|Pronunciation|| / /(|
|Trade names||Evekeo, Adderall , others|
| Routes of|
|Medical: oral, intravenous |
Recreational: oral, insufflation, rectal, intravenous, intramuscular
|Drug class||CNS stimulant, anorectic|
|Metabolism||CYP2D6, DBH, FMO3|
|Metabolites||4-hydroxyamphetamine , 4-hydroxynorephedrine , 4-hydroxyphenylacetone , benzoic acid, hippuric acid, norephedrine, phenylacetone|
|Onset of action||IR dosing: 30–60 minutes |
XR dosing: 1.5–2 hours
|Elimination half-life||D-amph: 9–11 hours |
L-amph: 11–14 hours
pH-dependent: 7–34 hours
|Duration of action||IR dosing: 3–6 hours |
XR dosing: 8–12 hours
pH-dependent range: 1–75%
|CompTox Dashboard (EPA)|
|ECHA InfoCard|| 100.005.543 |
|Chemical and physical data|
|Molar mass||135.210 g·mol−1|
|3D model (JSmol)|
|Density||.936 g/cm3 at 25 °C|
|Melting point||11.3 °C (52.3 °F) (predicted)|
|Boiling point||203 °C (397 °F) at 760 mmHg|
Amphetamine(contracted from alpha-methylphenethylamine) is a central nervous system (CNS) stimulant marketed under the brand name Evekeo, among others. It is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity. Amphetamine was discovered in 1887 and exists as two enantiomers: levoamphetamine and dextroamphetamine. 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 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.
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,dextroamphetamine, or the inactive prodrug lisdexamfetamine. Amphetamine increases monoamine and excitatory neurotransmission in the brain, with its most pronounced effects targeting the norepinephrine and dopamine neurotransmitter systems.
At therapeutic doses, amphetamine causes emotional and cognitive effects such as euphoria, change in desire for sex, increased wakefulness, and improved cognitive control. It induces physical effects such as improved reaction time, fatigue resistance, and increased muscle strength. Larger doses of amphetamine may impair cognitive function and induce rapid muscle breakdown. Addiction is a serious risk with heavy recreational amphetamine use, but is unlikely to occur from long-term medical use at therapeutic doses. Very high doses can result in psychosis (e.g., delusions and paranoia) which rarely occurs at therapeutic doses even during long-term use. Recreational doses are generally much larger than prescribed therapeutic doses and carry a far greater risk of serious side effects.
Amphetamine belongs to the phenethylamine class. It is also the parent compound of its own structural class, the substituted amphetamines, N-methylphenethylamine , both of which are produced within the human body. Phenethylamine is the parent compound of amphetamine, while N-methylphenethylamine is a positional isomer of amphetamine that differs only in the placement of the methyl group.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
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. Long-term amphetamine exposure at sufficiently high doses in some animal species is known to produce abnormal dopamine system development or nerve damage, but, in humans with ADHD, pharmaceutical amphetamines, at therapeutic dosages, appear to improve brain development and nerve growth. 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.
Reviews of clinical stimulant research have established the safety and effectiveness of long-term continuous amphetamine use for the treatment of ADHD. years have demonstrated treatment effectiveness and safety. 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 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. 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. 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.Randomized controlled trials of continuous stimulant therapy for the treatment of ADHD spanning 2
Current models of ADHD suggest that it is associated with functional impairments in some of the brain's neurotransmitter systems;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. Psychostimulants like methylphenidate and amphetamine are effective in treating ADHD because they increase neurotransmitter activity in these systems. Approximately 80% of those who use these stimulants see improvements in ADHD symptoms. 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. The Cochrane reviews on the treatment of ADHD in children, adolescents, and adults with pharmaceutical amphetamines stated that short-term studies have demonstrated that these drugs decrease the severity of symptoms, but they have higher discontinuation rates than non-stimulant medications due to their adverse side effects. A Cochrane review on the treatment of ADHD in children with tic disorders such as Tourette syndrome indicated that stimulants in general do not make tics worse, but high doses of dextroamphetamine could exacerbate tics in some individuals.
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; 5–35% of college students use diverted ADHD stimulants, which are primarily used for enhancement of academic performance rather than as recreational drugs. However, high amphetamine doses that are above the therapeutic range can interfere with working memory and other aspects of cognitive control.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. A systematic review from 2014 found that low doses of amphetamine also improve memory consolidation, in turn leading to improved recall of information. Therapeutic doses of amphetamine also enhance cortical network efficiency, an effect which mediates improvements in working memory in all individuals. Amphetamine and other ADHD stimulants also improve task saliency (motivation to perform a task) and increase arousal (wakefulness), in turn promoting goal-directed behavior. 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. Based upon studies of self-reported illicit stimulant use,
Amphetamine is used by some athletes for its psychological and athletic performance-enhancing effects, such as increased endurance and alertness;however, non-medical amphetamine use is prohibited at sporting events that are regulated by collegiate, national, and international anti-doping agencies. 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. Amphetamine improves endurance and reaction time primarily through reuptake inhibition and release of dopamine in the central nervous system. Amphetamine and other dopaminergic drugs also increase power output at fixed levels of perceived exertion by overriding a "safety switch", allowing the core temperature limit to increase in order to access a reserve capacity that is normally off-limits. At therapeutic doses, the adverse effects of amphetamine do not impede athletic performance; however, at much higher doses, amphetamine can induce effects that severely impair performance, such as rapid muscle breakdown and elevated body temperature.
According to the International Programme on Chemical Safety (IPCS) and the United States Food and Drug Administration (USFDA),amphetamine is contraindicated in people with a history of drug abuse, cardiovascular disease, severe agitation, or severe anxiety. It is also contraindicated in individuals with advanced arteriosclerosis (hardening of the arteries), glaucoma (increased eye pressure), hyperthyroidism (excessive production of thyroid hormone), or moderate to severe hypertension. These agencies indicate that people who have experienced allergic reactions to other stimulants or who are taking monoamine oxidase inhibitors (MAOIs) should not take amphetamine, although safe concurrent use of amphetamine and monoamine oxidase inhibitors has been documented. These agencies also state that anyone with anorexia nervosa, bipolar disorder, depression, hypertension, liver or kidney problems, mania, psychosis, Raynaud's phenomenon, seizures, thyroid problems, tics, or Tourette syndrome should monitor their symptoms while taking amphetamine. 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. Amphetamine has also been shown to pass into breast milk, so the IPCS and the USFDA advise mothers to avoid breastfeeding when using it. Due to the potential for reversible growth impairments, the USFDA advises monitoring the height and weight of children and adolescents prescribed an amphetamine pharmaceutical.
