC). ... AMPH release of DA from synapses requires both an action at VMAT2
VMAT2
to release DA to the cytoplasm and a concerted release of DA from the cytoplasm via "reverse transport" through DAT.  ^ a b c d Sulzer D, Cragg SJ, Rice ME (August 2016). "Striatal dopamine neurotransmission: regulation of release and uptake". Basal Ganglia. 6 (3): 123–148. doi:10.1016/j.baga.2016.02.001. PMC 4850498 . PMID 27141430. Despite the challenges in determining synaptic vesicle pH, the proton gradient across the vesicle membrane is of fundamental importance for its function. Exposure of isolated catecholamine vesicles to protonophores collapses the pH gradient and rapidly redistributes transmitter from inside to outside the vesicle. ... Amphetamine
Amphetamine
and its derivatives like methamphetamine are weak base compounds that are the only widely used class of drugs known to elicit transmitter release by a non-exocytic mechanism. As substrates for both DAT and VMAT, amphetamines can be taken up to the cytosol and then sequestered in vesicles, where they act to collapse the vesicular pH gradient.  ^ a b Ledonne A, Berretta N, Davoli A, Rizzo GR, Bernardi G, Mercuri NB (July 2011). "Electrophysiological effects of trace amines on mesencephalic dopaminergic neurons". Front. Syst. Neurosci. 5: 56. doi:10.3389/fnsys.2011.00056. PMC 3131148 . PMID 21772817. Three important new aspects of TAs action have recently emerged: (a) inhibition of firing due to increased release of dopamine; (b) reduction of D2 and GABAB receptor-mediated inhibitory responses (excitatory effects due to disinhibition); and (c) a direct TA1 receptor-mediated activation of GIRK channels which produce cell membrane hyperpolarization.  ^ a b "TAAR1". GenAtlas. University of Paris. 28 January 2012. Retrieved 29 May 2014.  • tonically activates inwardly rectifying K(+) channels, which reduces the basal firing frequency of dopamine (DA) neurons of the ventral tegmental area (VTA)  ^ a b c d e f Underhill SM, Wheeler DS, Li M, Watts SD, Ingram SL, Amara SG (July 2014). " Amphetamine
Amphetamine
modulates excitatory neurotransmission through endocytosis of the glutamate transporter EAAT3 in dopamine neurons". Neuron. 83 (2): 404–416. doi:10.1016/j.neuron.2014.05.043. PMC 4159050 . PMID 25033183. AMPH also increases intracellular calcium (Gnegy et al., 2004) that is associated with calmodulin/CamKII activation (Wei et al., 2007) and modulation and trafficking of the DAT (Fog et al., 2006; Sakrikar et al., 2012). ... For example, AMPH increases extracellular glutamate in various brain regions including the striatum, VTA and NAc (Del Arco et al., 1999; Kim et al., 1981; Mora and Porras, 1993; Xue et al., 1996), but it has not been established whether this change can be explained by increased synaptic release or by reduced clearance of glutamate. ... DHK-sensitive, EAAT2 uptake was not altered by AMPH (Figure 1A). The remaining glutamate transport in these midbrain cultures is likely mediated by EAAT3 and this component was significantly decreased by AMPH  ^ a b Vaughan RA, Foster JD (September 2013). "Mechanisms of dopamine transporter regulation in normal and disease states". Trends Pharmacol. Sci. 34 (9): 489–496. doi:10.1016/j.tips.2013.07.005. PMC 3831354 . PMID 23968642. AMPH and METH also stimulate DA efflux, which is thought to be a crucial element in their addictive properties [80], although the mechanisms do not appear to be identical for each drug [81]. These processes are PKCβ– and CaMK–dependent [72, 82], and PKCβ knock-out mice display decreased AMPH-induced efflux that correlates with reduced AMPH-induced locomotion [72].  ^ a b Maguire JJ, Davenport AP (2 December 2014). "TA1 receptor". IUPHAR database. International Union of Basic and Clinical Pharmacology. Retrieved 8 December 2014.  ^ Borowsky B, Adham N, Jones KA, Raddatz R, Artymyshyn R, Ogozalek KL, Durkin MM, Lakhlani PP, Bonini JA, Pathirana S, Boyle N, Pu X, Kouranova E, Lichtblau H, Ochoa FY, Branchek TA, Gerald C (July 2001). "Trace amines: identification of a family of mammalian G protein-coupled receptors". Proc. Natl. Acad. Sci. U.S.A. 98 (16): 8966–8971. doi:10.1073/pnas.151105198. PMC 55357 . PMID 11459929.  ^ a b "SLC18 family of vesicular amine transporters". IUPHAR database. International Union of Basic and Clinical Pharmacology. Retrieved 13 November 2015.  ^ a b c d " SLC1A1
SLC1A1
solute carrier family 1 (neuronal/epithelial high affinity glutamate transporter, system Xag), member 1 [ Homo sapiens (human) ]". NCBI Gene. United States National Library of Medicine – National Center for Biotechnology Information. Retrieved 11 November 2014. Amphetamine
Amphetamine
modulates excitatory neurotransmission through endocytosis of the glutamate transporter EAAT3 in dopamine neurons. ... internalization of EAAT3 triggered by amphetamine increases glutamatergic signaling and thus contributes to the effects of amphetamine on neurotransmission.  ^ Zhu HJ, Appel DI, Gründemann D, Markowitz JS (July 2010). "Interaction of organic cation transporter 3 (SLC22A3) and amphetamine". J. Neurochem. 114 (1): 142–149. doi:10.1111/j.1471-4159.2010.06738.x. PMC 3775896 . PMID 20402963.  ^ Rytting E, Audus KL (January 2005). "Novel organic cation transporter 2-mediated carnitine uptake in placental choriocarcinoma (BeWo) cells". J. Pharmacol. Exp. Ther. 312 (1): 192–198. doi:10.1124/jpet.104.072363. PMID 15316089.  ^ Inazu M, Takeda H, Matsumiya T (August 2003). "[The role of glial monoamine transporters in the central nervous system]". Nihon Shinkei Seishin Yakurigaku Zasshi (in Japanese). 23 (4): 171–178. PMID 13677912.  ^ a b c Vicentic A, Jones DC (February 2007). "The CART (cocaine- and amphetamine-regulated transcript) system in appetite and drug addiction". J. Pharmacol. Exp. Ther. 320 (2): 499–506. doi:10.1124/jpet.105.091512. PMID 16840648. The physiological importance of CART was further substantiated in numerous human studies demonstrating a role of CART in both feeding and psychostimulant addiction. ... Colocalization studies also support a role for CART in the actions of psychostimulants. ... CART and DA receptor transcripts colocalize (Beaudry et al., 2004). Second, dopaminergic nerve terminals in the NAc synapse on CART-containing neurons (Koylu et al., 1999), hence providing the proximity required for neurotransmitter signaling. These studies suggest that DA plays a role in regulating CART gene expression possibly via the activation of CREB.  ^ Zhang M, Han L, Xu Y (June 2012). "Roles of cocaine- and amphetamine-regulated transcript in the central nervous system". Clin. Exp. Pharmacol. Physiol. 39 (6): 586–592. doi:10.1111/j.1440-1681.2011.05642.x. PMID 22077697. Recently, it was demonstrated that CART, as a neurotrophic peptide, had a cerebroprotective against focal ischaemic stroke and inhibited the neurotoxicity of β-amyloid protein, which focused attention on the role of CART in the central nervous system (CNS) and neurological diseases. ... The literature indicates that there are many factors, such as regulation of the immunological system and protection against energy failure, that may be involved in the cerebroprotection afforded by CART  ^ a b Rogge G, Jones D, Hubert GW, Lin Y, Kuhar MJ (October 2008). "CART peptides: regulators of body weight, reward and other functions". Nat. Rev. Neurosci. 9 (10): 747–758. doi:10.1038/nrn2493. PMC 4418456 . PMID 18802445. Several studies on CART (cocaine- and amphetamine-regulated transcript)-peptide-induced cell signalling have demonstrated that CART peptides activate at least three signalling mechanisms. First, CART 55–102 inhibited voltage-gated L-type Ca2+ channels ...  ^ Lin Y, Hall RA, Kuhar MJ (October 2011). "CART peptide stimulation of G protein-mediated signaling in differentiated PC12 cells: identification of PACAP 6–38 as a CART receptor antagonist". Neuropeptides. 45 (5): 351–358. doi:10.1016/j.npep.2011.07.006. PMC 3170513 . PMID 21855138.  ^ " Monoamine oxidase
