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, decreased appetite, elevated heart rate, 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., hallucinations, 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]
Long-term amphetamine exposure at sufficiently high doses in some animal species is known to produce abnormal dopamine system development or nerve damage,[52][53] but, in humans with ADHD, long-term use of pharmaceutical amphetamines at therapeutic doses appears to improve brain development and nerve growth.[54][55][56] 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.[54][55][56]
Reviews of clinical stimulant research have established the safety and effectiveness of long-term continuous amphetamine use for the treatment of ADHD.[44][57][58]Randomized controlled trials of continuous stimulant therapy for the treatment of ADHD spanning 2years have demonstrated treatment effectiveness and safety.[44][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 6] across 9categories 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.[44][58] One review highlighted a nine-month randomized controlled trial of amphetamine treatment for ADHD in children that found an average increase of 4.5IQ points, continued increases in attention, and continued decreases in disruptive behaviors and hyperactivity.[57] 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.[44]
Current models of ADHD suggest that it is associated with functional impairments in some of the brain's neurotransmitter systems;[59] 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.[59] Stimulants like methylphenidate and amphetamine are effective in treating ADHD because they increase neurotransmitter activity in these systems.[26][59][60] Approximately 80% of those who use these stimulants see improvements in ADHD symptoms.[61] 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.[62][63] The Cochrane reviews[note 7] on the treatment of ADHD in children, adolescents, and adults with pharmaceutical amphetamines stated that short-term studies have demonstrated that these drugs decrease the severity of symptoms, but they have higher discontinuation rates than non-stimulant medications due to their adverse side effects.[65][66] 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.[67]
Binge eating disorder
Binge eating disorder (BED) is characterized by recurrent and persistent episodes of compulsive binge eating.[68] These episodes are often accompanied by marked distress and a feeling of loss of control over eating.[68] The pathophysiology of BED is not fully understood, but it is believed to involve dysfunctional dopaminergic reward circuitry along the cortico-striatal-thalamic-cortical loop.[69][70] As of July 2024, lisdexamfetamine is the only USFDA- and TGA-approved pharmacotherapy for BED.[36][71] Evidence suggests that lisdexamfetamine's treatment efficacy in BED is underpinned at least in part by a psychopathological overlap between BED and ADHD, with the latter conceptualized as a cognitive control disorder that also benefits from treatment with lisdexamfetamine.[69][70]
This diagram illustrates how TAAR1 activation induces incretin-like effects through the release of gastrointestinal hormones and influences food intake, blood glucose levels, and insulin release.[72] TAAR1 expression in the periphery is indicated with "x".[72]
Lisdexamfetamine's therapeutic effects for BED primarily involve direct action in the central nervous system after conversion to its pharmacologically active metabolite, dextroamphetamine.[71] Centrally, dextroamphetamine increases neurotransmitter activity of dopamine and norepinephrine in prefrontal cortical regions that regulate cognitive control of behavior.[69][71] Similar to its therapeutic effect in ADHD, dextroamphetamine enhances cognitive control and may reduce impulsivity in patients with BED by enhancing the cognitive processes responsible for overriding prepotent feeding responses that precede binge eating episodes.[69][73][74] In addition, dextroamphetamine's actions outside of the central nervous system may also contribute to its treatment effects in BED. Peripherally, dextroamphetamine triggers lipolysis through noradrenergic signaling in adipose fat cells, leading to the release of triglycerides into blood plasma to be utilized as a fuel substrate.[70][75] Dextroamphetamine also activates TAAR1 in peripheral organs along the gastrointestinal tract that are involved in the regulation of food intake and body weight.[72] Together, these actions confer an anorexigenic effect that promotes satiety in response to feeding and may decrease binge eating as a secondary effect.[74][72]
Medical reviews of randomized controlled trials have demonstrated that lisdexamfetamine, at doses between 50–70mg, is safe and effective for the treatment of moderate-to-severe BED in adults.[sources 5] These reviews suggest that lisdexamfetamine is persistently effective at treating BED and is associated with significant reductions in the number of binge eating days and binge eating episodes per week.[sources 5] Furthermore, a meta-analytic systematic review highlighted an open-label, 12-month extension safety and tolerability study that reported lisdexamfetamine remained effective at reducing the number of binge eating days for the duration of the study.[74] In addition, both a review and a meta-analytic systematic review found lisdexamfetamine to be superior to placebo in several secondary outcome measures, including persistent binge eating cessation, reduction of obsessive-compulsive related binge eating symptoms, reduction of body-weight, and reduction of triglycerides.[70][74] Lisdexamfetamine, like all pharmaceutical amphetamines, has direct appetite suppressant effects that may be therapeutically useful in both BED and its comorbidities.[36][74] Based on reviews of neuroimaging studies involving BED-diagnosed participants, therapeautic neuroplasticity in dopaminergic and noradrenergic pathways from long-term use of lisdexamfetamine may be implicated in lasting improvements in the regulation of eating behaviors that are observed even after the drug is discontinued.[36][71][74]
Amphetamine’s therapeutic mode of action in narcolepsy primarily involves increasing monoamine neurotransmitter activity in the ARAS.[17][81][82] This includes noradrenergic neurons in the locus coeruleus, dopaminergic neurons in the ventral tegmental area, histaminergic neurons in the tuberomammillary nucleus, and serotonergic neurons in the dorsal raphe nucleus.[80][82] Dextroamphetamine, the more dopaminergic enantiomer of amphetamine, is particularly effective at promoting wakefulness because dopamine release has the greatest influence on cortical activation and cognitive arousal, relative to other monoamines.[17] In contrast, levoamphetamine may have a greater effect on cataplexy, a symptom more sensitive to the effects of norepinephrine and serotonin.[17] Noradrenergic and serotonergic nuclei in the ARAS are involved in the regulation of the REM sleep cycle and function as "REM-off" cells, with amphetamine's effect on norepinephrine and serotonin contributing to the suppression of REM sleep and a possible reduction of cataplexy at high doses.[17][78][80]
The American Academy of Sleep Medicine (AASM) 2021 clinical practice guideline conditionally recommends dextroamphetamine for the treatment of both type 1 and type 2 narcolepsy.[83] Treatment with pharmaceutical amphetamines is generally less preferred relative to other stimulants (e.g., modafinil) and is considered a third-line treatment option.[47][84][85] Medical reviews indicate that amphetamine is safe and effective for the treatment of narcolepsy.[17][47][83] Amphetamine appears to be most effective at improving symptoms associated with hypersomnolence, with three reviews finding clinically significant reductions in daytime sleepiness in patients with narcolepsy.[17][47][83] Additionally, these reviews suggest that amphetamine may dose-dependently improve cataplexy symptoms.[17][47][83] However, the quality of evidence for these findings is low and is consequently reflected in the AASM's conditional recommendation for dextroamphetamine as a treatment option for narcolepsy.[83]
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;[86][87] these cognition-enhancing effects of amphetamine are known to be partially mediated through the indirect activation of both dopamine D1 receptor and α2-adrenergic receptor in the prefrontal cortex.[26][86] A systematic review from 2014 found that low doses of amphetamine also improve memory consolidation, in turn leading to improved recall of information.[88] Therapeutic doses of amphetamine also enhance cortical network efficiency, an effect which mediates improvements in working memory in all individuals.[26][89] 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][90][91] 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][91][92] Based upon studies of self-reported illicit stimulant use, 5–35% of college students use diverted ADHD stimulants, which are primarily used for enhancement of academic performance rather than as recreational drugs.[93][94][95] However, high amphetamine doses that are above the therapeutic range can interfere with working memory and other aspects of cognitive control.[26][91]
Physical performance
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.[96][97] 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][98][99] Amphetamine improves endurance and reaction time primarily through reuptake inhibition and release of dopamine in the central nervous system.[98][99][100] 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.[99][101][102] At therapeutic doses, the adverse effects of amphetamine do not impede athletic performance;[27][98] however, at much higher doses, amphetamine can induce effects that severely impair performance, such as rapid muscle breakdown and elevated body temperature.[28][98]
Recreational
Amphetamine, specifically the more dopaminergic dextrorotatory enantiomer (dextroamphetamine), is also used recreationally as a euphoriant and aphrodisiac, and like other amphetamines; is used as a club drug for its energetic and euphoric high. Dextroamphetamine (d-amphetamine) is considered to have a high potential for misuse in a recreational manner since individuals typically report feeling euphoric, more alert, and more energetic after taking the drug.[103][104][105] A notable part of the 1960s mod subculture in the UK was recreational amphetamine use, which was used to fuel all-night dances at clubs like Manchester's Twisted Wheel. Newspaper reports described dancers emerging from clubs at 5 a.m. with dilated pupils.[106] Mods used the drug for stimulation and alertness, which they viewed as different from the intoxication caused by alcohol and other drugs.[106] Dr. Andrew Wilson argues that for a significant minority, "amphetamines symbolised the smart, on-the-ball, cool image" and that they sought "stimulation not intoxication [...] greater awareness, not escape" and "confidence and articulacy" rather than the "drunken rowdiness of previous generations."[106] Dextroamphetamine's dopaminergic (rewarding) properties affect the mesocorticolimbic circuit; a group of neural structures responsible for incentive salience (i.e., "wanting"; desire or craving for a reward and motivation), positive reinforcement and positively-valenced emotions, particularly ones involving pleasure.[107] Large recreational doses of dextroamphetamine may produce symptoms of dextroamphetamine overdose.[105] Recreational users sometimes open dexedrine capsules and crush the contents in order to insufflate (snort) it or subsequently dissolve it in water and inject it.[105] Immediate-release formulations have higher potential for abuse via insufflation (snorting) or intravenous injection due to a more favorable pharmacokinetic profile and easy crushability (especially tablets).[108][109] Injection into the bloodstream can be dangerous because insoluble fillers within the tablets can block small blood vessels.[105] Chronic overuse of dextroamphetamine can lead to severe drug dependence, resulting in withdrawal symptoms when drug use stops.[105]