The adverse side effects of amphetamine are many and varied, and the amount of amphetamine used is the primary factor in determining the likelihood and severity of adverse effects.Amphetamine products such as Adderall, Dexedrine, and their generic equivalents are currently approved by the USFDA for long-term therapeutic use. Recreational use of amphetamine generally involves much larger doses, which have a greater risk of serious adverse drug effects than dosages used for therapeutic purposes.
Cardiovascular side effects can include hypertension or hypotension from a vasovagal response, Raynaud's phenomenon (reduced blood flow to the hands and feet), and tachycardia (increased heart rate).Sexual side effects in males may include erectile dysfunction, frequent erections, or prolonged erections. Gastrointestinal side effects may include abdominal pain, constipation, diarrhea, and nausea. Other potential physical side effects include appetite loss, blurred vision, dry mouth, excessive grinding of the teeth, nosebleed, profuse sweating, rhinitis medicamentosa (drug-induced nasal congestion), reduced seizure threshold, tics (a type of movement disorder), and weight loss. Dangerous physical side effects are rare at typical pharmaceutical doses.
Amphetamine stimulates the medullary respiratory centers, producing faster and deeper breaths.In a normal person at therapeutic doses, this effect is usually not noticeable, but when respiration is already compromised, it may be evident. Amphetamine also induces contraction in the urinary bladder sphincter, the muscle which controls urination, which can result in difficulty urinating. This effect can be useful in treating bed wetting and loss of bladder control. The effects of amphetamine on the gastrointestinal tract are unpredictable. If intestinal activity is high, amphetamine may reduce gastrointestinal motility (the rate at which content moves through the digestive system); however, amphetamine may increase motility when the smooth muscle of the tract is relaxed. Amphetamine also has a slight analgesic effect and can enhance the pain relieving effects of opioids.
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.However, amphetamine pharmaceuticals are contraindicated in individuals with cardiovascular disease.
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.Less common side effects include anxiety, change in libido, grandiosity, irritability, repetitive or obsessive behaviors, and restlessness; these effects depend on the user's personality and current mental state. Amphetamine psychosis (e.g., delusions and paranoia) can occur in heavy users. Although very rare, this psychosis can also occur at therapeutic doses during long-term therapy. According to the USFDA, "there is no systematic evidence" that stimulants produce aggressive behavior or hostility.
Amphetamine has also been shown to produce a conditioned place preference in humans taking therapeutic doses,meaning that individuals acquire a preference for spending time in places where they have previously used amphetamine.
|Addiction and dependence glossary|
|Transcription factor glossary|
Addiction is a serious risk with heavy recreational amphetamine use, but is unlikely to occur from long-term medical use at therapeutic doses;in fact, lifetime stimulant therapy for ADHD that begins during childhood reduces the risk of developing substance use disorders as an adult. 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. Individuals who frequently self-administer high doses of amphetamine have a high risk of developing an amphetamine addiction, since chronic use at high doses gradually increase the level of accumbal ΔFosB, a "molecular switch" and "master control protein" for addiction. Once nucleus accumbens ΔFosB is sufficiently overexpressed, it begins to increase the severity of addictive behavior (i.e., compulsive drug-seeking) with further increases in its expression. 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. Sustained aerobic exercise on a regular basis also appears to be an effective treatment for amphetamine addiction; exercise therapy improves clinical treatment outcomes and may be used as an adjunct therapy with behavioral therapies for addiction.
Chronic use of amphetamine at excessive doses causes alterations in gene expression in the mesocorticolimbic projection, which arise through transcriptional and epigenetic mechanisms.The most important transcription factors that produce these alterations are Delta FBJ murine osteosarcoma viral oncogene homolog B (ΔFosB), cAMP response element binding protein (CREB), and nuclear factor-kappa B (NF-κB). ΔFosB is the most significant biomolecular mechanism in addiction because ΔFosB overexpression (i.e., an abnormally high level of gene expression which produces a pronounced gene-related phenotype) in the D1-type medium spiny neurons in the nucleus accumbens is necessary and sufficient for many of the neural adaptations and regulates multiple behavioral effects (e.g., reward sensitization and escalating drug self-administration) involved in addiction. Once ΔFosB is sufficiently overexpressed, it induces an addictive state that becomes increasingly more severe with further increases in ΔFosB expression. It has been implicated in addictions to alcohol, cannabinoids, cocaine, methylphenidate, nicotine, opioids, phencyclidine, propofol, and substituted amphetamines, among others.
ΔJunD, a transcription factor, and G9a, a histone methyltransferase enzyme, both oppose the function of ΔFosB and inhibit increases in its expression.Sufficiently overexpressing ΔJunD in the nucleus accumbens with viral vectors can completely block many of the neural and behavioral alterations seen in chronic drug abuse (i.e., the alterations mediated by ΔFosB). Similarly, accumbal G9a hyperexpression results in markedly increased histone 3 lysine residue 9 dimethylation (H3K9me2) and blocks the induction of ΔFosB-mediated neural and behavioral plasticity by chronic drug use, which occurs via H3K9me2-mediated repression of transcription factors for ΔFosB and H3K9me2-mediated repression of various ΔFosB transcriptional targets (e.g., CDK5). ΔFosB also plays an important role in regulating behavioral responses to natural rewards, such as palatable food, sex, and exercise. Since both natural rewards and addictive drugs induce the expression of ΔFosB (i.e., they cause the brain to produce more of it), chronic acquisition of these rewards can result in a similar pathological state of addiction. Consequently, ΔFosB is the most significant factor involved in both amphetamine addiction and amphetamine-induced sexual addictions, which are compulsive sexual behaviors that result from excessive sexual activity and amphetamine use. These sexual addictions are associated with a dopamine dysregulation syndrome which occurs in some patients taking dopaminergic drugs.
The effects of amphetamine on gene regulation are both dose- and route-dependent.Most of the research on gene regulation and addiction is based upon animal studies with intravenous amphetamine administration at very high doses. 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. This suggests that medical use of amphetamine does not significantly affect gene regulation.