Monoamine oxidase
(Homo sapiens)". BRENDA. Technische Universität Braunschweig. 1 January 2014. Retrieved 4 May 2014.  ^ a b c "Targets". Amphetamine. T3DB. University of Alberta. Retrieved 24 February 2015.  ^ a b Toll L, Berzetei-Gurske IP, Polgar WE, Brandt SR, Adapa ID, Rodriguez L, Schwartz RW, Haggart D, O'Brien A, White A, Kennedy JM, Craymer K, Farrington L, Auh JS (March 1998). "Standard binding and functional assays related to medications development division testing for potential cocaine and opiate narcotic treatment medications". NIDA Res. Monogr. 178: 440–466. PMID 9686407.  ^ a b Finnema SJ, Scheinin M, Shahid M, Lehto J, Borroni E, Bang-Andersen B, Sallinen J, Wong E, Farde L, Halldin C, Grimwood S (November 2015). "Application of cross-species PET imaging to assess neurotransmitter release in brain". Psychopharmacology. 232 (21–22): 4129–4157. doi:10.1007/s00213-015-3938-6. PMC 4600473 . PMID 25921033. More recently, Colasanti and colleagues reported that a pharmacologically induced elevation in endogenous opioid release reduced [11C]carfentanil binding in several regions of the human brain, including the basal ganglia, frontal cortex, and thalamus (Colasanti et al. 2012). Oral administration
Oral administration
of d-amphetamine, 0.5 mg/kg, 3 h before [11C]carfentanil injection, reduced BPND values by 2–10 %. The results were confirmed in another group of subjects (Mick et al. 2014). However, Guterstam and colleagues observed no change in [11C]carfentanil binding when d-amphetamine, 0.3 mg/kg, was administered intravenously directly before injection of [11C]carfentanil (Guterstam et al. 2013). It has been hypothesized that this discrepancy may be related to delayed increases in extracellular opioid peptide concentrations following amphetamine-evoked monoamine release (Colasanti et al. 2012; Mick et al. 2014).  ^ a b Loseth GE, Ellingsen DM, Leknes S (December 2014). "State-dependent μ-opioid modulation of social motivation". Front. Behav. Neurosci. 8: 1–15. doi:10.3389/fnbeh.2014.00430. PMC 4264475 . PMID 25565999. Similar MOR activation patterns were reported during positive mood induced by an amusing video clip (Koepp et al., 2009) and following amphetamine administration in humans (Colasanti et al., 2012).  ^ a b Colasanti A, Searle GE, Long CJ, Hill SP, Reiley RR, Quelch D, Erritzoe D, Tziortzi AC, Reed LJ, Lingford-Hughes AR, Waldman AD, Schruers KR, Matthews PM, Gunn RN, Nutt DJ, Rabiner EA (September 2012). " Endogenous opioid
Endogenous opioid
release in the human brain reward system induced by acute amphetamine administration". Biol. Psychiatry. 72 (5): 371–377. doi:10.1016/j.biopsych.2012.01.027. PMID 22386378.  ^ a b c Gunne LM (2013). "Effects of Amphetamines in Humans". Drug Addiction
Addiction
II: Amphetamine, Psychotogen, and Marihuana Dependence. Berlin, Germany; Heidelberg, Germany: Springer. pp. 247–260. ISBN 9783642667091. Retrieved 4 December 2015.  ^ a b c Oswald LM, Wong DF, McCaul M, Zhou Y, Kuwabara H, Choi L, Brasic J, Wand GS (April 2005). "Relationships among ventral striatal dopamine release, cortisol secretion, and subjective responses to amphetamine". Neuropsychopharmacology. 30 (4): 821–832. doi:10.1038/sj.npp.1300667. PMID 15702139. Findings from several prior investigations have shown that plasma levels of glucocorticoids and ACTH are increased by acute administration of AMPH in both rodents and humans  ^ a b Lewin AH, Miller GM, Gilmour B (December 2011). "Trace amine-associated receptor 1 is a stereoselective binding site for compounds in the amphetamine class". Bioorg. Med. Chem. 19 (23): 7044–7048. doi:10.1016/j.bmc.2011.10.007. PMC 3236098 . PMID 22037049.  ^ a b Maguire JJ, Parker WA, Foord SM, Bonner TI, Neubig RR, Davenport AP (March 2009). "International Union of Pharmacology. LXXII. Recommendations for trace amine receptor nomenclature". Pharmacol. Rev. 61 (1): 1–8. doi:10.1124/pr.109.001107. PMC 2830119 . PMID 19325074.  ^ Revel FG, Moreau JL, Gainetdinov RR, Bradaia A, Sotnikova TD, Mory R, Durkin S, Zbinden KG, Norcross R, Meyer CA, Metzler V, Chaboz S, Ozmen L, Trube G, Pouzet B, Bettler B, Caron MG, Wettstein JG, Hoener MC (May 2011). " TAAR1
TAAR1
activation modulates monoaminergic neurotransmission, preventing hyperdopaminergic and hypoglutamatergic activity". Proc. Natl. Acad. Sci. U.S.A. 108 (20): 8485–8490. doi:10.1073/pnas.1103029108. PMC 3101002 . PMID 21525407.  ^ a b c d e f g "Vyvanse Prescribing Information" (PDF). United States Food and Drug Administration. Shire US Inc. May 2017. pp. 3–13, 17–21. Retrieved 10 July 2017.  ^ "Compound Summary". p-Hydroxyamphetamine. PubChem Compound. United States National Library of Medicine – National Center for Biotechnology Information. Retrieved 15 October 2013.  ^ "Compound Summary". p-Hydroxynorephedrine. PubChem Compound. United States National Library of Medicine – National Center for Biotechnology Information. Retrieved 15 October 2013.  ^ "Compound Summary". Phenylpropanolamine. PubChem Compound. United States National Library of Medicine – National Center for Biotechnology Information. Retrieved 15 October 2013.  ^ "Pharmacology and Biochemistry". Amphetamine. Pubchem Compound. United States National Library of Medicine – National Center for Biotechnology Information. Retrieved 12 October 2013.  ^ a b c Sjoerdsma A, von Studnitz W (April 1963). "Dopamine-beta-oxidase activity in man, using hydroxyamphetamine as substrate". Br. J. Pharmacol. Chemother. 20: 278–284. doi:10.1111/j.1476-5381.1963.tb01467.x. PMC 1703637 . PMID 13977820. Hydroxyamphetamine was administered orally to five human subjects ... Since conversion of hydroxyamphetamine to hydroxynorephedrine occurs in vitro by the action of dopamine-β-oxidase, a simple method is suggested for measuring the activity of this enzyme and the effect of its inhibitors in man. ... The lack of effect of administration of neomycin to one patient indicates that the hydroxylation occurs in body tissues. ... a major portion of the β-hydroxylation of hydroxyamphetamine occurs in non-adrenal tissue. Unfortunately, at the present time one cannot be completely certain that the hydroxylation of hydroxyamphetamine in vivo is accomplished by the same enzyme which converts dopamine to noradrenaline.  ^ a b Badenhorst CP, van der Sluis R, Erasmus E, van Dijk AA (September 2013). " Glycine
Glycine
conjugation: importance in metabolism, the role of glycine N-acyltransferase, and factors that influence interindividual variation". Expert Opin. Drug Metab. Toxicol. 9 (9): 1139–1153. doi:10.1517/17425255.2013.796929. PMID 23650932. Figure 1. Glycine
Glycine