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.[28][40] Amphetamine products such as Adderall, Dexedrine, and their generic equivalents are currently approved by the U.S. FDA for long-term therapeutic use.[37][28]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.[40]
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 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 also has a slight analgesic effect and can enhance the pain relieving effects of opioids.[1][40]
FDA-commissioned studies from 2011 indicate that in children, young adults, and adults there is no association between serious adverse cardiovascular events (sudden death, heart attack, and stroke) and the medical use of amphetamine or other ADHD stimulants.[sources 7] However, amphetamine pharmaceuticals are contraindicated in individuals with cardiovascular disease.[sources 8]
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.[28][40] Less common side effects include anxiety, change in libido, grandiosity, irritability, repetitive or obsessive behaviors, and restlessness;[sources 9] 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][41][42] Although very rare, this psychosis can also occur at therapeutic doses during long-term therapy.[28][42][43] According to the FDA, "there is no systematic evidence" that stimulants produce aggressive behavior or hostility.[28]
Amphetamine has also been shown to produce a conditioned place preference in humans taking therapeutic doses,[65][122] meaning that individuals acquire a preference for spending time in places where they have previously used amphetamine.[122][123]
addiction – a biopsychosocial disorder characterized by persistent use of drugs (including alcohol) despite substantial harm and adverse consequences
addictive drug – psychoactive substances that with repeated use are associated with significantly higher rates of substance use disorders, due in large part to the drug's effect on brain reward systems
dependence – an adaptive state associated with a withdrawal syndrome upon cessation of repeated exposure to a stimulus (e.g., drug intake)
drug sensitization or reverse tolerance – the escalating effect of a drug resulting from repeated administration at a given dose
drug withdrawal – symptoms that occur upon cessation of repeated drug use
psychological dependence – dependence socially seen as being extremely mild compared to physical dependence (e.g., with enough willpower it could be overcome)
reinforcing stimuli – stimuli that increase the probability of repeating behaviors paired with them
rewarding stimuli – stimuli that the brain interprets as intrinsically positive and desirable or as something to approach
sensitization – an amplified response to a stimulus resulting from repeated exposure to it
substance use disorder – a condition in which the use of substances leads to clinically and functionally significant impairment or distress
tolerance – the diminishing effect of a drug resulting from repeated administration at a given dose
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 glutamateco-release by such psychostimulants,[126][127]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.[126][128] Phosphorylated CREB increases levels of ΔFosB, which in turn represses the c-Fos gene with the help of corepressors;[126][129][130]c-Fosrepression acts as a molecular switch that enables the accumulation of ΔFosB in the neuron.[131] A highly stable (phosphorylated) form of ΔFosB, one that persists in neurons for 1–2months, slowly accumulates following repeated high-dose exposure to stimulants through this process.[129][130] 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.[129][130]
Addiction is a serious risk with heavy recreational amphetamine use, but is unlikely to occur from long-term medical use at therapeutic doses;[45][46][47] in fact, lifetime stimulant therapy for ADHD that begins during childhood reduces the risk of developing substance use disorders as an adult.[44] 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.[132][133] Individuals who frequently self-administer high doses of amphetamine have a high risk of developing an amphetamine addiction, since chronic use at high doses gradually increases the level of accumbalΔFosB, a "molecular switch" and "master control protein" for addiction.[124][134][135] 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.[134][136] 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.[137][138] Exercise therapy improves clinical treatment outcomes and may be used as an adjunct therapy with behavioral therapies for addiction.[137][139][sources 10]
ΔJunD, a transcription factor, and G9a, a histone methyltransferase enzyme, both oppose the function of ΔFosB and inhibit increases in its expression.[124][135][145] 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).[135] Similarly, accumbal G9a hyperexpression results in markedly increased histone 3 lysineresidue 9 dimethylation (H3K9me2) and blocks the induction of ΔFosB-mediated neural and behavioral plasticity by chronic drug use,[sources 12] which occurs via H3K9me2-mediated repression of transcription factors for ΔFosB and H3K9me2-mediated repression of various ΔFosB transcriptional targets (e.g., CDK5).[135][145][146] ΔFosB also plays an important role in regulating behavioral responses to natural rewards, such as palatable food, sex, and exercise.[136][135][149] 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.[136][135] 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.[136][150][151] These sexual addictions are associated with a dopamine dysregulation syndrome which occurs in some patients taking dopaminergic drugs.[136][149]
The effects of amphetamine on gene regulation are both dose- and route-dependent.[141] Most of the research on gene regulation and addiction is based upon animal studies with intravenous amphetamine administration at very high doses.[141] 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.[141] This suggests that medical use of amphetamine does not significantly affect gene regulation.[141]
As of December 2019,[update] there is no effective pharmacotherapy for amphetamine addiction.[152][153][154] Reviews from 2015 and 2016 indicated that TAAR1-selective agonists have significant therapeutic potential as a treatment for psychostimulant addictions;[39][155] however, as of February 2016,[update] the only compounds which are known to function as TAAR1-selective agonists are experimental drugs.[39][155] Amphetamine addiction is largely mediated through increased activation of dopamine receptors and co-localizedNMDA receptors[note 13] in the nucleus accumbens;[133]magnesium ions inhibit NMDA receptors by blocking the receptor calcium channel.[133][156] One review suggested that, based upon animal testing, pathological (addiction-inducing) psychostimulant use significantly reduces the level of intracellular magnesium throughout the brain.[133]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.[133]
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 10] Exercise leads to better treatment outcomes when used as an adjunct treatment, particularly for psychostimulant addictions.[137][139][158] 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.[136][158] This is the opposite of pathological stimulant use, which induces decreased striatal DRD2 density.[136] One review noted that exercise may also prevent the development of a drug addiction by altering ΔFosB or c-Fosimmunoreactivity in the striatum or other parts of the reward system.[138]
More information Form of neuroplasticity or behavioral plasticity, Type of reinforcer ...
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.[159][160]
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 24hours of their last dose."[161] This review noted that withdrawal symptoms in chronic, high-dose users are frequent, occurring in roughly 88% of cases, and persist for 3–4weeks with a marked "crash" phase occurring during the first week.[161] 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.[161] The review indicated that the severity of withdrawal symptoms is positively correlated with the age of the individual and the extent of their dependence.[161] Mild withdrawal symptoms from the discontinuation of amphetamine treatment at therapeutic doses can be avoided by tapering the dose.[1]
An amphetamine overdose can lead to many different symptoms, but is rarely fatal with appropriate care.[1][111][162] The severity of overdose symptoms increases with dosage and decreases with drug tolerance to amphetamine.[40][111] Tolerant individuals have been known to take as much as 5grams of amphetamine in a day, which is roughly 100times the maximum daily therapeutic dose.[111] 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 3,788deaths worldwide (3,425–4,145deaths, 95%confidence).[note 15][163]
In rodents and primates, sufficiently high doses of amphetamine cause dopaminergic neurotoxicity, or damage to dopamine neurons, which is characterized by dopamine terminaldegeneration and reduced transporter and receptor function.[165][166] There is no evidence that amphetamine is directly neurotoxic in humans.[167][168] 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 14]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.[166] 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.[166]
An amphetamine overdose can result in a stimulant psychosis that may involve a variety of symptoms, such as delusions and paranoia.[41][42] A Cochrane review on treatment for amphetamine, dextroamphetamine, and methamphetamine psychosis states that about 5–15% of users fail to recover completely.[41][171] 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 rarely arises from therapeutic use.[28][42][43]
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.[28] Acidic substances reduce the absorption of amphetamine and increase urinary excretion, and alkaline substances do the opposite.[28] 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).[28]
Pharmacodynamics
For a simpler and less technical explanation of amphetamine's mechanism of action, see Adderall §Mechanism of action.