As of December 2019, [update] there is no effective pharmacotherapy for amphetamine addiction. Reviews from 2015 and 2016 indicated that TAAR1-selective agonists have significant therapeutic potential as a treatment for psychostimulant addictions; however, as of February 2016, [update] the only compounds which are known to function as TAAR1-selective agonists are experimental drugs. Amphetamine addiction is largely mediated through increased activation of dopamine receptors and co-localized NMDA receptors in the nucleus accumbens; magnesium ions inhibit NMDA receptors by blocking the receptor calcium channel. One review suggested that, based upon animal testing, pathological (addiction-inducing) psychostimulant use significantly reduces the level of intracellular magnesium throughout the brain. Supplemental magnesium 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.
A systematic review and meta-analysis from 2019 assessed the efficacy of 17 different pharmacotherapies used in RCTs for amphetamine and methamphetamine addiction;it found only low-strength evidence that methylphenidate might reduce amphetamine or methamphetamine self-administration. There was low- to moderate-strength evidence of no benefit for most of the other medications used in RCTs, which included antidepressants (bupropion, mirtazapine, sertraline), antipsychotics (aripiprazole), anticonvulsants (topiramate, baclofen, gabapentin), naltrexone, varenicline, citicoline, ondansetron, prometa, riluzole, atomoxetine, dextroamphetamine, and modafinil.
A 2018 systematic review and network meta-analysis of 50 trials involving 12 different psychosocial interventions for amphetamine, methamphetamine, or cocaine addiction found that combination therapy with both contingency management and community reinforcement approach had the highest efficacy (i.e., abstinence rate) and acceptability (i.e., lowest dropout rate).Other treatment modalities examined in the analysis included monotherapy with contingency management or community reinforcement approach, cognitive behavioral therapy, 12-step programs, non-contingent reward-based therapies, psychodynamic therapy, and other combination therapies involving these.
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. c-Fos immunoreactivity in the striatum or other parts of the reward system.Exercise leads to better treatment outcomes when used as an adjunct treatment, particularly for psychostimulant addictions. 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. This is the opposite of pathological stimulant use, which induces decreased striatal DRD2 density. One review noted that exercise may also prevent the development of a drug addiction by altering ΔFosB or
|Form of neuroplasticity |
or behavioral plasticity
|Type of reinforcer||Sources|
|Opiates||Psychostimulants||High fat or sugar food||Sexual intercourse|| Physical exercise|
| ΔFosB expression in|
nucleus accumbens D1-type MSNs
|Escalation of intake||Yes||Yes||Yes|
conditioned place preference
|Reinstatement of drug-seeking behavior||↑||↑||↓||↓|
| CREB phosphorylation |
in the nucleus accumbens
|Sensitized dopamine response|
in the nucleus accumbens
|Altered striatal dopamine signaling||↓DRD2, ↑DRD3||↑DRD1, ↓DRD2, ↑DRD3||↑DRD1, ↓DRD2, ↑DRD3||↑DRD2||↑DRD2|
|Altered striatal opioid signaling||No change or|
|↑μ-opioid receptors |
|↑μ-opioid receptors||↑μ-opioid receptors||No change||No change|
|Changes in striatal opioid peptides||↑dynorphin |
No change: enkephalin
|Mesocorticolimbic synaptic plasticity|
|Number of dendrites in the nucleus accumbens||↓||↑||↑|
| Dendritic spine density in|
the nucleus accumbens
Drug tolerance develops rapidly in amphetamine abuse (i.e., recreational amphetamine use), so periods of extended abuse require increasingly larger doses of the drug in order to achieve the same effect. hours of their last dose." 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. 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. The review indicated that the severity of withdrawal symptoms is positively correlated with the age of the individual and the extent of their dependence. Mild withdrawal symptoms from the discontinuation of amphetamine treatment at therapeutic doses can be avoided by tapering the dose.According to a Cochrane review on withdrawal in individuals who compulsively use amphetamine and methamphetamine, "when chronic heavy users abruptly discontinue amphetamine use, many report a time-limited withdrawal syndrome that occurs within 24
An amphetamine overdose can lead to many different symptoms, but is rarely fatal with appropriate care. grams of amphetamine in a day, which is roughly 100 times the maximum daily therapeutic dose. Symptoms of a moderate and extremely large overdose are listed below; fatal amphetamine poisoning usually also involves convulsions and coma. 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).The severity of overdose symptoms increases with dosage and decreases with drug tolerance to amphetamine. Tolerant individuals have been known to take as much as 5
|System||Minor or moderate overdose||Severe overdose|
| Central nervous|
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. ≥ 40 °C) is necessary for the development of amphetamine-induced neurotoxicity. 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.There is no evidence that amphetamine is directly neurotoxic in humans. 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. Animal models of neurotoxicity from high-dose amphetamine exposure indicate that the occurrence of hyperpyrexia (i.e., core body temperature
An amphetamine overdose can result in a stimulant psychosis that may involve a variety of symptoms, such as delusions and paranoia. 5–15% of users fail to recover completely. According to the same review, there is at least one trial that shows antipsychotic medications effectively resolve the symptoms of acute amphetamine psychosis. Psychosis rarely arises from therapeutic use.A Cochrane review on treatment for amphetamine, dextroamphetamine, and methamphetamine psychosis states that about
Many types of substances are known to interact with amphetamine, resulting in altered drug action or metabolism of amphetamine, the interacting substance, or both.Inhibitors of enzymes that metabolize amphetamine (e.g., CYP2D6 and FMO3) will prolong its elimination half-life, meaning that its effects will last longer. Amphetamine also interacts with MAOIs, particularly monoamine oxidase A inhibitors, since both MAOIs and amphetamine increase plasma catecholamines (i.e., norepinephrine and dopamine); therefore, concurrent use of both is dangerous. 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. Amphetamine may also decrease the effects of antihypertensives and antipsychotics due to its effects on blood pressure and dopamine respectively. Zinc supplementation may reduce the minimum effective dose of amphetamine when it is used for the treatment of ADHD.
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.Acidic substances reduce the absorption of amphetamine and increase urinary excretion, and alkaline substances do the opposite. 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).
Pharmacodynamics of amphetamine in a dopamine neuron
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.The concentrations of the main neurotransmitters involved in reward circuitry and executive functioning, dopamine and norepinephrine, increase dramatically in a dose-dependent manner by amphetamine because of its effects on monoamine transporters. The reinforcing and motivational salience-promoting effects of amphetamine are due mostly to enhanced dopaminergic activity in the mesolimbic pathway. 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.