conjugation of benzoic acid. The glycine conjugation pathway consists of two steps. First benzoate is ligated to CoASH to form the high-energy benzoyl-CoA thioester. This reaction is catalyzed by the HXM-A and HXM-B medium-chain acid:CoA ligases and requires energy in the form of ATP. ... The benzoyl-CoA is then conjugated to glycine by GLYAT to form hippuric acid, releasing CoASH. In addition to the factors listed in the boxes, the levels of ATP, CoASH, and glycine may influence the overall rate of the glycine conjugation pathway.  ^ Horwitz D, Alexander RW, Lovenberg W, Keiser HR (May 1973). "Human serum dopamine-β-hydroxylase. Relationship to hypertension and sympathetic activity". Circ. Res. 32 (5): 594–599. doi:10.1161/01.RES.32.5.594. PMID 4713201. The biologic significance of the different levels of serum DβH activity was studied in two ways. First, in vivo ability to β-hydroxylate the synthetic substrate hydroxyamphetamine was compared in two subjects with low serum DβH activity and two subjects with average activity. ... In one study, hydroxyamphetamine (Paredrine), a synthetic substrate for DβH, was administered to subjects with either low or average levels of serum DβH activity. The percent of the drug hydroxylated to hydroxynorephedrine was comparable in all subjects (6.5-9.62) (Table 3).  ^ Freeman JJ, Sulser F (December 1974). "Formation of p-hydroxynorephedrine in brain following intraventricular administration of p-hydroxyamphetamine". Neuropharmacology. 13 (12): 1187–1190. PMID 4457764. In species where aromatic hydroxylation of amphetamine is the major metabolic pathway, p-hydroxyamphetamine (POH) and p-hydroxynorephedrine (PHN) may contribute to the pharmacological profile of the parent drug. ... The location of the p-hydroxylation and β-hydroxylation reactions is important in species where aromatic hydroxylation of amphetamine is the predominant pathway of metabolism. Following systemic administration of amphetamine to rats, POH has been found in urine and in plasma. The observed lack of a significant accumulation of PHN in brain following the intraventricular administration of (+)-amphetamine and the formation of appreciable amounts of PHN from (+)-POH in brain tissue in vivo supports the view that the aromatic hydroxylation of amphetamine following its systemic administration occurs predominantly in the periphery, and that POH is then transported through the blood-brain barrier, taken up by noradrenergic neurones in brain where (+)-POH is converted in the storage vesicles by dopamine β-hydroxylase to PHN.  ^ Matsuda LA, Hanson GR, Gibb JW (December 1989). "Neurochemical effects of amphetamine metabolites on central dopaminergic and serotonergic systems". J. Pharmacol. Exp. Ther. 251 (3): 901–908. PMID 2600821. The metabolism of p-OHA to p-OHNor is well documented and dopamine-β hydroxylase present in noradrenergic neurons could easily convert p-OHA to p-OHNor after intraventricular administration.  ^ a b Khan MZ, Nawaz W (October 2016). "The emerging roles of human trace amines and human trace amine-associated receptors (hTAARs) in central nervous system". Biomed. Pharmacother. 83: 439–449. doi:10.1016/j.biopha.2016.07.002. PMID 27424325.  ^ a b c d e Lindemann L, Hoener MC (May 2005). "A renaissance in trace amines inspired by a novel GPCR family". Trends Pharmacol. Sci. 26 (5): 274–281. doi:10.1016/j.tips.2005.03.007. PMID 15860375.  ^ " Amphetamine
Amphetamine
Hydrochloride". Pubchem Compound. United States National Library of Medicine – National Center for Biotechnology Information. Retrieved 8 November 2013.  ^ " Amphetamine
Amphetamine
Phosphate". Pubchem Compound. United States National Library of Medicine – National Center for Biotechnology Information. Retrieved 8 November 2013.  ^ Brussee J, Jansen AC (May 1983). "A highly stereoselective synthesis of s(−)-[1,1'-binaphthalene]-2,2'-diol". Tetrahedron Lett. 24 (31): 3261–3262. doi:10.1016/S0040-4039(00)88151-4.  ^ a b Schep LJ, Slaughter RJ, Beasley DM (August 2010). "The clinical toxicology of metamfetamine". Clin. Toxicol. 48 (7): 675–694. doi:10.3109/15563650.2010.516752. ISSN 1556-3650. PMID 20849327.  ^ Lillsunde P, Korte T (March 1991). "Determination of ring- and N-substituted amphetamines as heptafluorobutyryl derivatives". Forensic Sci. Int. 49 (2): 205–213. doi:10.1016/0379-0738(91)90081-s. PMID 1855720.  ^ a b c d "Historical overview of methamphetamine". Vermont Department of Health. Government of Vermont. Archived from the original on 5 October 2012. Retrieved 29 January 2012.  ^ a b c Allen A, Ely R (April 2009). "Review: Synthetic Methods for Amphetamine" (PDF). Crime Scene. Northwest Association of Forensic Scientists. 37 (2): 15–25. Retrieved 6 December 2014.  ^ a b c Allen A, Cantrell TS (August 1989). "Synthetic reductions in clandestine amphetamine and methamphetamine laboratories: A review". Forensic Science International. 42 (3): 183–199. doi:10.1016/0379-0738(89)90086-8.  ^ a b c d "Recommended methods of the identification and analysis of amphetamine, methamphetamine, and their ring-substituted analogues in seized materials" (PDF). United Nations
United Nations
Office on Drugs and Crime. United Nations. 2006. pp. 9–12. Retrieved 14 October 2013.  ^ Pollard CB, Young DC (May 1951). "The Mechanism of the Leuckart Reaction". J. Org. Chem. 16 (5): 661–672. doi:10.1021/jo01145a001.  ^ US patent 2276508, Nabenhauer FP, "Method for the separation of optically active alpha-methylphenethylamine", published 17 March 1942, assigned to Smith Kline French  ^ a b Gray DL (2007). "Approved Treatments for Attention Deficit Hyperactivity Disorder: Amphetamine
Amphetamine
(Adderall), Methylphenidate (Ritalin), and Atomoxetine
Atomoxetine
(Straterra)". In Johnson DS, Li JJ. The Art of Drug Synthesis. New York, USA: Wiley-Interscience. p. 247. ISBN 9780471752158.  ^ Patrick TM, McBee ET, Hass HB (June 1946). "Synthesis of arylpropylamines; from allyl chloride". J. Am. Chem. Soc. 68 (6): 1009–1011. doi:10.1021/ja01210a032. PMID 20985610.  ^ Ritter JJ, Kalish J (December 1948). "A new reaction of nitriles; synthesis of t-carbinamines". J. Am. Chem. Soc. 70 (12): 4048–4050. doi:10.1021/ja01192a023. PMID 18105933.  ^ Krimen LI, Cota DJ (March 2011). "The Ritter Reaction". Organic Reactions. 17: 216. doi:10.1002/0471264180.or017.03.  ^ US patent 2413493, Bitler WP, Flisik AC, Leonard N, "Synthesis of isomer-free benzyl methyl acetoacetic methyl ester", published 31 December 1946, assigned to Kay Fries Chemicals Inc.  ^ Collins M, Salouros H, Cawley AT, Robertson J, Heagney AC, Arenas-Queralt A (June 2010). "δ13C and δ2H isotope ratios in amphetamine synthesized from benzaldehyde and nitroethane". Rapid Commun. Mass Spectrom. 24 (11): 1653–1658. doi:10.1002/rcm.4563. PMID 20486262.  ^ Kraemer T, Maurer HH (August 1998). "Determination of amphetamine, methamphetamine and amphetamine-derived designer drugs or medicaments in blood and urine". J. Chromatogr. B. 713 (1): 163–187. doi:10.1016/S0378-4347(97)00515-X. PMID 9700558.  ^ Kraemer T, Paul LD (August 2007). "Bioanalytical procedures for determination of drugs of abuse in blood". Anal. Bioanal. Chem. 388 (7): 1415–1435. doi:10.1007/s00216-007-1271-6. PMID 17468860.  ^ Goldberger BA, Cone EJ (July 1994). "Confirmatory tests for drugs in the workplace by gas chromatography-mass spectrometry". J. Chromatogr. A. 674 (1–2): 73–86. doi:10.1016/0021-9673(94)85218-9. PMID 8075776.  ^ a b "Clinical Drug Testing in Primary Care" (PDF). Substance Abuse and Mental Health Services Administration. Technical Assistance Publication Series 32. United States Department of Health and Human Services. 2012. p. 55. Retrieved 31 October 2013. A single dose of amphetamine or methamphetamine can be detected in the urine for approximately 24 hours, depending upon urine pH and individual metabolic differences. People who use chronically and at high doses may continue to have positive urine specimens for 2–4 days after last use (SAMHSA, 2010b).  ^ a b c d e Paul BD, Jemionek J, Lesser D, Jacobs A, Searles DA (September 2004). "Enantiomeric separation and quantitation of (±)-amphetamine, (±)-methamphetamine, (±)-MDA, (±)-MDMA, and (±)-MDEA in urine specimens by GC-EI-MS after derivatization with (R)-(−)- or (S)-(+)-α-methoxy-α-(trifluoromethyl)phenylacetyl chloride (MTPA)". J. Anal. Toxicol. 28 (6): 449–455. doi:10.1093/jat/28.6.449. PMID 15516295.  ^ "Part 341 – cold, cough, allergy, bronchodilator, and antiasthmatic drug products for over-the-counter human use". Code of Federal Regulations Title 21: Subchapter D – Drugs for human use. United States Food and Drug Administration. April 2015. Retrieved 7 March 2016. Topical nasal decongestants --(i) For products containing levmetamfetamine identified in 341.20(b)(1) when used in an inhalant dosage form. The product delivers in each 800 milliliters of air 0.04 to 0.150 milligrams of levmetamfetamine.  ^ "Identification". Levomethamphetamine. Pubchem Compound. United States National Library of Medicine – National Center for Biotechnology Information. Retrieved 2 January 2014.  ^ a b Verstraete AG, Heyden FV (August 2005). "Comparison of the sensitivity and specificity of six immunoassays for the detection of amphetamines in urine". J. Anal. Toxicol. 29 (5): 359–364. doi:10.1093/jat/29.5.359. PMID 16105261.  ^ Baselt RC (2011). Disposition of Toxic Drugs and Chemicals in Man (9th ed.). Seal Beach, USA: Biomedical Publications. pp. 85–88. ISBN 9780962652387.  ^ a b Musshoff F (February 2000). "Illegal or legitimate use? Precursor compounds to amphetamine and methamphetamine". Drug Metab. Rev. 32 (1): 15–44. doi:10.1081/DMR-100100562. PMID 10711406.  ^ a b Cody JT (May 2002). "Precursor medications as a source of methamphetamine and/or amphetamine positive drug testing results". J. Occup. Environ. Med. 44 (5): 435–450. doi:10.1097/00043764-200205000-00012. PMID 12024689.  ^ "Statistical tables". World Drug Report 2016 (pdf). Vienna, Austria: United Nations
United Nations
Office on Drugs and Crime. 2016. ISBN 9789210578622. Retrieved 1 August 2016.  ^ Rassool GH (2009). Alcohol and Drug Misuse: A Handbook for Students and Health Professionals. London, England: Routledge. p. 113. ISBN 9780203871171.  ^ a b Sulzer D, Sonders MS, Poulsen NW, Galli A (April 2005). "Mechanisms of neurotransmitter release by amphetamines: a review". Prog. Neurobiol. 75 (6): 406–433. doi:10.1016/j.pneurobio.2005.04.003. PMID 15955613.  ^ Rasmussen N (August 2011). "Medical science and the military: the Allies' use of amphetamine during World War II". J. Interdiscip. Hist. 42 (2): 205–233. doi:10.1162/JINH_a_00212. PMID 22073434.  ^ Defalque RJ, Wright AJ (April 2011). " Methamphetamine
Methamphetamine
for Hitler's Germany: 1937 to 1945". Bull. Anesth. Hist. 29 (2): 21–24, 32. doi:10.1016/s1522-8649(11)50016-2. PMID 22849208.  ^ "Controlled Substances Act". United States Food and Drug Administration. 11 June 2009. Archived from the original on 2 March 2017. Retrieved 4 November 2013.  ^ Gyenis A. "Forty Years of On the Road 1957–1997". wordsareimportant.com. DHARMA beat. Archived from the original on 14 February 2008. Retrieved 18 March 2008.  ^ Wilson A (2008). "Mixing the Medicine: The unintended consequence of amphetamine control on the Northern Soul Scene" (PDF). Internet Journal of Criminology. Archived from the original (PDF) on 13 July 2011. Retrieved 25 May 2013.  ^ Hill J (4 June 2004). "Paul Erdos, Mathematical Genius, Human (In That Order)" (PDF). Retrieved 2 November 2013.  ^ a b c Mohan J, ed. (June 2014). "World Drug Report 2014" (PDF). United Nations
United Nations
Office on Drugs and Crime. p. 3. Retrieved 18 August 2014.  ^ a b c "European drug report 2014: Trends and developments" (PDF). Lisbon, Portugal: European Monitoring Centre for Drugs and Drug Addiction. May 2014: 13, 24. doi:10.2810/32306. ISSN 2314-9086. Retrieved 18 August 2014. 1.2 million or 0.9% of young adults (15–34) used amphetamines in the last year  ^ United Nations
United Nations
Office on Drugs and Crime (2007). Preventing Amphetamine-type Stimulant
Stimulant
Use Among Young People: A Policy and Programming Guide (PDF). New York, USA: United Nations. ISBN 9789211482232. Retrieved 11 November 2013.  ^ "List of psychotropic substances under international control" (PDF). International Narcotics Control Board. United Nations. August 2003. Archived from the original (PDF) on 5 December 2005. Retrieved 19 November 2005.  ^ Park Jin-seng (25 May 2012). "Moving to Korea brings medical, social changes". The Korean Times. Retrieved 14 November 2013.  ^ "Importing or Bringing Medication into Japan for Personal Use". Japanese Ministry of Health, Labour and Welfare. 1 April 2004. Retrieved 3 November 2013.  ^ "Controlled Drugs and Substances Act". Canadian Justice Laws Website. Government of Canada. Archived from the original on 22 November 2013. Retrieved 11 November 2013.  ^ "Opiumwet". Government of the Netherlands. Retrieved 3 April 2015.  ^ "Schedule 8". Poisons Standard. Australian Government Department of Health. October 2015. Retrieved 15 December 2015.  ^ "Table of controlled Narcotic Drugs under the Thai Narcotics Act" (PDF). Thailand Food and Drug Administration. 22 May 2013. Archived from the original (PDF) on 8 March 2014. Retrieved 11 November 2013.  ^ "Class A, B and C drugs". Home Office, Government of the United Kingdom. Archived from the original on 4 August 2007. Retrieved 23 July 2007.  ^ a b "Dyanavel XR". United States Food and Drug Administration. Retrieved 1 January 2016.  ^ a b "Adzenys XR-ODT Prescribing Information" (PDF). United States Food and Drug Administration. Neos Therapeutics, Inc. January 2017. p. 16. Retrieved 10 August 2017. ADZENYS XR-ODT (amphetamine extended-release orally disintegrating tablet) contains a 3 to 1 ratio of d- to l-amphetamine, a central nervous system stimulant.  ^ "Mydayis Prescribing Information" (PDF). United States Food and Drug Administration. Shire US Inc. June 2017. pp. 1–21. Retrieved 8 August 2017.  ^ "Adzenys XR-ODT". United States Food and Drug Administration. Retrieved 7 March 2016.  ^ "Evekeo". United States Food and Drug Administration. Retrieved 11 August 2015.  ^ "Molecular Weight Calculator". Lenntech. Retrieved 19 August 2015.  ^ a b " Dextroamphetamine
Dextroamphetamine
Sulfate USP". Mallinckrodt Pharmaceuticals. March 2014. Retrieved 19 August 2015.  ^ a b "D-amphetamine sulfate". Tocris. 2015. Retrieved 19 August 2015.  ^ a b " Amphetamine
Amphetamine
Sulfate USP". Mallinckrodt Pharmaceuticals. March 2014. Retrieved 19 August 2015.  ^ " Dextroamphetamine
Dextroamphetamine
Saccharate". Mallinckrodt Pharmaceuticals. March 2014. Retrieved 19 August 2015.  ^ " Amphetamine
Amphetamine
Aspartate". Mallinckrodt Pharmaceuticals. March 2014. Retrieved 19 August 2015. 