Pharmacodynamics of amphetamine in a dopamine neuron
Amphetamine enters the presynaptic neuron across the neuronal membrane or through DAT.[38] Once inside, it binds to TAAR1 or enters synaptic vesicles through VMAT2.[38][177] 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.[177][178] When amphetamine binds to TAAR1, it reduces the firing rate of the dopamine neuron via G protein-coupled inwardly rectifying potassium channels (GIRKs) and activates protein kinase A (PKA) and protein kinase C (PKC), which subsequently phosphorylate DAT.[38][179][180]PKA phosphorylation causes DAT to withdraw into the presynaptic neuron (internalize) and cease transport.[38]PKC-phosphorylated DAT may either operate in reverse or, like PKA-phosphorylated DAT, internalize and cease transport.[38] 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.[181][182]
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.[38][60] 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.[38][60][177] The reinforcing and motivational salience-promoting effects of amphetamine are due mostly 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.[2]
Amphetamine has been identified as a potent full agonist of trace amine-associated receptor 1 (TAAR1), a Gs-coupled and Gq-coupledG protein-coupled receptor (GPCR) discovered in 2001, which is important for regulation of brain monoamines.[38][183] Activation of TAAR1 increases cAMPTooltip cyclic adenosine monophosphate production via adenylyl cyclase activation and inhibits monoamine transporter function.[38][184] 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.[38][39] Notably, amphetamine and trace amines possess high binding affinities for TAAR1, but not for monoamine autoreceptors.[38][39] 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.[38]
Dextroamphetamine is a more potent agonist of TAAR1 than levoamphetamine.[203] Consequently, dextroamphetamine produces greater CNS stimulation than levoamphetamine, roughly three to four times more, but levoamphetamine has slightly stronger cardiovascular and peripheral effects.[40][203]
Dopamine
In certain brain regions, amphetamine increases the concentration of dopamine in the synaptic cleft.[38] Amphetamine can enter the presynaptic neuron either through DAT or by diffusing across the neuronal membrane directly.[38] As a consequence of DAT uptake, amphetamine produces competitive reuptake inhibition at the transporter.[38] Upon entering the presynaptic neuron, amphetamine activates TAAR1 which, through protein kinase A (PKA) and protein kinase C (PKC) signaling, causes DAT phosphorylation.[38] Phosphorylation by either protein kinase can result in DAT internalization (non-competitive reuptake inhibition), but PKC-mediated phosphorylation alone induces the reversal of dopamine transport through DAT (i.e., dopamine efflux).[note 16][38][204] 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.[183][181][182] Through direct activation of G protein-coupled inwardly-rectifying potassium channels, TAAR1 reduces the firing rate of dopamine neurons, preventing a hyper-dopaminergic state.[179][180][205]
Amphetamine is also a substrate for the presynaptic vesicular monoamine transporter, VMAT2.[177][178] 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.[177][178] Subsequently, the cytosolic dopamine molecules are released from the presynaptic neuron into the synaptic cleft via reverse transport at DAT.[38][177][178]
Norepinephrine
Similar to dopamine, amphetamine dose-dependently increases the level of synaptic norepinephrine, the direct precursor of epinephrine.[48][60] Based upon neuronal TAAR1 mRNA expression, amphetamine is thought to affect norepinephrine analogously to dopamine.[38][177][204] 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.[38][177]
Serotonin
Amphetamine exerts analogous, yet less pronounced, effects on serotonin as on dopamine and norepinephrine.[38][60] Amphetamine affects serotonin via VMAT2 and, like norepinephrine, is thought to phosphorylate SERT via TAAR1.[38][177] Like dopamine, amphetamine has low, micromolar affinity at the human 5-HT1A receptor.[195][196]
Other neurotransmitters, peptides, hormones, and enzymes
More information Enzyme, KA (nMTooltip nanomolar) ...
In December 2017, the first study assessing the interaction between amphetamine and human carbonic anhydrase enzymes was published;[202] 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.[202] Based upon preclinical research, cerebral carbonic anhydrase activation has cognition-enhancing effects;[207] 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.[207]
Pharmacokinetics
The oral bioavailability of amphetamine varies with gastrointestinal pH;[28] it is well absorbed from the gut, and bioavailability is typically 90%.[9] Amphetamine is a weak base with a pKa of 9.9;[3] 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.[3][28] Conversely, an acidic pH means the drug is predominantly in a water-soluble cationic (salt) form, and less is absorbed.[3] Approximately 20% 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-lives of amphetamine enantiomers differ and vary with urine pH.[3] At normal urine pH, the half-lives of dextroamphetamine and levoamphetamine are 9–11hours and 11–14hours, respectively.[3] Highly acidic urine will reduce the enantiomer half-lives to 7hours;[16] highly alkaline urine will increase the half-lives up to 34hours.[16] The immediate-release and extended release variants of salts of both isomers reach peak plasma concentrations at 3hours and 7hours post-dose respectively.[3] Amphetamine is eliminated via the kidneys, with 30–40% of the drug being excreted unchanged at normal urinary pH.[3] When the urinary pH is basic, amphetamine is in its free base form, so less is excreted.[3] 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.[3] Following oral administration, amphetamine appears in urine within 3hours.[16] Roughly 90% of ingested amphetamine is eliminated 3days after the last oral dose.[16]
Lisdexamfetamine is a prodrug of dextroamphetamine.[208][209] It is not as sensitive to pH as amphetamine when being absorbed in the gastrointestinal tract.[209] Following absorption into the blood stream, lisdexamfetamine is completely converted by red blood cells to dextroamphetamine and the amino acidL-lysine by hydrolysis via undetermined aminopeptidaseenzymes.[209][208][210] This is the rate-limiting step in the bioactivation of lisdexamfetamine.[208] The elimination half-life of lisdexamfetamine is generally less than 1hour.[209][208] Due to the necessary conversion of lisdexamfetamine into dextroamphetamine, levels of dextroamphetamine with lisdexamfetamine peak about one hour later than with an equivalent dose of immediate-release dextroamphetamine.[208][210] Presumably due to its rate-limited activation by red blood cells, intravenous administration of lisdexamfetamine shows greatly delayed time to peak and reduced peak levels compared to intravenous administration of an equivalent dose of dextroamphetamine.[208] The pharmacokinetics of lisdexamfetamine are similar regardless of whether it is administered orally, intranasally, or intravenously.[208][210] Hence, in contrast to dextroamphetamine, parenteral use does not enhance the subjective effects of lisdexamfetamine.[208][210] Because of its behavior as a prodrug and its pharmacokinetic differences, lisdexamfetamine has a longer duration of therapeutic effect than immediate-release dextroamphetamine and shows reduced misuse potential.[208][210]
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).[3] The remaining 10–20% is excreted as the active metabolites.[3] Benzoic acid is metabolized by XM-ligase into an intermediate product, benzoyl-CoA, which is then metabolized by GLYAT into hippuric acid.[216]
Pharmacomicrobiomics
The human metagenome (i.e., the genetic composition of an individual and all microorganisms that reside on or within the individual's body) varies considerably between individuals.[220][221] Since the total number of microbial and viral cells in the human body (over 100trillion) greatly outnumbers human cells (tens of trillions),[note 18][220][222] 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.[220][221][223] The field that studies these interactions is known as pharmacomicrobiomics.[220]
Similar to most biomolecules and other orally administeredxenobiotics (i.e., drugs), amphetamine is predicted to undergo promiscuous metabolism by human gastrointestinal microbiota (primarily bacteria) prior to absorption into the blood stream.[223] The first amphetamine-metabolizing microbial enzyme, tyramine oxidase from a strain of E. coli commonly found in the human gut, was identified in 2019.[223] This enzyme was found to metabolize amphetamine, tyramine, and phenethylamine with roughly the same binding affinity for all three compounds.[223]
Related endogenous compounds
Further informationon related compounds: Trace amine
Amphetamine has a very similar structure and function to the endogenous trace amines, which are naturally occurring neuromodulator molecules produced in the human body and brain.[38][48][224] Among this group, the most closely related compounds are phenethylamine, the parent compound of amphetamine, and N-methylphenethylamine, a structural isomer of amphetamine (i.e., it has an identical molecular formula).[38][48][225] 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.[48][225] In turn, N-methylphenethylamine is metabolized from phenethylamine by phenylethanolamine N-methyltransferase, the same enzyme that metabolizes norepinephrine into epinephrine.[48][225] Like amphetamine, both phenethylamine and N-methylphenethylamine regulate monoamine neurotransmission via TAAR1;[38][224][225] unlike amphetamine, both of these substances are broken down by monoamine oxidase B, and therefore have a shorter half-life than amphetamine.[48][225]
The substituted derivatives of amphetamine, or "substituted amphetamines", are a broad range of chemicals that contain amphetamine as a "backbone";[4][50][231] specifically, this chemical class includes derivative compounds that are formed by replacing one or more hydrogen atoms in the amphetamine core structure with substituents.[4][50][232] The class includes amphetamine itself, stimulants like methamphetamine, serotonergic empathogens like MDMA, and decongestants like ephedrine, among other subgroups.[4][50][231]
Since the first preparation was reported in 1887,[233] numerous synthetic routes to amphetamine have been developed.[234][235] The most common route of both legal and illicit amphetamine synthesis employs a non-metal reduction known as the Leuckart reaction (method1).[49][236] 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.[236][237]
A number of chiral resolutions have been developed to separate the two enantiomers of amphetamine.[234] For example, racemic amphetamine can be treated with d-tartaric acid to form a diastereoisomeric salt which is fractionally crystallized to yield dextroamphetamine.[238] Chiral resolution remains the most economical method for obtaining optically pure amphetamine on a large scale.[239] 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.[239]
A large number of alternative synthetic routes to amphetamine have been developed based on classic organic reactions.[234][235] 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 (method2).[240] Another example employs the Ritter reaction (method3). 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.[241][242] 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 (method4).[243]
Top: Chiral resolution of amphetamine Bottom: Stereoselective synthesis of amphetamine
Method2: Synthesis by Friedel–Crafts alkylation
Method3: Ritter synthesis
Method4: Synthesis via Hofmann and Curtius rearrangements
Method5: Synthesis by Knoevenagel condensation
Method6: Synthesis using phenylacetone and ammonia
Detection in body fluids