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. Activation of TAAR1 increases cAMP production via adenylyl cyclase activation and inhibits monoamine transporter function. 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. Notably, amphetamine and trace amines possess high binding affinities for TAAR1, but not for monoamine autoreceptors. Imaging studies indicate that monoamine reuptake inhibition by amphetamine and trace amines is site specific and depends upon the presence of TAAR1 co-localization in the associated monoamine neurons.
In addition to the neuronal monoamine transporters, amphetamine also inhibits both vesicular monoamine transporters, VMAT1 and VMAT2, as well as SLC1A1, SLC22A3, and SLC22A5. Gi/Go-coupled GPCR. Amphetamine also inhibits monoamine oxidases at very high doses, resulting in less monoamine and trace amine metabolism and consequently higher concentrations of synaptic monoamines. In humans, the only post-synaptic receptor at which amphetamine is known to bind is the 5-HT1A receptor, where it acts as an agonist with low micromolar affinity.SLC1A1 is excitatory amino acid transporter 3 (EAAT3), a glutamate transporter located in neurons, SLC22A3 is an extraneuronal monoamine transporter that is present in astrocytes, and SLC22A5 is a high-affinity carnitine transporter. Amphetamine is known to strongly induce cocaine- and amphetamine-regulated transcript (CART) gene expression, a neuropeptide involved in feeding behavior, stress, and reward, which induces observable increases in neuronal development and survival in vitro . The CART receptor has yet to be identified, but there is significant evidence that CART binds to a unique
The full profile of amphetamine's short-term drug effects in humans is mostly derived through increased cellular communication or neurotransmission of dopamine, 5-HT1A, EAAT3, TAAR1, VMAT1, VMAT2, and possibly other biological targets. Amphetamine also activates seven human carbonic anhydrase enzymes, several of which are expressed in the human brain.serotonin, norepinephrine, epinephrine, histamine, CART peptides, endogenous opioids, adrenocorticotropic hormone, corticosteroids, and glutamate, which it effects through interactions with CART,
Dextroamphetamine is a more potent agonist of TAAR1 than levoamphetamine.Consequently, dextroamphetamine produces greater CNS stimulation than levoamphetamine, roughly three to four times more, but levoamphetamine has slightly stronger cardiovascular and peripheral effects.
In certain brain regions, amphetamine increases the concentration of dopamine in the synaptic cleft. non-competitive reuptake inhibition), but PKC-mediated phosphorylation alone induces the reversal of dopamine transport through DAT (i.e., dopamine efflux). Amphetamine is also known to increase intracellular calcium, an effect which is associated with DAT phosphorylation through an unidentified Ca2+/calmodulin-dependent protein kinase (CAMK)-dependent pathway, in turn producing dopamine efflux. Through direct activation of G protein-coupled inwardly-rectifying potassium channels, TAAR1 reduces the firing rate of dopamine neurons, preventing a hyper-dopaminergic state.Amphetamine can enter the presynaptic neuron either through DAT or by diffusing across the neuronal membrane directly. As a consequence of DAT uptake, amphetamine produces competitive reuptake inhibition at the transporter. Upon entering the presynaptic neuron, amphetamine activates TAAR1 which, through protein kinase A (PKA) and protein kinase C (PKC) signaling, causes DAT phosphorylation. Phosphorylation by either protein kinase can result in DAT internalization (
Amphetamine is also a substrate for the presynaptic vesicular monoamine transporter, VMAT2.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. Subsequently, the cytosolic dopamine molecules are released from the presynaptic neuron into the synaptic cleft via reverse transport at DAT.
Similar to dopamine, amphetamine dose-dependently increases the level of synaptic norepinephrine, the direct precursor of epinephrine. non-competitive reuptake inhibition at phosphorylated NET, competitive NET reuptake inhibition, and norepinephrine release from VMAT2.Based upon neuronal TAAR1mRNA expression, amphetamine is thought to affect norepinephrine analogously to dopamine. In other words, amphetamine induces TAAR1-mediated efflux and
Amphetamine exerts analogous, yet less pronounced, effects on serotonin as on dopamine and norepinephrine.Amphetamine affects serotonin via VMAT2 and, like norepinephrine, is thought to phosphorylate SERT via TAAR1. Like dopamine, amphetamine has low, micromolar affinity at the human 5-HT1A receptor.
Acute amphetamine administration in humans increases endogenous opioid release in several brain structures in the reward system.Extracellular levels of glutamate, the primary excitatory neurotransmitter in the brain, have been shown to increase in the striatum following exposure to amphetamine. This increase in extracellular glutamate presumably occurs via the amphetamine-induced internalization of EAAT3, a glutamate reuptake transporter, in dopamine neurons. Amphetamine also induces the selective release of histamine from mast cells and efflux from histaminergic neurons through VMAT2. Acute amphetamine administration can also increase adrenocorticotropic hormone and corticosteroid levels in blood plasma by stimulating the hypothalamic–pituitary–adrenal axis.
In December 2017, the first study assessing the interaction between amphetamine and human carbonic anhydrase enzymes was published;of the eleven carbonic anhydrase enzymes it examined, it found that amphetamine potently activates seven, four of which are highly expressed in the human brain, with low nanomolar through low micromolar activating effects. Based upon preclinical research, cerebral carbonic anhydrase activation has cognition-enhancing effects; but, based upon the clinical use of carbonic anhydrase inhibitors, carbonic anhydrase activation in other tissues may be associated with adverse effects, such as ocular activation exacerbating glaucoma.