External links

Find more aboutAmphetamineat's sister projects

Definitions from Wiktionary Media from Wikimedia Commons News from Wikinews Data from Wikidata

CID 3007 from PubChem – Amphetamine CID 5826 from PubChem – Dextroamphetamine CID 32893 from PubChem – Levoamphetamine Comparative Toxicogenomics Database entry: Amphetamine Comparative Toxicogenomics Database entry: CARTPT

v t e

Amphetamine

Main articles and pharmaceuticals

Amphetamine

Adzenys XR-ODT Dyanavel XR Evekeo Mixed amphetamine salts

Adderall Adderall
Adderall
XR Mydayis

Levoamphetamine

N/A

Dextroamphetamine

Dexedrine ProCentra Zenzedi

Lisdexamfetamine

Vyvanse

Neuropharmacology

Biomolecular targets

TAAR1
TAAR1
(full agonist) CART (mRNA inducer) 5-HT1A receptor
5-HT1A receptor
(low affinity ligand) MAO (weak competitive inhibitor)

Inhibited transporters

DAT NET SERT VMAT1 VMAT2 EAAT3 SLC22A3 SLC22A5

Active metabolites

4-Hydroxyamphetamine 4-Hydroxynorephedrine Norephedrine

Related articles

ADHD ADHD management Amphetamine
Amphetamine
psychosis Dopamine Doping in sport Formetorex ΔFosB History and culture of substituted amphetamines History of Benzedrine Methamphetamine Methylphenidate N-Methylphenethylamine Narcolepsy Neurobiological effects of physical exercise
Neurobiological effects of physical exercise
§ Attention deficit hyperactivity disorder Nootropic Norepinephrine Obesity Performance-enhancing substance Pharmaceutical drug Phenethylamine Phentermine Phenylacetone Recreational drug use Serotonin Substituted amphetamine Trace amine

v t e

ADHD pharmacotherapies

CNS stimulants

Amphetamine

Adzenys XR-ODT Dyanavel XR Evekeo Mixed amphetamine salts

Adderall Adderall
Adderall
XR Mydayis

Levoamphetamine

N/A

Dextroamphetamine

Dexedrine ProCentra Zenzedi

Lisdexamfetamine

Vyvanse

Methylphenidate

Ritalin Concerta Aptensio Biphentin Daytrana Equasym Medikinet Metadate Methylin Quillivant

Dexmethylphenidate

Focalin

Non-classical CNS stimulants

Atomoxetine Modafinil

α2-adrenoceptor agonists

Clonidine Guanfacine

Antidepressants

Amitriptyline Bupropion Buspirone Desipramine Duloxetine Imipramine Milnacipran Moclobemide Nortriptyline Reboxetine Venlafaxine