Amphetamine is frequently measured in urine or blood as part of a drug test for sports, employment, poisoning diagnostics, and forensics.[sources 18] Techniques such as immunoassay, which is the most common form of amphetamine test, may cross-react with a number of sympathomimetic drugs.[248] Chromatographic methods specific for amphetamine are employed to prevent false positive results.[249] Chiral separation techniques may be employed to help distinguish the source of the drug, whether prescription amphetamine, prescription amphetamine prodrugs, (e.g., selegiline), over-the-counter drug products that contain levomethamphetamine,[note 20] or illicitly obtained substituted amphetamines.[249][252][253] Several prescription drugs produce amphetamine as a metabolite, including benzphetamine, clobenzorex, famprofazone, fenproporex, lisdexamfetamine, mesocarb, methamphetamine, prenylamine, and selegiline, among others.[2][254][255] These compounds may produce positive results for amphetamine on drug tests.[254][255] Amphetamine is generally only detectable by a standard drug test for approximately 24hours, although a high dose may be detectable for 2–4days.[248]
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.[252]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.[249] GC–MS of amphetamine and methamphetamine with the chiral derivatizing agent Mosher'sacid chloride allows for the detection of both dextroamphetamine and dextromethamphetamine in urine.[249] 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.[249]
Amphetamine was first synthesized in 1887 in Germany by Romanian chemist Lazăr Edeleanu who named it phenylisopropylamine;[233][257][258] its stimulant effects remained unknown until 1927, when it was independently resynthesized by Gordon Alles and reported to have sympathomimetic properties.[258] 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 3years 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.[51][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.[233][259][260] As the addictive properties of the drug became known, governments began to place strict controls on the sale of amphetamine.[233] For example, during the early 1970s in the United States, amphetamine became a scheduleII controlled substance under the Controlled Substances Act.[261] In spite of strict government controls, amphetamine has been used legally or illicitly by people from a variety of backgrounds, including authors,[262] musicians,[263] mathematicians,[264] and athletes.[27]
Amphetamine is still illegally synthesized today in clandestine labs and sold on the black market, primarily in European countries.[265] Among European Union (EU) member states in 2018,[update] 11.9million adults of ages 15–64 have used amphetamine or methamphetamine at least once in their lives and 1.7million have used either in the last year.[266] During 2012, approximately 5.9metric tons of illicit amphetamine were seized within EU member states;[267] the "street price" of illicit amphetamine within the EU ranged from €6–38per gram during the same period.[267] Outside Europe, the illicit market for amphetamine is much smaller than the market for methamphetamine and MDMA.[265]
Several currently marketed amphetamine formulations contain both enantiomers, including those marketed under the brand names Adderall, AdderallXR, Mydayis,[note 1] AdzenysER, Adzenys XR-ODT, DyanavelXR, Evekeo, and EvekeoODT. Of those, Evekeo (including EvekeoODT) is the only product containing only racemic amphetamine (as amphetamine sulfate), and is therefore the only one whose active moiety can be accurately referred to simply as "amphetamine".[1][35][115] 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.[37][209] The free base of racemic amphetamine was previously available as Benzedrine, Psychedrine, and Sympatedrine.[2] Levoamphetamine was previously available as Cydril.[2] Many current amphetamine pharmaceuticals are salts due to the comparatively high volatility of the free base.[2][37][49] However, oral suspension and orally disintegrating tablet (ODT) dosage forms composed of the free base were introduced in 2015 and 2016, respectively.[115][278][279] Some of the current brands and their generic equivalents are listed below.
More information Brand name, United StatesAdopted Name ...
Adderall and other mixed amphetamine salts products such as Mydayis are not racemic amphetamine – they are a mixture composed of equal parts racemate and dextroamphetamine. See Mixed amphetamine salts for more information about the mixture, and this section for information about the various mixtures of amphetamine enantiomers currently marketed.
Enantiomers are molecules that are mirror images of one another; they are structurally identical, but of the opposite orientation.[24] Levoamphetamine and dextroamphetamine are also known as L-amph or levamfetamine (INN) and D-amph or dexamfetamine (INN) respectively.[22]
The brand name Adderall is used throughout this article to refer to the amphetamine four-salt mixture it contains (dextroamphetamine sulfate 25%, dextroamphetamine saccharate 25%, amphetamine sulfate 25%, and amphetamine aspartate 25%). The nonproprietary name, which lists all four active constituent chemicals, is excessively lengthy.[37]
The term "amphetamines" also refers to a chemical class, but, unlike the class of substituted amphetamines,[4] the "amphetamines" class does not have a standardized definition in academic literature.[18] One of the more restrictive definitions of this class includes only the racemate and enantiomers of amphetamine and methamphetamine.[18] The most general definition of the class encompasses a broad range of pharmacologically and structurally related compounds.[18] 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).[58]
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).[58]
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.[58]
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.[110]
According to one review, amphetamine can be prescribed to individuals with a history of abuse provided that appropriate medication controls are employed, such as requiring daily pick-ups of the medication from the prescribing physician.[2]
In individuals who experience sub-normal height and weight gains, a rebound to normal levels is expected to occur if stimulant therapy is briefly interrupted.[44][57][114] The average reduction in final adult height from 3years of continuous stimulant therapy is 2cm.[114]
In simpler terms, this necessary and sufficient relationship means that ΔFosB overexpression in the nucleus accumbens and addiction-related behavioral and neural adaptations always occur together and never occur alone.
4-Hydroxyamphetamine has been shown to be metabolized into 4-hydroxynorephedrine by dopamine beta-hydroxylase (DBH) in vitro and it is presumed to be metabolized similarly in vivo.[4][215] Evidence from studies that measured the effect of serum DBH concentrations on 4-hydroxyamphetamine metabolism in humans suggests that a different enzyme may mediate the conversion of 4-hydroxyamphetamine to 4-hydroxynorephedrine;[215][217] however, other evidence from animal studies suggests that this reaction is catalyzed by DBH in synaptic vesicles within noradrenergic neurons in the brain.[218][219]
There is substantial variation in microbiome composition and microbial concentrations by anatomical site.[220][221] Fluid from the human colon– which contains the highest concentration of microbes of any anatomical site– contains approximately one trillion (10^12) bacterial cells/ml.[220]
For uniformity, molar masses were calculated using the Lenntech Molecular Weight Calculator[289] and were within 0.01 g/mol of published pharmaceutical values.
dose = (1 / amphetamine base percentage) × scaling factor = (molecular masstotal / molecular massbase) × scaling factor. The values in this column were scaled to a 30mg 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.
Heal DJ, Smith SL, Gosden J, Nutt DJ (June 2013). "Amphetamine, past and present – a pharmacological and clinical perspective". Journal of Psychopharmacology. 27 (6): 479–496. doi:10.1177/0269881113482532. PMC3666194. PMID23539642. 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).
"Adderall XR Prescribing Information"(PDF). United States Food and Drug Administration. Shire US Inc. December 2013. pp.12–13. Retrieved 30 December 2013.
Glennon RA (2013). "Phenylisopropylamine stimulants: amphetamine-related agents". In Lemke TL, Williams DA, Roche VF, Zito W (eds.). Foye's principles of medicinal chemistry (7thed.). Philadelphia, US: Wolters Kluwer Health/Lippincott Williams & Wilkins. pp.646–648. ISBN9781609133450. 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.
Cashman JR, Xiong YN, Xu L, Janowsky A (March 1999). "N-oxygenation of amphetamine and methamphetamine by the human flavin-containing monooxygenase (form 3): role in bioactivation and detoxication". Journal of Pharmacology and Experimental Therapeutics. 288 (3): 1251–1260. PMID10027866.
Patel VB, Preedy VR, eds. (2022). Handbook of Substance Misuse and Addictions. Cham: Springer International Publishing. p.2006. doi:10.1007/978-3-030-92392-1. ISBN978-3-030-92391-4. Amphetamine is usually consumed via inhalation or orally, either in the form of a racemic mixture (levoamphetamine and dextroamphetamine) or dextroamphetamine alone (Childress et al. 2019). In general, all amphetamines have high bioavailability when consumed orally, and in the specific case of amphetamine, 90% of the consumed dose is absorbed in the gastrointestinal tract, with no significant differences in the rate and extent of absorption between the two enantiomers (Carvalho et al. 2012; Childress et al. 2019). The onset of action occurs approximately 30 to 45 minutes after consumption, depending on the ingested dose and on the degree of purity or on the concomitant consumption of certain foods (European Monitoring Centre for Drugs and Drug Addiction 2021a; Steingard et al. 2019). It is described that those substances that promote acidification of the gastrointestinal tract cause a decrease in amphetamine absorption, while gastrointestinal alkalinization may be related to an increase in the compound's absorption (Markowitz and Patrick 2017).
Santagati NA, Ferrara G, Marrazzo A, Ronsisvalle G (September 2002). "Simultaneous determination of amphetamine and one of its metabolites by HPLC with electrochemical detection". Journal of Pharmaceutical and Biomedical Analysis. 30 (2): 247–255. doi:10.1016/S0731-7085(02)00330-8. PMID12191709.
"Metabolism/Pharmacokinetics". Amphetamine. Hazardous Substances Data Bank. United States National Library of Medicine– Toxicology Data Network. Archived from the original on 2 October 2017. Retrieved 2 October 2017. Duration of effect varies depending on agent and urine pH. Excretion is enhanced in more acidic urine. Half-life is 7 to 34hours 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 3hours following oral administration.... Three days after a dose of (+ or -)-amphetamine, human subjects had excreted 91% of the (14)C in the urine
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. PMC3480574. PMID23065655. At the pathophysiological level, it is now clear that most narcolepsy cases with cataplexy, and a minority of cases (5–30%) without cataplexy or with atypical cataplexy-like symptoms, are caused by a lack of hypocretin (orexin) of likely an autoimmune origin. In these cases, once the disease is established, the majority of the 70,000 hypocretin-producing cells have been destroyed, and the disorder is irreversible.... Amphetamines are exceptionally wake-promoting, and at high doses also reduce cataplexy in narcoleptic patients, an effect best explained by its action on adrenergic and serotoninergic synapses.... The D-isomer is more specific for DA transmission and is a better stimulant compound. Some effects on cataplexy (especially for the L-isomer), secondary to adrenergic effects, occur at higher doses.... Numerous studies have shown that increased dopamine release is the main property explaining wake-promotion, although norepinephrine effects also contribute.