The oral bioavailability of amphetamine varies with gastrointestinal pH; 75% for dextroamphetamine. Amphetamine is a weak base with a pKa of 9.9; 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. Conversely, an acidic pH means the drug is predominantly in a water-soluble cationic (salt) form, and less is absorbed. Approximately 20% of amphetamine circulating in the bloodstream is bound to plasma proteins. Following absorption, amphetamine readily distributes into most tissues in the body, with high concentrations occurring in cerebrospinal fluid and brain tissue.it is well absorbed from the gut, and bioavailability is typically over
The half-lives of amphetamine enantiomers differ and vary with urine pH. 9–11 hours and 11–14 hours, respectively. Highly acidic urine will reduce the enantiomer half-lives to 7 hours; highly alkaline urine will increase the half-lives up to 34 hours. 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. Amphetamine is eliminated via the kidneys, with 30–40% of the drug being excreted unchanged at normal urinary pH. When the urinary pH is basic, amphetamine is in its free base form, so less is excreted. 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. Following oral administration, amphetamine appears in urine within 3 hours. Roughly 90% of ingested amphetamine is eliminated 3 days after the last oral dose.At normal urine pH, the half-lives of dextroamphetamine and levoamphetamine are
The prodrug lisdexamfetamine is not as sensitive to pH as amphetamine when being absorbed in the gastrointestinal tract; hour.following absorption into the blood stream, it is converted by red blood cell-associated enzymes to dextroamphetamine via hydrolysis. The elimination half-life of lisdexamfetamine is generally less than 1
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. 4-hydroxyamphetamine , 4-hydroxynorephedrine , 4-hydroxyphenylacetone , benzoic acid, hippuric acid, norephedrine, and phenylacetone. Among these metabolites, the active sympathomimetics are 4-hydroxyamphetamine, 4-hydroxynorephedrine, and norephedrine. The main metabolic pathways involve aromatic para-hydroxylation, aliphatic alpha- and beta-hydroxylation, N-oxidation, N-dealkylation, and deamination. The known metabolic pathways, detectable metabolites, and metabolizing enzymes in humans include the following:Amphetamine has a variety of excreted metabolic products, including
The human metagenome (i.e., the genetic composition of an individual and all microorganisms that reside on or within the individual's body) varies considerably between individuals. trillion) greatly outnumbers human cells (tens of trillions), there is considerable potential for interactions between drugs and an individual's microbiome, including: drugs altering the composition of the human microbiome, drug metabolism by microbial enzymes modifying the drug's pharmacokinetic profile, and microbial drug metabolism affecting a drug's clinical efficacy and toxicity profile. The field that studies these interactions is known as pharmacomicrobiomics.Since the total number of microbial and viral cells in the human body (over 100
Similar to most biomolecules and other orally administered xenobiotics (i.e., drugs), amphetamine is predicted to undergo promiscuous metabolism by human gastrointestinal microbiota (primarily bacteria) prior to absorption into the blood stream.The first amphetamine-metabolizing microbial enzyme, tyramine oxidase from a strain of E. coli commonly found in the human gut, was identified in 2019. This enzyme was found to metabolize amphetamine, tyramine, and phenethylamine with roughly the same binding affinity for all three compounds.
Amphetamine has a very similar structure and function to the endogenous trace amines, which are naturally occurring neuromodulator molecules produced in the human body and brain. N-methylphenethylamine , an isomer of amphetamine (i.e., it has an identical molecular formula). In humans, phenethylamine is produced directly from L-phenylalanine by the aromatic amino acid decarboxylase (AADC) enzyme, which converts L-DOPA into dopamine as well. In turn, N-methylphenethylamine is metabolized from phenethylamine by phenylethanolamine N-methyltransferase, the same enzyme that metabolizes norepinephrine into epinephrine. Like amphetamine, both phenethylamine and N-methylphenethylamine regulate monoamine neurotransmission via TAAR1; unlike amphetamine, both of these substances are broken down by monoamine oxidase B, and therefore have a shorter half-life than amphetamine.Among this group, the most closely related compounds are phenethylamine, the parent compound of amphetamine, and
Amphetamine is a methyl homolog of the mammalian neurotransmitter phenethylamine with the chemical formula C 9 H 13 N . The carbon atom adjacent to the primary amine is a stereogenic center, and amphetamine is composed of a racemic 1:1 mixture of two enantiomers. 1,1'-bi-2-naphthol .This racemic mixture can be separated into its optical isomers: levoamphetamine and dextroamphetamine. 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. Frequently prepared solid salts of amphetamine include amphetamine adipate, aspartate, hydrochloride, phosphate, saccharate, sulfate, and tannate. Dextroamphetamine sulfate is the most common enantiopure salt. Amphetamine is also the parent compound of its own structural class, which includes a number of psychoactive derivatives. In organic chemistry, amphetamine is an excellent chiral ligand for the stereoselective synthesis of
The substituted derivatives of amphetamine, or "substituted amphetamines", are a broad range of chemicals that contain amphetamine as a "backbone";specifically, this chemical class includes derivative compounds that are formed by replacing one or more hydrogen atoms in the amphetamine core structure with substituents. The class includes amphetamine itself, stimulants like methamphetamine, serotonergic empathogens like MDMA, and decongestants like ephedrine, among other subgroups.
Since the first preparation was reported in 1887, 1). 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.numerous synthetic routes to amphetamine have been developed. The most common route of both legal and illicit amphetamine synthesis employs a non-metal reduction known as the Leuckart reaction (method
A number of chiral resolutions have been developed to separate the two enantiomers of amphetamine. d-tartaric acid to form a diastereoisomeric salt which is fractionally crystallized to yield dextroamphetamine. Chiral resolution remains the most economical method for obtaining optically pure amphetamine on a large scale. 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.For example, racemic amphetamine can be treated with
A large number of alternative synthetic routes to amphetamine have been developed based on classic organic reactions. 2). Another example employs the Ritter reaction (method 3). In this route, allylbenzene is reacted acetonitrile in sulfuric acid to yield an organosulfate which in turn is treated with sodium hydroxide to give amphetamine via an acetamide intermediate. 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).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
A significant number of amphetamine syntheses feature a reduction of a nitro, imine, oxime, or other nitrogen-containing functional groups. 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). 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).In one such example, a Knoevenagel condensation of benzaldehyde with nitroethane yields
Amphetamine is frequently measured in urine or blood as part of a drug test for sports, employment, poisoning diagnostics, and forensics. hours, although a high dose may be detectable for 2–4 days.Techniques such as immunoassay, which is the most common form of amphetamine test, may cross-react with a number of sympathomimetic drugs. Chromatographic methods specific for amphetamine are employed to prevent false positive results. 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, or illicitly obtained substituted amphetamines. Several prescription drugs produce amphetamine as a metabolite, including benzphetamine, clobenzorex, famprofazone, fenproporex, lisdexamfetamine, mesocarb, methamphetamine, prenylamine, and selegiline, among others. These compounds may produce positive results for amphetamine on drug tests. Amphetamine is generally only detectable by a standard drug test for approximately 24
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. (S)-(−)-trifluoroacetylprolyl chloride allows for the detection of methamphetamine in urine. 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. 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.Gas chromatography–mass spectrometry (GC–MS) of amphetamine and methamphetamine with the derivatizing agent
Amphetamine was first synthesized in 1887 in Germany by Romanian chemist Lazăr Edeleanu who named it phenylisopropylamine; 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. During World War II, amphetamine and methamphetamine were used extensively by both the Allied and Axis forces for their stimulant and performance-enhancing effects. As the addictive properties of the drug became known, governments began to place strict controls on the sale of amphetamine. For example, during the early 1970s in the United States, amphetamine became a schedule II controlled substance under the Controlled Substances Act. In spite of strict government controls, amphetamine has been used legally or illicitly by people from a variety of backgrounds, including authors, musicians, mathematicians, and athletes.its stimulant effects remained unknown until 1927, when it was independently resynthesized by Gordon Alles and reported to have sympathomimetic properties. 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. Benzedrine sulfate was introduced 3
Amphetamine is still illegally synthesized today in clandestine labs and sold on the black market, primarily in European countries. in 2018, [update] 11.9 million adults of ages 15–64 have used amphetamine or methamphetamine at least once in their lives and 1.7 million have used either in the last year. During 2012, approximately 5.9 metric tons of illicit amphetamine were seized within EU member states; the "street price" of illicit amphetamine within the EU ranged from €6–38 per gram during the same period. Outside Europe, the illicit market for amphetamine is much smaller than the market for methamphetamine and MDMA.Among European Union (EU) member states
As a result of the United Nations 1971 Convention on Psychotropic Substances, amphetamine became a schedule II controlled substance, as defined in the treaty, in all 183 state parties. Consequently, it is heavily regulated in most countries. Some countries, such as South Korea and Japan, have banned substituted amphetamines even for medical use. In other nations, such as Canada (schedule I drug), the Netherlands (List I drug), the United States (schedule II drug), Australia (schedule 8), Thailand (category 1 narcotic), and United Kingdom (class B drug), amphetamine is in a restrictive national drug schedule that allows for its use as a medical treatment.