Miscellaneous/others

Amantadine Carbamazepine Memantine

Related articles

Attention deficit hyperactivity disorder
Attention deficit hyperactivity disorder
(ADHD) Attention deficit hyperactivity disorder
Attention deficit hyperactivity disorder
management Monoamine releasing agent Dopamine
Dopamine
(DA) Dopamine
Dopamine
transporter (DAT) Dopamine
Dopamine
reuptake inhibitor (DRI) Norepinephrine
Norepinephrine
(NE) Norepinephrine
Norepinephrine
transporter (NET) Norepinephrine
Norepinephrine
reuptake inhibitor (NRI) Serotonin
Serotonin
(5-HT) Serotonin transporter
Serotonin transporter
(SERT) Selective serotonin reuptake inhibitor
Selective serotonin reuptake inhibitor
(SSRI) Serotonin-norepinephrine reuptake inhibitor
Serotonin-norepinephrine reuptake inhibitor
(SNRI) Norepinephrine-dopamine reuptake inhibitor
Norepinephrine-dopamine reuptake inhibitor
(NDRI) Serotonin-norepinephrine-dopamine reuptake inhibitor (SNDRI)

v t e

Human trace amine-associated receptor ligands

TAAR1

Agonists

Endogenous†

Classical monoamine neurotransmitters

Dopamine Histamine Norepinephrine Serotonin

Trace amines

3-Iodothyronamine 3-Methoxytyramine N-Methylphenethylamine N-Methyltyramine m-Octopamine p-Octopamine Phenethylamine Phenylethanolamine Synephrine Tryptamine m-Tyramine p-Tyramine

Synthetic‡

Amphetamine DOB DOET 4-Hydroxyamphetamine Isoprenaline MDA (tenamfetamine) MDMA
MDMA
(midomafetamine) 2-Methylphenethylamine 3-Methylphenethylamine 4-Methylphenethylamine β-Methylphenethylamine Methamphetamine 3-MMA Norfenfluramine Phentermine o-PIT Propylhexedrine RO5166017 N,N-Dimethylphenethylamine

Neutral antagonists

 

Inverse agonists

EPPTB
EPPTB
(RO5212773)

TAAR2

Agonists‡

3-Iodothyronamine Phenethylamine Tyramine

Neutral antagonists

 

TAAR5

Agonists‡

Dimethylethylamine Trimethylamine

Neutral antagonists

 

Inverse agonists‡

3-Iodothyronamine

† References for all endogenous human TAAR1
TAAR1
ligands are provided at List of trace amines

‡ References for synthetic TAAR1
TAAR1
agonists can be found at TAAR1
TAAR1
or in the associated compound articles. For TAAR2
TAAR2
and TAAR5
TAAR5
agonists and inverse agonists, see TAAR for references.

See also: Receptor/signaling modulators

v t e

Monoamine releasing agents

DRAs

Morpholines: Fenbutrazate Fenmetramide Morazone Morforex Phendimetrazine Phenmetrazine Pseudophenmetrazine

Oxazolines: 4-MAR Aminorex Clominorex Cyclazodone Fenozolone Fluminorex Pemoline Thozalinone

Phenethylamines: 2-OH-PEA 4-CAB 4-FA 4-FMA 4-MA 4-MMA Alfetamine Amfecloral Amfepentorex Amfepramone Amphetamine
Amphetamine
(Dextroamphetamine Levoamphetamine) Amphetaminil β-Me-PEA BDB BOH Benzphetamine Buphedrone Butylone Cathine Cathinone Clobenzorex Clortermine D-Deprenyl DMA DMMA Dimethylamphetamine Ephedrine Ethcathinone EBDB Ethylone Etilamfetamine Famprofazone Fenethylline Fenproporex Flephedrone Fludorex Furfenorex Hordenine 4-Hydroxyamphetamine Iofetamine
Iofetamine
(123I) Lophophine Mefenorex Mephedrone Metamfepramone Methamphetamine

Dextromethamphetamine Levomethamphetamine

Methcathinone Methedrone MMDA MMDMA MBDB MDA (tenamfetamine) MDEA MDMA
MDMA
(midomafetamine) MDMPEA MDOH MDPEA Methylone Morforex Ortetamine pBA pCA pIA Pholedrine Phenethylamine Pholedrine Phenpromethamine Prenylamine Propylamphetamine Pseudoephedrine Tiflorex Tyramine Xylopropamine Zylofuramine

Piperazines: 2C-B-BZP BZP MBZP MDBZP MeOPP oMPP

Others: 2-ADN 2-AI 2-AT 4-BP 5-APDI 5-IAI Amineptine Clofenciclan Cyclopentamine Cypenamine Cyprodenate Feprosidnine Gilutensin Heptaminol Hexacyclonate Indanorex Isometheptene Methylhexanamine Naphthylaminopropane Octodrine Phthalimidopropiophenone Phenylbiguanide Propylhexedrine

Levopropylhexedrine

NRAs

Morpholines: Fenbutrazate Fenmetramide Morazone Morforex Phendimetrazine Phenmetrazine Pseudophenmetrazine

Oxazolines: 4-MAR Aminorex Clominorex Cyclazodone Fenozolone Fluminorex Pemoline Thozalinone

Phenethylamines: 2-OH-PEA 4-CAB 4-FA 4-FMA 4-MA 4-MMA Alfetamine Amfecloral Amfepentorex Amfepramone Amphetamine

Dextroamphetamine Levoamphetamine

Amphetaminil β-Me-PEA BDB Benzphetamine BOH Buphedrone Butylone Cathine Cathinone Clobenzorex Clortermine Dimethylamphetamine DMA DMMA EBDB Ephedrine Ethcathinone Ethylone Etilamfetamine Famprofazone Fenethylline Fenproporex Flephedrone Fludorex Furfenorex Hordenine 4-Hydroxyamphetamine 5-APDI
5-APDI
(IAP) 5-MAPDI
5-MAPDI
(IMP) Iofetamine
Iofetamine
(123I) Lisdexamfetamine Lophophine MBDB MDA (tenamfetamine) MDEA MDMA
MDMA
(midomafetamine) Metamfepramone MDMPEA MDOH MDPEA Mefenorex Mephedrone Mephentermine Methamphetamine

Dextromethamphetamine Levomethamphetamine

Methcathinone Methedrone Methylone Morforex Naphthylaminopropane Ortetamine pBA pCA Pentorex Phenethylamine Pholedrine Phenpromethamine Phentermine Phenylpropanolamine pIA Prenylamine Propylamphetamine Pseudoephedrine Selegiline
Selegiline
(also D-Deprenyl) Tiflorex Tyramine Xylopropamine Zylofuramine

Piperazines: 2C-B-BZP BZP MBZP mCPP MDBZP MeOPP oMPP pFPP

Others: 2-ADN 2-AI 2-AT 2-BP 4-BP 5-IAI Clofenciclan Cyclopentamine Cypenamine Cyprodenate Feprosidnine Gilutensin Heptaminol Hexacyclonate Indanorex Isometheptene Methylhexanamine Octodrine Phthalimidopropiophenone Propylhexedrine
Propylhexedrine
(Levopropylhexedrine) Tuaminoheptane