"Density". Amphetamine. United States National Library of Medicine– National Center for Biotechnology Information. PubChem Compound Database. 5 November 2016. Retrieved 9 November 2016.
"Chemical and Physical Properties". Amphetamine. United States National Library of Medicine– National Center for Biotechnology Information. PubChem Compound Database. Retrieved 13 October 2013.
"Compound Summary". Amphetamine. United States National Library of Medicine– National Center for Biotechnology Information. PubChem Compound Database. 11 April 2015. Retrieved 17 April 2015.
"Enantiomer". IUPAC Compendium of Chemical Terminology. International Union of Pure and Applied Chemistry. IUPAC Goldbook. 2009. doi:10.1351/goldbook.E02069. ISBN9780967855097. 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.
Rasmussen N (January 2015). Taba P, Lees A, Sikk K (eds.). "Amphetamine-Type Stimulants: The Early History of Their Medical and Non-Medical Uses". International Review of Neurobiology. The Neuropsychiatric Complications of Stimulant Abuse. 120. Academic Press: 9–25. doi:10.1016/bs.irn.2015.02.001. PMID26070751.
Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 13: Higher Cognitive Function and Behavioral Control". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nded.). New York, US: McGraw-Hill Medical. pp.318, 321. ISBN9780071481274. 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.
Liddle DG, Connor DJ (June 2013). "Nutritional supplements and ergogenic AIDS". Primary Care: Clinics in Office Practice. 40 (2): 487–505. doi:10.1016/j.pop.2013.02.009. PMID23668655. 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
Rasmussen N (July 2006). "Making the first anti-depressant: amphetamine in American medicine, 1929–1950". Journal of the History of Medicine and Allied Sciences. 61 (3): 288–323. doi:10.1093/jhmas/jrj039. PMID16492800. S2CID24974454. 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.
Wilens TE, Adler LA, Adams J, Sgambati S, Rotrosen J, Sawtelle R, etal. (January 2008). "Misuse and diversion of stimulants prescribed for ADHD: a systematic review of the literature". Journal of the American Academy of Child & Adolescent Psychiatry. 47 (1): 21–31. doi:10.1097/chi.0b013e31815a56f1. PMID18174822. 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.
"Guidelines on the Use of International Nonproprietary Names (INNS) for Pharmaceutical Substances". World Health Organization. 1997. Archived from the original on 9 January 2015. Retrieved 1 December 2014. In principle, INNs are selected only for the active part of the molecule which is usually the base, acid or alcohol. In some cases, however, the active molecules need to be expanded for various reasons, such as formulation purposes, bioavailability or absorption rate. In 1975 the experts designated for the selection of INN decided to adopt a new policy for naming such molecules. In future, names for different salts or esters of the same active substance should differ only with regard to the inactive moiety of the molecule.... The latter are called modified INNs (INNMs).
Rodan SC, Bryant E, Le A, Maloney D, Touyz S, McGregor IS, etal. (July 2023). "Pharmacotherapy, alternative and adjunctive therapies for eating disorders: findings from a rapid review". Journal of Eating Disorders. 11 (1): 112. doi:10.1186/s40337-023-00833-9. PMC10327007. PMID37415200. LDX is commonly used in the treatment of ADHD, and is the only treatment for BED that is currently approved by the Food and Drug Administration (FDA) and the Therapeutic Goods Administration (TGA). LDX, like all amphetamine stimulants, has direct appetite suppressant effects that may be therapeutically useful in BED, although long-term neuroadaptations in dopaminergic and noradrenergic systems caused by LDX may also be relevant, leading to improved regulation of eating behaviours, attentional processes and goal-directed behaviours.... Evidently, there is a substantial volume of trials with high-quality evidence supporting the efficacy of LDX in reducing binge eating frequency in treatment of adults with moderate to severe BED at 50–70 mg/day.
Shoptaw SJ, Kao U, Ling W (January 2009). Shoptaw SJ, Ali R (eds.). "Treatment for amphetamine psychosis". Cochrane Database of Systematic Reviews. 2009 (1): CD003026. doi:10.1002/14651858.CD003026.pub3. PMC7004251. PMID19160215. 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.
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. PMID21699268. S2CID3449435. Several other studies,[97-101] including a meta-analytic review[98] and a retrospective study,[97] suggested that stimulant therapy in childhood is associated with a reduced risk of subsequent substance use, cigarette smoking and alcohol use disorders.... Recent studies have demonstrated that stimulants, along with the non-stimulants atomoxetine and extended-release guanfacine, are continuously effective for more than 2-year treatment periods with few and tolerable adverse effects. The effectiveness of long-term therapy includes not only the core symptoms of ADHD, but also improved quality of life and academic achievements. The most concerning short-term adverse effects of stimulants, such as elevated blood pressure and heart rate, waned in long-term follow-up studies.... The current data do not support the potential impact of stimulants on the worsening or development of tics or substance abuse into adulthood. In the longest follow-up study (of more than 10years), lifetime stimulant treatment for ADHD was effective and protective against the development of adverse psychiatric disorders.
Malenka RC, Nestler EJ, Hyman SE, Holtzman DM (2015). "Chapter 16: Reinforcement and Addictive Disorders". Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (3rded.). New York: McGraw-Hill Medical. ISBN9780071827706. 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.
Kollins SH (May 2008). "A qualitative review of issues arising in the use of psycho-stimulant medications in patients with ADHD and co-morbid substance use disorders". Current Medical Research and Opinion. 24 (5): 1345–1357. doi:10.1185/030079908X280707. PMID18384709. S2CID71267668. 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.
Barateau L, Lopez R, Dauvilliers Y (October 2016). "Management of Narcolepsy". Current Treatment Options in Neurology. 18 (10): 43. doi:10.1007/s11940-016-0429-y. PMID27549768. The usefulness of amphetamines is limited by a potential risk of abuse, and their cardiovascular adverse effects (Table 1). That is why, even though they are cheaper than other drugs, and efficient, they remain third-line therapy in narcolepsy. Three class II studies showed an improvement of EDS in that disease.... Despite the potential for drug abuse or tolerance using stimulants, patients with narcolepsy rarely exhibit addiction to their medication.... Some stimulants, such as mazindol, amphetamines, and pitolisant, may also have some anticataplectic effects.
Hagel JM, Krizevski R, Marsolais F, Lewinsohn E, Facchini PJ (2012). "Biosynthesis of amphetamine analogs in plants". Trends in Plant Science. 17 (7): 404–412. Bibcode:2012TPS....17..404H. doi:10.1016/j.tplants.2012.03.004. PMID22502775. 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.
Millichap JG (2010). "Chapter 9: Medications for ADHD". In Millichap JG (ed.). Attention Deficit Hyperactivity Disorder Handbook: A Physician's Guide to ADHD (2nded.). New York, US: Springer. pp.121–123, 125–127. ISBN9781441913968. 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.
Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nded.). New York, US: McGraw-Hill Medical. pp.154–157. ISBN9780071481274.
Millichap JG (2010). "Chapter 9: Medications for ADHD". In Millichap JG (ed.). Attention Deficit Hyperactivity Disorder Handbook: A Physician's Guide to ADHD (2nded.). New York, US: Springer. pp.111–113. ISBN9781441913968.
Heal DJ, Smith SL (June 2022). "Prospects for new drugs to treat binge-eating disorder: Insights from psychopathology and neuropharmacology". Journal of Psychopharmacology. 36 (6): 680–703. doi:10.1177/02698811211032475. PMC9150143. PMID34318734. BED subjects have substantial decrements in their ventral striatal reward pathways and diminished ability to recruit fronto-cortical impulse-control circuits to implement dietary restraint.... There is not only substantial overlap between the psychopathology of BED and ADHD but also a clear association between these two disorders. Lisdexamfetamine's ability to reduce impulsivity and increase cognitive control in ADHD supports the hypothesis that efficacy in BED is dependent on treating its core obsessive, compulsive and impulsive behaviours.
McElroy SL (2017). "Pharmacologic Treatments for Binge-Eating Disorder". The Journal of Clinical Psychiatry. 78 Suppl 1: 14–19. doi:10.4088/JCP.sh16003su1c.03. PMID28125174. Genetic polymorphisms associated with abnormal dopaminergic signaling have been found in individuals who exhibit binge-eating behavior, and the binge-eating episodes,which often involve the consumption of highly palatable food, further stimulate the dopaminergic system. This ongoing stimulation may contribute to progressive impairments in dopamine signaling. Lisdexamfetamine is hypothesized to reduce binge-eating behavior by normalizing dopaminergic activity.... After 12 weeks, both studies found significant reductions in the number of binge-eating days per week in the active treatment group compared with placebo (P < .001 for both studies; Figure 1). Lisdexamfetamine was also found to be superior to placebo on a number of secondary outcome measures including global improvement, binge-eating cessation for 4 weeks, and reduction of obsessive-compulsive binge-eating symptoms, body weight, and triglycerides.