Several currently marketed amphetamine formulations contain both enantiomers, including those marketed under the brand names Adderall, Adderall XR, Mydayis, Adzenys ER, Adzenys XR-ODT, Dyanavel XR, Evekeo, and Evekeo ODT. Of those, Evekeo (including Evekeo ODT) is the only product containing only racemic amphetamine (as amphetamine sulfate), and is therefore the only one whose active moiety can be accurately referred to simply as "amphetamine". Dextroamphetamine, marketed under the brand names Dexedrine and Zenzedi, is the only enantiopure amphetamine product currently available. A prodrug form of dextroamphetamine, lisdexamfetamine, is also available and is marketed under the brand name Vyvanse. As it is a prodrug, lisdexamfetamine is structurally different from dextroamphetamine, and is inactive until it metabolizes into dextroamphetamine. The free base of racemic amphetamine was previously available as Benzedrine, Psychedrine, and Sympatedrine. Levoamphetamine was previously available as Cydril. Many current amphetamine pharmaceuticals are salts due to the comparatively high volatility of the free base. However, oral suspension and orally disintegrating tablet (ODT) dosage forms composed of the free base were introduced in 2015 and 2016, respectively. Some of the current brands and their generic equivalents are listed below.
| United States|
| (D:L) ratio ||Dosage|
|Adderall XR||–||3:1 (salts)||capsule||2001||GoodRx|
|Adzenys ER||amphetamine||3:1 (base)||suspension||2017||GoodRx|
|Adzenys XR-ODT||amphetamine||3:1 (base)||ODT||2016||GoodRx|
|Dyanavel XR||amphetamine||3.2:1 (base)||suspension||2015||GoodRx|
|Evekeo||amphetamine sulfate||1:1 (salts)||tablet||2012||GoodRx|
|Evekeo ODT||amphetamine sulfate||1:1 (salts)||ODT||2019||GoodRx|
|Dexedrine||dextroamphetamine sulfate||1:0 (salts)||capsule||1976||GoodRx|
|Zenzedi||dextroamphetamine sulfate||1:0 (salts)||tablet||2013||GoodRx|
|Vyvanse||lisdexamfetamine dimesylate||1:0 (prodrug)||capsule||2007||GoodRx|
|drug||formula|| molecular mass ||amphetamine base||amphetamine base|
in equal doses
|(g/mol)||(percent)||(30 mg dose)|
|25%||amphetamine aspartate monohydrate||(C9H13N)•C4H7NO4•H2O|
|amphetamine base suspension||C9H13N|
Stimulants is an overarching term that covers many drugs including those that increase activity of the central nervous system and the body, drugs that are pleasurable and invigorating, or drugs that have sympathomimetic effects. Stimulants are widely used throughout the world as prescription medicines as well as without a prescription as performance-enhancing or recreational drugs. The most frequently prescribed stimulants as of 2013 were lisdexamfetamine, methylphenidate, and amphetamine. It was estimated in 2015 that the percentage of the world population that had used cocaine during a year was 0.4%. For the category "Amphetamines and prescription stimulants" the value was 0.7%, and for Ecstasy (drug) 0.4%.
Methylphenidate, abbreviated MP or MPH, sold under the trade name Ritalin among others, is a stimulant medication used to treat attention deficit hyperactivity disorder (ADHD) and narcolepsy. It is a first line medication for ADHD. It may be taken by mouth or applied to the skin, and different formulations have varying durations of effect.
Monoamine transporters (MATs) are protein structures that function as integral plasma-membrane transporters to regulate concentrations of extracellular monoamine neurotransmitters. Three major classes of MATs are responsible for the reuptake of their associated amine neurotransmitters. MATs are located just outside the synaptic cleft (peri-synaptically), transporting monoamine transmitter overflow from the synaptic cleft back to the cytoplasm of the pre-synaptic neuron. MAT regulation generally occurs through phosphorylation and posttranslational modification. Due to their significance in neuronal signaling, MATs are commonly associated with drugs used to treat mental disorders as well as recreational drugs. Compounds targeting MATs range from medications such as the wide variety of tricyclic antidepressants, selective serotonin reuptake inhibitors such as fluoxetine (Prozac) to stimulant medications such as methylphenidate (Ritalin) and amphetamine in its many forms and derivatives methamphetamine (Desoxyn) and lisdexamfetamine (Vyvanse). Furthermore, drugs such as MDMA and natural alkaloids such as cocaine exert their effects in part by their interaction with MATs, by blocking the transporters from mopping up dopamine, serotonin, and other neurotransmitters from the synapse.