SRAs

Aminoindanes: 5-IAI AMMI ETAI MDAI MDMAI MMAI TAI

Aminotetralins: 6-CAT 8-OH-DPAT MDAT MDMAT

Oxazolines: 4-Methylaminorex Aminorex Clominorex Fluminorex

Phenethylamines: 2-Methyl-MDA 4-CAB 4-FA 4-FMA 4-HA 4-MTA 5-APDB 5-Methyl-MDA 6-APDB 6-Methyl-MDA AEMMA Amiflamine BDB BOH Brephedrone Butylone Chlorphentermine Cloforex Amfepramone Metamfepramone DCA Dexfenfluramine DFMDA DMA DMMA EBDB EDMA Ethylone Etolorex Fenfluramine Flephedrone Flucetorex IAP IMP Iofetamine Levofenfluramine Lophophine MBDB MDA (tenamfetamine) MDEA MDHMA MDMA
MDMA
(midomafetamine) MDMPEA MDOH MDPEA Mephedrone Methedrone Methylone MMA MMDA MMDMA MMMA NAP Norfenfluramine 4-TFMA pBA pCA pIA PMA PMEA PMMA TAP

Piperazines: 2C-B-BZP 3-MeOPP BZP DCPP MBZP mCPP MDBZP MeOPP Mepiprazole oMPP pCPP pFPP pTFMPP TFMPP

Tryptamines: 4-Methyl-αET 4-Methyl-αMT 5-CT 5-MeO-αET 5-MeO-αMT 5-MT αET αMT DMT Tryptamine

Others: Indeloxazine Viqualine

Others

Monoamine activity enhancers: BPAP PPAP

DAT modulators: Agonist-like: SoRI-9804 SoRI-20040; Antagonist-like: SoRI-20041

Adrenergic release blockers: Bethanidine Bretylium Guanadrel Guanazodine Guanethidine Guanoxan

See also: Receptor/signaling modulators • Monoamine reuptake inhibitors • Adrenergics • Dopaminergics • Serotonergics • Monoamine metabolism modulators • Monoamine neurotoxins

v t e

Phenethylamines

Phenethylamines

Psychedelics: 25B-NBOMe 25C-NBOMe 25D-NBOMe 25I-NBOMe 25N-NBOMe

2C-B 2C-B-AN 2C-Bn 2C-Bu 2C-C 2C-CN 2C-CP 2C-D 2C-E 2C-EF 2C-F 2C-G 2C-G-1 2C-G-2 2C-G-3 2C-G-4 2C-G-5 2C-G-6 2C-G-N 2C-H 2C-I 2C-iP 2C-N 2C-NH2 2C-O 2C-O-4 2C-P 2C-Ph 2C-SE 2C-T 2C-T-2 2C-T-3 2C-T-4 2C-T-5 2C-T-6 2C-T-7 2C-T-8 2C-T-9 2C-T-10 2C-T-11 2C-T-12 2C-T-13 2C-T-14 2C-T-15 2C-T-16 2C-T-17 2C-T-18 2C-T-19 2C-T-20 2C-T-21 2C-T-22 2C-T-22.5 2C-T-23 2C-T-24 2C-T-25 2C-T-27 2C-T-28 2C-T-30 2C-T-31 2C-T-32 2C-T-33 2C-TFE 2C-TFM 2C-YN 2C-V

Allylescaline DESOXY Escaline Isoproscaline Jimscaline Macromerine MEPEA Mescaline Metaescaline Methallylescaline Proscaline Psi-2C-T-4 TCB-2 Stimulants: Phenylethanolamine Hordenine Phenethylamine α- Methylphenethylamine
Methylphenethylamine
(amphetamine) β-Methylphenethylamine m-Methylphenethylamine N-Methylphenethylamine o-Methylphenethylamine p-Methylphenethylamine

Entactogens: Lophophine MDPEA MDMPEA Others: BOH DMPEA

Amphetamines

Psychedelics: 3C-BZ 3C-E 3C-P Aleph Beatrice Bromo-DragonFLY D-Deprenyl DMA DMCPA DMMDA DOB DOC DOEF DOET DOI DOM DON DOPR DOTFM Ganesha MMDA MMDA-2 Psi-DOM TMA TeMA Stimulants: 2-FA 2-FMA 3-FA 3-FMA Acridorex Alfetamine Amfecloral Amfepentorex Amphetamine
Amphetamine
(Dextroamphetamine, Levoamphetamine) Amphetaminil Benfluorex Benzphetamine Cathine Clobenzorex Dimethylamphetamine Ephedrine Etilamfetamine Fencamfamin Fencamine Fenethylline Fenfluramine
Fenfluramine
(Dexfenfluramine, Levofenfluramine) Fenproporex Flucetorex Fludorex Formetorex Furfenorex Gepefrine 4-Hydroxyamphetamine Iofetamine Isopropylamphetamine Lefetamine Lisdexamfetamine Mefenorex Metaraminol Methamphetamine
Methamphetamine
(Dextromethamphetamine, Levomethamphetamine) Methoxyphenamine MMA Morforex Norfenfluramine L -Norpseudoephedrine N,alpha-Diethylphenylethylamine Oxifentorex Oxilofrine Ortetamine PBA PCA Phenpromethamine PFA PFMA PIA PMA PMEA PMMA Phenylpropanolamine Pholedrine Prenylamine Propylamphetamine Pseudoephedrine Sibutramine Tiflorex Tranylcypromine Xylopropamine Zylofuramine Entactogens: 4-FA 4-FMA 4-MA 4-MMA 4-MTA 5-APB 5-APDB 5-EAPB 5-IT 5-MAPB 5-MAPDB 6-APB 6-APDB 6-Chloro-MDMA 6-EAPB 6-IT 6-MAPB 6-MAPDB EDA IAP 2,3-MDA 3,4-MDA (tenamfetamine) MDEA MDHMA MDMA
MDMA
(midomafetamine) MDOH Methamnetamine MMDMA Naphthylaminopropane TAP Others: 3,4-DCA Amiflamine DiFMDA Selegiline
Selegiline
(also D -Deprenyl)

Phentermines

Stimulants: Chlorphentermine Cloforex Clortermine Etolorex Mephentermine Pentorex Phentermine Entactogens: MDPH MDMPH Others: Cericlamine

Cathinones

Stimulants: 3-FMC 4-MC 4-BMC 4-CMC 4-EMC 4-FMC 4-MEC 4-MeMABP 4-MPD Amfepramone Benzedrone Brephedrone Buphedrone Bupropion Cathinone Dimethylcathinone Ethcathinone Eutylone Hydroxybupropion Methcathinone Methedrone NEB Pentedrone Pentylone Radafaxine Entactogens: 3,4-DMMC 3-MMC Butylone Ethylone Methylone Methylenedioxycathinone Mephedrone

Phenylisobutylamines

Entactogens: 4-CAB 4-MAB Ariadne BDB Butylone EBDB Eutylone MBDB Stimulants: Phenylisobutylamine