Boswell RG, Potenza MN, Grilo CM (January 2021). "The Neurobiology of Binge-eating Disorder Compared with Obesity: Implications for Differential Therapeutics". Clinical Therapeutics. 43 (1): 50–69. doi:10.1016/j.clinthera.2020.10.014. PMC7902428. PMID33257092. Stimulant medications may be especially effective for individuals with BED because of dual effects on reward and executive function systems. Indeed, the only FDA-approved pharmacotherapy for BED is LDX, a d-amphetamine prodrug.... In humans, RCTs found that LDX reduced binge eating and impulsivity/compulsivity symptoms. Notably, there is a strong correlation between compulsivity symptoms and severity/frequency of binge eating episodes observed in LDX trials. Further, in individuals with BED, changes in prefrontal brain systems associated with LDX treatment were related to treatment outcome.
Malenka RC, Nestler EJ, Hyman SE, Holtzman DM (2015). "Chapter 14: Higher Cognitive Function and Behavioral Control". Molecular neuropharmacology: a foundation for clinical neuroscience (3rded.). New York: McGraw-Hill Medical. ISBN9780071827706. Because behavioral responses in humans are not rigidly dictated by sensory inputs and drives, behavioral responses can instead be guided in accordance with short- or long-term goals, prior experience, and the environmental context. The response to a delicious-looking dessert is different depending on whether a person is alone staring into his or her refrigerator, is at a formal dinner party attended by his or her punctilious boss, or has just formulated the goal of losing 10 lb.... Adaptive responses depend on the ability to inhibit automatic or prepotent responses (eg, to ravenously eat the dessert or run from the snake) given certain social or environmental contexts or chosen goals and, in those circumstances, to select more appropriate responses. In conditions in which prepotent responses tend to dominate behavior, such as in drug addiction, where drug cues can elicit drug seeking (Chapter 16), or inattention deficit hyperactivity disorder (ADHD; described below), significant negative consequences can result.
Schneider E, Higgs S, Dourish CT (December 2021). "Lisdexamfetamine and binge-eating disorder: A systematic review and meta-analysis of the preclinical and clinical data with a focus on mechanism of drug action in treating the disorder"(PDF). European Neuropsychopharmacology. 53: 49–78. doi:10.1016/j.euroneuro.2021.08.001. PMID34461386. Our meta-analysis of the four RCT data sets (Guerdjikova et al., 2016; McElroy et al., 2015b; McElroy et al., 2016a) showed an overall significant effect of LDX on binge-eating symptom change.... BED has been described as an impulse control disorder since one of the key symptoms of the disorder is a lack of control over eating (American Psychiatric Association, 2013) and it is possible that LDX may be effective in treating BED at least in part by reducing impulsivity, compulsivity, and the repetitive nature of binge eating. There is extensive evidence that loss of impulse control in BED is a causal factor in provoking bingeing symptoms (Colles et al., 2008; Galanti et al., 2007; Giel et al., 2017; McElroy et al., 2016a; Nasser et al., 2004; Schag et al., 2013). More specifically, BED is associated with motor impulsivity and non-planning impulsivity which could initiate and maintain binge eating (Nasser et al., 2004). Neuroimaging studies using the Stroop task to measure impulse control have shown that BED patients have decreased BOLD fMRI activity in brain areas involved in self-regulation and impulse control including VMPFC, inferior frontal gyrus (IFG), and insula during performance of the task compared to lean and obese controls (Balodis et al., 2013b).... It is conceivable that in BED patients a low 30 mg dose of LDX could reduce food intake by suppressing appetite or enhancing satiety and higher (50 and 70 mg) doses of the drug may have a dual suppressant effect on food intake and binge-eating frequency.
Branis NM, Wittlin SD (2015). "Amphetamine-Like Analogues in Diabetes: Speeding towards Ketogenesis". Case Reports in Endocrinology. 2015: 917869. doi:10.1155/2015/917869. PMC4417573. PMID25960894. Peripheral norepinephrine concentration rises as well. As demonstrated after Dextroamphetamine administration, plasma norepinephrine can rise up to 400 pg/mL, a level comparable to that achieved during mild physical activity. Cumulative effect on norepinephrine concentration is likely when amphetamine-type medications are given in the setting of acute illness or combined with activities leading to catecholamine release, such as exercise.... The primary effect of norepinephrine on ketogenesis is mediated through increased substrate availability. As shown by Krentz et al., at high physiological concentrations, norepinephrine induces accelerated lipolysis and increases NEFA formation significantly. Secondly, norepinephrine stimulates ketogenesis directly at the hepatocyte level. As reported by Keller et al., norepinephrine infusion increased ketone bodies concentration to a greater degree when compared to NEFA concentration (155 ± 30 versus 57 ± 16%), suggesting direct hepatic ketogenic effect.
Muratore AF, Attia E (July 2022). "Psychopharmacologic Management of Eating Disorders". Current Psychiatry Reports. 24 (7): 345–351. doi:10.1007/s11920-022-01340-5. PMC9233107. PMID35576089. An 11-week, double-blind RCT examined the effects of three doses of lisdexamfetamine (30 mg/day, 50 mg/day, 70 mg/day) and placebo on binge eating frequency. Results indicated that 50 mg and 70 mg doses were superior to placebo in reducing binge eating. Two follow-up 12-week RCTs confirmed the superiority of 50 and 70 mg doses to placebo in improving binge eating and secondary outcome measures, including obsessive–compulsive symptoms, body weight, and global improvement. ... Subsequent studies of lisdexamfetamine provided further support for the medication's safety and efficacy and provided additional evidence that continued use may be better than placebo in preventing relapse. While it is considered safe and effective, lisdexamfetamine's side effect profile and risk for misuse may make it inappropriate for certain patients.
Barateau L, Pizza F, Plazzi G, Dauvilliers Y (August 2022). "Narcolepsy". Journal of Sleep Research. 31 (4): e13631. doi:10.1111/jsr.13631. PMID35624073. Narcolepsy type 1 was called "narcolepsy with cataplexy" before 2014 (AASM, 2005), but was renamed NT1 in the third and last international classification of sleep disorders (AASM, 2014).... A low level of Hcrt-1 in the CSF is very sensitive and specific for the diagnosis of NT1.... All patients with low CSF Hcrt-1 levels are considered as NT1 patients, even if they report no cataplexy (in about 10–20% of cases), and all patients with normal CSF Hcrt-1 levels (or without cataplexy when the lumbar puncture is not performed) as NT2 patients (Baumann et al., 2014).... In patients with NT1, the absence of Hcrt leads to the inhibition of regions that suppress REM sleep, thus allowing the activation of descending pathways inhibiting motoneurons, leading to cataplexy.
Malenka RC, Nestler EJ, Hyman SE, Holtzman DM (2015). "Chapter 10: Neural and Neuroendocrine Control of the Internal Milieu". Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (3rded.). New York: McGraw-Hill Medical. pp.456–457. ISBN9780071827706. More recently, the lateral hypothalamus was also found to play a central role in arousal. Neurons in this region contain cell bodies that produce the orexin (also called hypocretin) peptides (Chapter 6). These neurons project widely throughout the brain and are involved in sleep, arousal, feeding, reward,aspects of emotion, and learning. In fact, orexin is thought to promote feeding primarily by promoting arousal. Mutations in orexin receptors are responsible for narcolepsy in a canine model, knockout of the orexin gene produces narcolepsy in mice, and humans with narcolepsy have low or absent levels of orexin peptides in cerebrospinal fluid (Chapter 13). Lateral hypothalamus neurons have reciprocal connections with neurons that produce monoamine neurotransmitters (Chapter 6).
Malenka RC, Nestler EJ, Hyman SE, Holtzman DM (2015). "Chapter 13: Sleep and Arousal". Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (3rded.). McGraw-Hill Medical. p.521. ISBN9780071827706. The ARAS consists of several different circuits including the four main monoaminergic pathways discussed in Chapter 6. The norepinephrine pathway originates from the LC and related brainstem nuclei; the serotonergic neurons originate from the RN within the brainstem as well; the dopaminergic neurons originate in the ventral tegmental area (VTA); and the histaminergic pathway originates from neurons in the tuberomammillary nucleus (TMN) of the posterior hypothalamus. As discussed in Chapter 6, these neurons project widely throughout the brain from restricted collections of cell bodies. Norepinephrine, serotonin,dopamine, and histamine have complex modulatory functions and, in general, promote wakefulness. The PT in the brainstem is also an important component of the ARAS. Activity of PT cholinergic neurons (REM-on cells) promotes REM sleep, as noted earlier. During waking, REM-on cells are inhibited by a subset of ARAS norepinephrine and serotonin neurons called REM-off cells.
Shneerson JM (2009). Sleep medicine a guide to sleep and its disorders (2nded.). John Wiley & Sons. p.81. ISBN9781405178518. All the amphetamines enhance activity at dopamine, noradrenaline and 5HT synapses. They cause presynaptic release of preformed transmitters, and also inhibit the re-uptake of dopamine and noradrenaline. These actions are most prominent in the brainstem ascending reticular activating system and the cerebral cortex.