Dextroamphetamine is a central nervous system (CNS) stimulant and an amphetamine enantiomer that is prescribed for the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. It is also used as an athletic performance and cognitive enhancer, and recreationally as an aphrodisiac and euphoriant. Dextroamphetamine was also used in the past by some countries' military forces to fight fatigue during extended combat operations.
Stimulant psychosis is a mental disorder characterized by psychotic symptoms which involves and typically occurs following an overdose on psychostimulants; however, it has also been reported to occur in approximately 0.1% of individuals, or 1 out of every 1,000 people, within the first several weeks after starting amphetamine or methylphenidate therapy. Methamphetamine psychosis, or long-term effects of stimulant use in the brain, depend upon genetics and may persist for some time.
Adderall and Mydayis are trade names for a combination drug containing four salts of amphetamine. The mixture is composed of equal parts racemic amphetamine and dextroamphetamine, which produces a (3:1) ratio between dextroamphetamine and levoamphetamine, the two enantiomers of amphetamine. Both enantiomers are stimulants, but differ enough to give Adderall an effects profile distinct from those of racemic amphetamine or dextroamphetamine, which are marketed as Evekeo and Dexedrine/Zenzedi, respectively. Adderall is used in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. It is also used as an athletic performance enhancer, cognitive enhancer, appetite suppressant, and recreationally as an aphrodisiac and euphoriant. It is a central nervous system (CNS) stimulant of the phenethylamine class.
A dopamine reuptake inhibitor (DRI) is a class of drug which acts as a reuptake inhibitor of the monoamine neurotransmitter dopamine by blocking the action of the dopamine transporter (DAT). Reuptake inhibition is achieved when extracellular dopamine not absorbed by the postsynaptic neuron is blocked from re-entering the presynaptic neuron. This results in increased extracellular concentrations of dopamine and increase in dopaminergic neurotransmission.
Dexmethylphenidate, sold under the brand name Focalin among others, is a medication used to treat attention deficit hyperactivity disorder (ADHD) in those over the age of 5 years. If no benefit is seen after 4 weeks it is reasonable to discontinue its use. It is taken by mouth. The immediate release formulation lasts up to 5 hours while the extended release formulation lasts up to 12 hours.
Propylhexedrine, sold under the brand names Benzedrex and Obesin among others, is a nasal decongestant, appetite suppressant, and psychostimulant medication. It is used medicinally for relief of congestion due to colds, allergies and allergic rhinitis and recreationally for its euphoric effects. The effects are similar to those of methamphetamine, though the duration of propylhexedrine is much shorter. Propylhexedrine differs from methamphetamine only in that it has a saturated cyclohexane ring where methamphetamine has a phenyl ring.
The vesicular monoamine transporter (VMAT) is a transport protein integrated into the membrane of synaptic vesicles of presynaptic neurons. It acts to transport monoamine neurotransmitters – such as dopamine, serotonin, norepinephrine, epinephrine, and histamine – into the vesicles, which release the neurotransmitters into synapses as chemical messages to postsynaptic neurons. VMATs utilize a proton gradient generated by V-ATPases in vesicle membranes to power monoamine import.
Dopaminergic means "related to dopamine" (literally, "working on dopamine"), dopamine being a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain. Dopaminergic brain pathways facilitate dopamine-related activity. For example, certain proteins such as the dopamine transporter (DAT), vesicular monoamine transporter 2 (VMAT2), and dopamine receptors can be classified as dopaminergic, and neurons that synthesize or contain dopamine and synapses with dopamine receptors in them may also be labeled as dopaminergic. Enzymes that regulate the biosynthesis or metabolism of dopamine such as aromatic L-amino acid decarboxylase or DOPA decarboxylase, monoamine oxidase (MAO), and catechol O-methyl transferase (COMT) may be referred to as dopaminergic as well. Also, any endogenous or exogenous chemical substance that acts to affect dopamine receptors or dopamine release through indirect actions (for example, on neurons that synapse onto neurons that release dopamine or express dopamine receptors) can also be said to have dopaminergic effects, two prominent examples being opioids, which enhance dopamine release indirectly in the reward pathways, and some substituted amphetamines, which enhance dopamine release directly by binding to and inhibiting VMAT2.
Lisdexamfetamine, sold under the brand name Vyvanse among others, is a medication that is a derivative of amphetamine. It is mainly used to treat attention deficit hyperactivity disorder (ADHD) in people over the age of five as well as moderate-to-severe binge eating disorder in adults. Lisdexamfetamine is taken by mouth. In the United Kingdom it is usually less preferred than methylphenidate. Its effects generally begin within 2 hours and last for up to 12 hours.
Attention deficit hyperactivity disorder management options are evidence-based practices with established treatment efficacy for ADHD. The American Academy of Pediatrics recommends different treatment paradigms depending on the age of the person being treated. For those aged 4–5, the Academy recommends evidence-based parent- and/or teacher-administered behavior therapy, with the addition of methylphenidate only if there is continuing moderate-to-severe functional disturbances. For those aged 6–11, the use of medication in combination with behavior therapy is recommended, with the evidence for stimulant medications being stronger than that for other classes. For those aged 12–18, medication should be prescribed with the consent of the treated adolescent, preferably in combination with behavioral therapy. The evidence for the utility of behavioral interventions in this aged group was rated only "C" quality, however.
Mesocarb is a drug that is currently being developed for Parkinson's disease.
Methamphetamine is a potent central nervous system (CNS) stimulant that is mainly used as a recreational drug and less commonly as a second-line treatment for attention deficit hyperactivity disorder and obesity. Methamphetamine was discovered in 1893 and exists as two enantiomers: levo-methamphetamine and dextro-methamphetamine. Methamphetamine properly refers to a specific chemical, the racemic free base, which is an equal mixture of levomethamphetamine and dextromethamphetamine in their pure amine forms. It is rarely prescribed over concerns involving human neurotoxicity and potential for recreational use as an aphrodisiac and euphoriant, among other concerns, as well as the availability of safer substitute drugs with comparable treatment efficacy. Dextromethamphetamine is a stronger CNS stimulant than levomethamphetamine.
Protein fosB, also known as FosB and G0/G1 switch regulatory protein 3 (G0S3), is a protein that in humans is encoded by the FBJ murine osteosarcoma viral oncogene homolog B (FOSB) gene.