Phenylalkylpyrrolidines

Stimulants: α-PBP α-PHP α-PPP α-PVP MDPBP MDPPP MDPV 4-MePBP 4-MePHP 4-MePPP MOPPP MOPVP MPBP MPHP MPPP Naphyrone PEP Prolintane Pyrovalerone

Catecholamines (and close relatives)

6-FNE 6-OHDA a-Me-DA a-Me-TRA Adrenochrome Ciladopa D -DOPA (Dextrodopa) Dimetofrine Dopamine Epinephrine Epinine Etilefrine Ethylnorepinephrine Fenclonine Ibopamine Isoprenaline Isoetarine L -DOPA (Levodopa) L -DOPS (Droxidopa) L -Phenylalanine L -Tyrosine m-Tyramine Metanephrine Metaraminol Metaterol Metirosine Methyldopa N,N-Dimethyldopamine Nordefrin
Nordefrin
(Levonordefrin) Norepinephrine Norfenefrine
Norfenefrine
(m-Octopamine) Normetanephrine Orciprenaline p-Octopamine p-Tyramine Phenylephrine Synephrine

Miscellaneous

AL-LAD Amidephrine Arbutamine Cafedrine Denopamine Desvenlafaxine Diphenidine Dizocilpine Dobutamine Dopexamine Ephenidine Etafedrine ETH-LAD Famprofazone Fluorolintane Hexapradol IP-LAD Lysergic acid amide Lysergic acid 2-butyl amide Lysergic acid 2,4-dimethylazetidide Lysergic acid diethylamide Methoxamine Methoxphenidine MT-45 PARGY-LAD Phenibut PRO-LAD Pronethalol Salbutamol
Salbutamol
(Levosalbutamol) Solriamfetol Theodrenaline Thiamphenicol UWA-101

v t e

Recreational drug use

Major recreational drugs

Depressants

Barbiturates Benzodiazepines Carbamates Ethanol (alcohol)

Alcoholic drinks Beer Wine

Gabapentinoids GHB Inhalants

Medical

Nitrous oxide

Hazardous solvents

contact adhesives Gasoline nail polish remover Paint thinner

Other

Freon

Kava Nonbenzodiazepines Quinazolinones

Opioids

Buprenorphine

Suboxone Subutex

Codeine Desomorphine

Krokodil

Dextropropoxyphene

Darvocet Darvon

Fentanyl Diamorphine

Heroin

Hydrocodone Hydromorphone

Dilaudid

Methadone Mitragyna speciosa

Kratom

Morphine

Opium

Oxycodone

/paracetamol

Tramadol

Stimulants

Amphetamine Arecoline

Areca

Betel Caffeine

Coffee Energy drinks Tea

Cathinone

Khat

Cocaine

Coca Crack

Ephedrine

Ephedra

MDPV Mephedrone Methamphetamine Methylone Methylphenidate Modafinil Nicotine

Tobacco

Theobromine

Cocoa Chocolate

Entactogens

2C series 6-APB

Benzofury

AMT MDA MDMA

Ecstasy

Hallucinogens

Psychedelics

Bufotenin

Psychoactive toads Vilca Yopo

DMT

Ayahuasca

LSA LSD-25 Mescaline

Peruvian torch Peyote San Pedro

Psilocybin
Psilocybin
/ Psilocin

Psilocybin
Psilocybin
mushrooms

Dissociatives

DXM Glaucine Inhalants

Nitrous oxide alkyl nitrites poppers amyl nitrite

Ketamine MXE Muscimol

Amanita muscaria

PCP Salvinorin A

Salvia divinorum

Deliriants

Atropine
Atropine
and Scopolamine

Atropa belladonna Datura Hyoscyamus niger Mandragora officinarum

Dimenhydrinate Diphenhydramine

Cannabinoids

JWH-018 THC

Cannabis Hashish Hash oil Marijuana

Oneirogens

Calea zacatechichi Silene capensis

Club drugs

Cocaine Quaaludes MDMA
MDMA
(Ecstasy) Nitrous oxide Poppers

Drug culture

Cannabis culture

420 Cannabis cultivation Cannabis smoking Head shop Legal history of cannabis in the United States Legality of cannabis Marijuana
Marijuana
Policy Project Medical cannabis NORML Cannabis and religion Stoner film

Coffee
Coffee
culture

Coffee
Coffee
break Coffeehouse Latte art Tea
Tea
house

Drinking culture

Bartending Beer
Beer
culture Beer
Beer
festival Binge drinking Diethyl ether Drinking games Drinking song Happy hour Hip flask Nightclub Pub Pub
Pub
crawl Sommelier Sports bar Tailgate party Wine
Wine
bar Wine
Wine
tasting

Psychedelia

Psychonautics Art Drug Era Experience Literature Music Microdosing Therapy

Smoking culture

Cigarette card Fashion cigarettes Cloud-chasing Loosie Smokeasy Smoking fetishism Tobacco
Tobacco
smoking

Other

Club drug Counterculture of the 1960s Dance party Drug paraphernalia Drug tourism Entheogen Hippie Nootropic Party and play Poly drug use Rave Religion and drugs Self-medication Sex and drugs Whoonga

Drug production and trade

Drug production

Coca
Coca
production in Colombia Drug precursors Opium
Opium
production in Afghanistan Rolling meth lab

Drug trade

Illegal drug trade

Colombia

Darknet market Drug distribution

Beer
Beer
shop Cannabis shop Liquor store Liquor license

Issues with drug use

Abuse Date rape drug Impaired driving Drug harmfulness

Effects of cannabis

Addiction Dependence

Prevention Opioid
Opioid
replacement therapy Rehabilitation Responsible use

Drug-related crime Fetal alcohol spectrum disorder Long-term effects of cannabis Neurotoxicity Overdose Passive smoking

of tobacco or other substances

Legality of drug use

International

1961 Narcotic Drugs 1971 Psychotropic Substances 1988 Drug Trafficking Council of the European Union decisions on designer drugs

State level

Drug policy

Decriminalization Prohibition Supply reduction

Policy reform

Demand reduction Drug Policy Alliance Harm reduction Law Enforcement Action Partnership Liberalization

Latin America

Students for Sensible Drug Policy Transform Drug Policy Foundation

Drug policy by country

Australia Canada Germany India Netherlands Portugal Slovakia Soviet Union Sweden Switzerland United States

Just Say No Office of National Drug Control Policy School district drug policies California Colorado Maryland Virginia

Other

Arguments for and against drug prohibition Capital punishment for drug trafficking Cognitive liberty Designer drug Drug court Drug possession Drug test Narc Politics of drug abuse War on Drugs

Mexican Drug War Plan Colombia Philippine Drug War

Zero tolerance

Lists of countries by...

Alcohol legality

Alcohol consumption

Anabolic steroid legality Cannabis legality

Annual use Lifetime use

Cigarette consumption Cocaine
Cocaine
legality

Cocaine
Cocaine
use

Methamphetamine
Methamphetamine
legality Opiates use Psilocybin
Psilocybin
mushrooms legality Salvia legality

Pharmacy and Pharmacology portal Medicine portal Chemistry portal Neuroscience portal Molecular and c

.