Amphetamine dependence refers to a state of psychological dependence on a drug in the amphetamine class. In individuals with substance use disorder, psychotherapy is currently the best treatment option as no pharmacological treatment has been approved. Tolerance is expected to develop with regular substituted amphetamine use. When substituted amphetamines are abused, drug tolerance develops rapidly. Psychostimulants – including amphetamine and methamphetamine – do not cause physical dependence.
Addiction is a brain disorder characterized by compulsive engagement in rewarding stimuli despite adverse consequences. Despite the involvement of a number of psychosocial factors, a biological process—one that is induced by repeated exposure to an addictive stimulus—is the core pathology that drives the development and maintenance of an addiction, according to the "brain disease model" of addiction. However, many scholars who study addiction argue that the brain disease model is incomplete and misleading.
A monoamine reuptake inhibitor (MRI) is a drug that acts as a reuptake inhibitor of one or more of the three major monoamine neurotransmitters serotonin, norepinephrine, and dopamine by blocking the action of one or more of the respective monoamine transporters (MATs), which include the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT). This in turn results in an increase in the synaptic concentrations of one or more of these neurotransmitters and therefore an increase in monoaminergic neurotransmission.
Amphetamine type stimulants (ATS) are a group of synthetic drugs that are chemical derivatives of the parent compound alpha-methylphenethylamine, also known as amphetamine. Common ATS includes amphetamine, methamphetamine, ephedrine, pseudoephedrine, 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyamphetamine (MDA) and 3,4-methylenedioxymethamphetamine (MDEA). ATS when used illicitly has street names including ice, meth, crystal, crank, bennies, and speed. Within the group of Amphetamine-type stimulants, there are also generic drugs including Adderall, Dexedrine (Dextroamphetamine), and Vyvanse (Lisdexamfetamine).
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).
The simplest unsubstituted phenylisopropylamine, 1-phenyl-2-aminopropane, or amphetamine, serves as a common structural template for hallucinogens and psychostimulants. Amphetamine produces central stimulant, anorectic, and sympathomimetic actions, and it is the prototype member of this class (39). ... The phase 1 metabolism of amphetamine analogs is catalyzed by two systems: cytochrome P450 and flavin monooxygenase. ... Amphetamine can also undergo aromatic hydroxylation to p-hydroxyamphetamine. ... Subsequent oxidation at the benzylic position by DA β-hydroxylase affords p-hydroxynorephedrine. Alternatively, direct oxidation of amphetamine by DA β-hydroxylase can afford norephedrine.
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.
Onset of action: 30–60 min
Table 9.2 Dextroamphetamine formulations of stimulant medication
Dexedrine [Peak:2–3 h] [Duration:5–6 h] ...
Adderall [Peak:2–3 h] [Duration:5–7 h]
Dexedrine spansules [Peak:7–8 h] [Duration:12 h] ...
Adderall XR [Peak:7–8 h] [Duration:12 h]
Vyvanse [Peak:3–4 h] [Duration:12 h]
Duration of effect varies depending on agent and urine pH. Excretion is enhanced in more acidic urine. Half-life is 7 to 34 hours and is, in part, dependent on urine pH (half-life is longer with alkaline urine). ... Amphetamines are distributed into most body tissues with high concentrations occurring in the brain and CSF. Amphetamine appears in the urine within about 3 hours following oral administration. ... Three days after a dose of (+ or -)-amphetamine, human subjects had excreted 91% of the (14)C in the urine
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.
One of a pair of molecular entities which are mirror images of each other and non-superposable.
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.
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 alertness and attention to task
However the firm happened to discover the drug, SKF first packaged it as an inhaler so as to exploit the base's volatility and, after sponsoring some trials by East Coast otolaryngological specialists, began to advertise the Benzedrine Inhaler as a decongestant in late 1933.
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.
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).
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 minority of individuals who use amphetamines develop full-blown psychosis requiring care at emergency departments or psychiatric hospitals. In such cases, symptoms of amphetamine psychosis commonly include paranoid and persecutory delusions as well as auditory and visual hallucinations in the presence of extreme agitation. More common (about 18%) is for frequent amphetamine users to report psychotic symptoms that are sub-clinical and that do not require high-intensity intervention ...
About 5–15% of the users who develop an amphetamine psychosis fail to recover completely (Hofmann 1983) ...
Findings from one trial indicate use of antipsychotic medications effectively resolves symptoms of acute amphetamine psychosis.
psychotic symptoms of individuals with amphetamine psychosis may be due exclusively to heavy use of the drug or heavy use of the drug may exacerbate an underlying vulnerability to schizophrenia.
In these studies, amphetamine was given in consecutively higher doses until psychosis was precipitated, often after 100–300 mg of amphetamine ... Secondly, psychosis has been viewed as an adverse event, although rare, in children with ADHD who have been treated with amphetamine
Several other studies,[97-101] including a meta-analytic review and a retrospective study, suggested that stimulant therapy in childhood is associated with a reduced risk of subsequent substance use, cigarette smoking and alcohol use disorders. ... Recent studies have demonstrated that stimulants, along with the non-stimulants atomoxetine and extended-release guanfacine, are continuously effective for more than 2-year treatment periods with few and tolerable adverse effects. The effectiveness of long-term therapy includes not only the core symptoms of ADHD, but also improved quality of life and academic achievements. The most concerning short-term adverse effects of stimulants, such as elevated blood pressure and heart rate, waned in long-term follow-up studies. ... The current data do not support the potential impact of stimulants on the worsening or development of tics or substance abuse into adulthood. In the longest follow-up study (of more than 10 years), lifetime stimulant treatment for ADHD was effective and protective against the development of adverse psychiatric disorders.
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.
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.
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) . ...
[Figure 4](b) Examples of synthetic, pharmaceutically important substituted amphetamines.
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.
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.
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.
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.
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.
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.
Amphetamine has been shown to improve consolidation of information (0.02 ≥ P ≤ 0.05), leading to improved recall.
Dopamine acts in the nucleus accumbens to attach motivational significance to stimuli associated with reward.
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.
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.
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.
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.
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.
Aside from accounting for the reduced performance of mentally fatigued participants, this model rationalizes the reduced RPE and hence improved cycling time trial performance of athletes using a glucose mouthwash (Chambers et al., 2009) and the greater power output during a RPE matched cycling time trial following amphetamine ingestion (Swart, 2009). ... Dopamine stimulating drugs are known to enhance aspects of exercise performance (Roelands et al., 2008)
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.
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.