Schwartz JR, Roth T (2008). "Neurophysiology of sleep and wakefulness: basic science and clinical implications". Current Neuropharmacology. 6 (4): 367–378. doi:10.2174/157015908787386050. PMC2701283. PMID19587857. Alertness and associated forebrain and cortical arousal are mediated by several ascending pathways with distinct neuronal components that project from the upper brain stem near the junction of the pons and the midbrain.... Key cell populations of the ascending arousal pathway include cholinergic, noradrenergic, serotoninergic, dopaminergic, and histaminergic neurons located in the pedunculopontine and laterodorsal tegmental nucleus (PPT/LDT), locus coeruleus, dorsal and median raphe nucleus, and tuberomammillary nucleus (TMN), respectively.... The mechanism of action of sympathomimetic alerting drugs (eg, dextro- and methamphetamine, methylphenidate) is direct or indirect stimulation of dopaminergic and noradrenergic nuclei, which in turn heightens the efficacy of the ventral periaqueductal grey area and locus coeruleus, both components of the secondary branch of the ascending arousal system.... Sympathomimetic drugs have long been used to treat narcolepsy
Maski K, Trotti LM, Kotagal S, Robert Auger R, Rowley JA, Hashmi SD, etal. (September 2021). "Treatment of central disorders of hypersomnolence: an American Academy of Sleep Medicine clinical practice guideline". Journal of Clinical Sleep Medicine. 17 (9): 1881–1893. doi:10.5664/jcsm.9328. PMC8636351. PMID34743789. The TF identified 1 double-blind RCT, 1 single-blind RCT, and 1 retrospective observational long-term self-reported case series assessing the efficacy of dextroamphetamine in patients with narcolepsy type 1 and narcolepsy type 2. These studies demonstrated clinically significant improvements in excessive daytime sleepiness and cataplexy.
Dauvilliers Y, Barateau L (August 2017). "Narcolepsy and Other Central Hypersomnias". Continuum. 23 (4, Sleep Neurology): 989–1004. doi:10.1212/CON.0000000000000492. PMID28777172. Recent clinical trials and practice guidelines have confirmed that stimulants such as modafinil, armodafinil, or sodium oxybate (as first line); methylphenidate and pitolisant (as second line [pitolisant is currently only available in Europe]); and amphetamines (as third line) are appropriate medications for excessive daytime sleepiness.
Thorpy MJ, Bogan RK (April 2020). "Update on the pharmacologic management of narcolepsy: mechanisms of action and clinical implications". Sleep Medicine. 68: 97–109. doi:10.1016/j.sleep.2019.09.001. PMID32032921. The first agents used to treat EDS (ie, amphetamines, methylphenidate) are now considered second- or third-line options because newer medications have been developed with improved tolerability and lower abuse potential (eg, modafinil/armodafinil, solriamfetol, pitolisant)
Spencer RC, Devilbiss DM, Berridge CW (June 2015). "The Cognition-Enhancing Effects of Psychostimulants Involve Direct Action in the Prefrontal Cortex". Biological Psychiatry. 77 (11): 940–950. doi:10.1016/j.biopsych.2014.09.013. PMC4377121. PMID25499957. 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.
Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 10: Neural and Neuroendocrine Control of the Internal Milieu". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nded.). New York, US: McGraw-Hill Medical. p.266. ISBN9780071481274. Dopamine acts in the nucleus accumbens to attach motivational significance to stimuli associated with reward.
Clemow DB, Walker DJ (September 2014). "The potential for misuse and abuse of medications in ADHD: a review". Postgraduate Medicine. 126 (5): 64–81. doi:10.3810/pgm.2014.09.2801. PMID25295651. S2CID207580823. 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.
Parr JW (July 2011). "Attention-deficit hyperactivity disorder and the athlete: new advances and understanding". Clinics in Sports Medicine. 30 (3): 591–610. doi:10.1016/j.csm.2011.03.007. PMID21658550. 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.
Roelands B, de Koning J, Foster C, Hettinga F, Meeusen R (May 2013). "Neurophysiological determinants of theoretical concepts and mechanisms involved in pacing". Sports Medicine. 43 (5): 301–311. doi:10.1007/s40279-013-0030-4. PMID23456493. S2CID30392999. In high-ambient temperatures, dopaminergic manipulations clearly improve performance. The distribution of the power output reveals that after dopamine reuptake inhibition, subjects are able to maintain a higher power output compared with placebo.... Dopaminergic drugs appear to override a safety switch and allow athletes to use a reserve capacity that is 'off-limits' in a normal (placebo) situation.
Parker KL, Lamichhane D, Caetano MS, Narayanan NS (October 2013). "Executive dysfunction in Parkinson's disease and timing deficits". Frontiers in Integrative Neuroscience. 7: 75. doi:10.3389/fnint.2013.00075. PMC3813949. PMID24198770. Manipulations of dopaminergic signaling profoundly influence interval timing, leading to the hypothesis that dopamine influences internal pacemaker, or "clock," activity. For instance, amphetamine, which increases concentrations of dopamine at the synaptic cleft advances the start of responding during interval timing, whereas antagonists of D2 type dopamine receptors typically slow timing;... Depletion of dopamine in healthy volunteers impairs timing, while amphetamine releases synaptic dopamine and speeds up timing.
Rattray B, Argus C, Martin K, Northey J, Driller M (March 2015). "Is it time to turn our attention toward central mechanisms for post-exertional recovery strategies and performance?". Frontiers in Physiology. 6: 79. doi:10.3389/fphys.2015.00079. PMC4362407. PMID25852568. Aside from accounting for the reduced performance of mentally fatigued participants, this model rationalizes the reduced RPE and hence improved cycling time trial performance of athletes using a glucose mouthwash (Chambers et al., 2009) and the greater power output during a RPE matched cycling time trial following amphetamine ingestion (Swart, 2009).... Dopamine stimulating drugs are known to enhance aspects of exercise performance (Roelands et al., 2008)
Roelands B, De Pauw K, Meeusen R (June 2015). "Neurophysiological effects of exercise in the heat". Scandinavian Journal of Medicine & Science in Sports. 25 (Suppl 1): 65–78. doi:10.1111/sms.12350. PMID25943657. S2CID22782401. 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.
Schultz W (2015). "Neuronal reward and decision signals: from theories to data". Physiological Reviews. 95 (3): 853–951. doi:10.1152/physrev.00023.2014. PMC4491543. PMID26109341. Rewards in operant conditioning are positive reinforcers.... Operant behavior gives a good definition for rewards. Anything that makes an individual come back for more is a positive reinforcer and therefore a reward. Although it provides a good definition, positive reinforcement is only one of several reward functions.... Rewards are attractive. They are motivating and make us exert an effort.... Rewards induce approach behavior, also called appetitive or preparatory behavior, sexual behavior, and consummatory behavior.... Thus any stimulus, object, event, activity, or situation that has the potential to make us approach and consume it is by definition a reward.... Rewarding stimuli, objects, events, situations, and activities consist of several major components. First, rewards have basic sensory components (visual, auditory, somatosensory, gustatory, and olfactory)... Second, rewards are salient and thus elicit attention, which are manifested as orienting responses. The salience of rewards derives from three principal factors, namely, their physical intensity and impact (physical salience), their novelty and surprise (novelty/surprise salience), and their general motivational impact shared with punishers (motivational salience). A separate form not included in this scheme, incentive salience, primarily addresses dopamine function in addiction and refers only to approach behavior (as opposed to learning)... Third, rewards have a value component that determines the positively motivating effects of rewards and is not contained in, nor explained by, the sensory and attentional components. This component reflects behavioral preferences and thus is subjective and only partially determined by physical parameters. Only this component constitutes what we understand as a reward. It mediates the specific behavioral reinforcing, approach generating, and emotional effects of rewards that are crucial for the organism's survival and reproduction, whereas all other components are only supportive of these functions.... Rewards can also be intrinsic to behavior. They contrast with extrinsic rewards that provide motivation for behavior and constitute the essence of operant behavior in laboratory tests. Intrinsic rewards are activities that are pleasurable on their own and are undertaken for their own sake, without being the means for getting extrinsic rewards.... Intrinsic rewards are genuine rewards in their own right, as they induce learning, approach, and pleasure, like perfectioning, playing, and enjoying the piano. Although they can serve to condition higher order rewards, they are not conditioned, higher order rewards, as attaining their reward properties does not require pairing with an unconditioned reward.... These emotions are also called liking (for pleasure) and wanting (for desire) in addiction research and strongly support the learning and approach generating functions of reward.
Kessler S (January 1996). "Drug therapy in attention-deficit hyperactivity disorder". Southern Medical Journal. 89 (1): 33–38. doi:10.1097/00007611-199601000-00005. PMID8545689. S2CID12798818. 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.
Feinberg SS (November 2004). "Combining stimulants with monoamine oxidase inhibitors: a review of uses and one possible additional indication". The Journal of Clinical Psychiatry. 65 (11): 1520–1524. doi:10.4088/jcp.v65n1113. PMID15554766.
"Dyanavel XR- amphetamine suspension, extended release". DailyMed. Tris Pharma, Inc. 6 February 2019. Retrieved 22 December 2019. DYANAVEL XR contains d-amphetamine and l-amphetamine in a ratio of 3.2 to 1... The most common (≥2% in the DYANAVEL XR group and greater than placebo) adverse reactions reported in the Phase 3 controlled study conducted in 108 patients with ADHD (aged 6 to 12 years) were: epistaxis, allergic rhinitis and upper abdominal pain.... DOSAGE FORMS AND STRENGTHS Extended-release oral suspension contains 2.5 mg amphetamine base equivalents per mL.
Childs E, de Wit H (May 2009). "Amphetamine-induced place preference in humans". Biological Psychiatry. 65 (10): 900–904. doi:10.1016/j.biopsych.2008.11.016. PMC2693956. PMID19111278. 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.
Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and Addictive Disorders". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nded.). New York: McGraw-Hill Medical. pp.364–375. ISBN9780071481274.
Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues in Clinical Neuroscience. 15 (4): 431–443. PMC3898681. PMID24459410. Despite the importance of numerous psychosocial factors, at its core, drug addiction involves a biological process: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction.... A large body of literature has demonstrated that such ΔFosB induction in D1-type [nucleus accumbens] neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement... Another ΔFosB target is cFos: as ΔFosB accumulates with repeated drug exposure it represses c-Fos and contributes to the molecular switch whereby ΔFosB is selectively induced in the chronic drug-treated state.41.... Moreover, there is increasing evidence that, despite a range of genetic risks for addiction across the population, exposure to sufficiently high doses of a drug for long periods of time can transform someone who has relatively lower genetic loading into an addict.
Volkow ND, Koob GF, McLellan AT (January 2016). "Neurobiologic Advances from the Brain Disease Model of Addiction". New England Journal of Medicine. 374 (4): 363–371. doi:10.1056/NEJMra1511480. PMC6135257. PMID26816013. 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.
Renthal W, Nestler EJ (September 2009). "Chromatin regulation in drug addiction and depression". Dialogues in Clinical Neuroscience. 11 (3): 257–268. doi:10.31887/DCNS.2009.11.3/wrenthal. PMC2834246. PMID19877494. [Psychostimulants] increase cAMP levels in striatum, which activates protein kinase A (PKA) and leads to phosphorylation of its targets. This includes the cAMP response element binding protein (CREB), the phosphorylation of which induces its association with the histone acetyltransferase, CREB binding protein (CBP) to acetylate histones and facilitate gene activation. This is known to occur on many genes including fosB and c-fos in response to psychostimulant exposure. ΔFosB is also upregulated by chronic psychostimulant treatments, and is known to activate certain genes (eg, cdk5) and repress others (eg, c-fos) where it recruits HDAC1 as a corepressor.... Chronic exposure to psychostimulants increases glutamatergic [signaling] from the prefrontal cortex to the NAc. Glutamatergic signaling elevates Ca2+ levels in NAc postsynaptic elements where it activates CaMK (calcium/calmodulin protein kinases) signaling, which, in addition to phosphorylating CREB, also phosphorylates HDAC5. Figure 2: Psychostimulant-induced signaling events
Broussard JI (January 2012). "Co-transmission of dopamine and glutamate". The Journal of General Physiology. 139 (1): 93–96. doi:10.1085/jgp.201110659. PMC3250102. PMID22200950. Coincident and convergent input often induces plasticity on a postsynaptic neuron. The NAc integrates processed information about the environment from basolateral amygdala, hippocampus, and prefrontal cortex (PFC), as well as projections from midbrain dopamine neurons. Previous studies have demonstrated how dopamine modulates this integrative process. For example, high frequency stimulation potentiates hippocampal inputs to the NAc while simultaneously depressing PFC synapses (Goto and Grace, 2005). The converse was also shown to be true; stimulation at PFC potentiates PFC–NAc synapses but depresses hippocampal–NAc synapses. In light of the new functional evidence of midbrain dopamine/glutamate co-transmission (references above), new experiments of NAc function will have to test whether midbrain glutamatergic inputs bias or filter either limbic or cortical inputs to guide goal-directed behavior.
Kanehisa Laboratories (10 October 2014). "Amphetamine – Homo sapiens (human)". KEGG Pathway. Retrieved 31 October 2014. Most addictive drugs increase extracellular concentrations of dopamine (DA) in nucleus accumbens (NAc) and medial prefrontal cortex (mPFC), projection areas of mesocorticolimbic DA neurons and key components of the "brain reward circuit". Amphetamine achieves this elevation in extracellular levels of DA by promoting efflux from synaptic terminals.... Chronic exposure to amphetamine induces a unique transcription factor delta FosB, which plays an essential role in long-term adaptive changes in the brain.
Robison AJ, Nestler EJ (November 2011). "Transcriptional and epigenetic mechanisms of addiction". Nature Reviews Neuroscience. 12 (11): 623–637. doi:10.1038/nrn3111. PMC3272277. PMID21989194. ΔFosB serves as one of the master control proteins governing this structural plasticity.... ΔFosB also represses G9a expression, leading to reduced repressive histone methylation at the cdk5 gene. The net result is gene activation and increased CDK5 expression.... In contrast, ΔFosB binds to the c-fos gene and recruits several co-repressors, including HDAC1 (histone deacetylase 1) and SIRT 1 (sirtuin 1).... The net result is c-fos gene repression. Figure 4: Epigenetic basis of drug regulation of gene expression
Nestler EJ (December 2012). "Transcriptional mechanisms of drug addiction". Clinical Psychopharmacology and Neuroscience. 10 (3): 136–143. doi:10.9758/cpn.2012.10.3.136. PMC3569166. PMID23430970. The 35-37 kD ΔFosB isoforms accumulate with chronic drug exposure due to their extraordinarily long half-lives.... As a result of its stability, the ΔFosB protein persists in neurons for at least several weeks after cessation of drug exposure.... ΔFosB overexpression in nucleus accumbens induces NFκB... In contrast, the ability of ΔFosB to repress the c-Fos gene occurs in concert with the recruitment of a histone deacetylase and presumably several other repressive proteins such as a repressive histone methyltransferase
Nestler EJ (October 2008). "Transcriptional mechanisms of addiction: Role of ΔFosB". Philosophical Transactions of the Royal Society B: Biological Sciences. 363 (1507): 3245–3255. doi:10.1098/rstb.2008.0067. PMC2607320. PMID18640924. Recent evidence has shown that ΔFosB also represses the c-fos gene that helps create the molecular switch—from the induction of several short-lived Fos family proteins after acute drug exposure to the predominant accumulation of ΔFosB after chronic drug exposure
Ruffle JK (November 2014). "Molecular neurobiology of addiction: what's all the (Δ)FosB about?". The American Journal of Drug and Alcohol Abuse. 40 (6): 428–437. doi:10.3109/00952990.2014.933840. PMID25083822. S2CID19157711. ΔFosB is an essential transcription factor implicated in the molecular and behavioral pathways of addiction following repeated drug exposure.
Robison AJ, Nestler EJ (November 2011). "Transcriptional and epigenetic mechanisms of addiction". Nature Reviews Neuroscience. 12 (11): 623–637. doi:10.1038/nrn3111. PMC3272277. PMID21989194. ΔFosB has been linked directly to several addiction-related behaviors... Importantly, genetic or viral overexpression of ΔJunD, a dominant negative mutant of JunD which antagonizes ΔFosB- and other AP-1-mediated transcriptional activity, in the NAc or OFC blocks these key effects of drug exposure14,22–24. This indicates that ΔFosB is both necessary and sufficient for many of the changes wrought in the brain by chronic drug exposure. ΔFosB is also induced in D1-type NAc MSNs by chronic consumption of several natural rewards, including sucrose, high fat food, sex, wheel running, where it promotes that consumption14,26–30. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states.... ΔFosB serves as one of the master control proteins governing this structural plasticity.
Olsen CM (December 2011). "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology. 61 (7): 1109–1122. doi:10.1016/j.neuropharm.2011.03.010. PMC3139704. PMID21459101. 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).
Lynch WJ, Peterson AB, Sanchez V, Abel J, Smith MA (September 2013). "Exercise as a novel treatment for drug addiction: a neurobiological and stage-dependent hypothesis". Neuroscience & Biobehavioral Reviews. 37 (8): 1622–1644. doi:10.1016/j.neubiorev.2013.06.011. PMC3788047. PMID23806439. 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.
Zhou Y, Zhao M, Zhou C, Li R (July 2015). "Sex differences in drug addiction and response to exercise intervention: From human to animal studies". Frontiers in Neuroendocrinology. 40: 24–41. doi:10.1016/j.yfrne.2015.07.001. PMC4712120. PMID26182835. Collectively, these findings demonstrate that exercise may serve as a substitute or competition for drug abuse by changing ΔFosB or cFos immunoreactivity in the reward system to protect against later or previous drug use.... The postulate that exercise serves as an ideal intervention for drug addiction has been widely recognized and used in human and animal rehabilitation.
Linke SE, Ussher M (January 2015). "Exercise-based treatments for substance use disorders: evidence, theory, and practicality". The American Journal of Drug and Alcohol Abuse. 41 (1): 7–15. doi:10.3109/00952990.2014.976708. PMC4831948. PMID25397661. 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.
Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 4: Signal Transduction in the Brain". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nded.). New York, US: McGraw-Hill Medical. p.94. ISBN9780071481274.
Biliński P, Wojtyła A, Kapka-Skrzypczak L, Chwedorowicz R, Cyranka M, Studziński T (2012). "Epigenetic regulation in drug addiction". Annals of Agricultural and Environmental Medicine. 19 (3): 491–496. PMID23020045.
Blum K, Werner T, Carnes S, Carnes P, Bowirrat A, Giordano J, etal. (March 2012). "Sex, drugs, and rock 'n' roll: hypothesizing common mesolimbic activation as a function of reward gene polymorphisms". Journal of Psychoactive Drugs. 44 (1): 38–55. doi:10.1080/02791072.2012.662112. PMC4040958. PMID22641964. It has been found that deltaFosB gene in the NAc is critical for reinforcing effects of sexual reward. Pitchers and colleagues (2010) reported that sexual experience was shown to cause DeltaFosB accumulation in several limbic brain regions including the NAc, medial pre-frontal cortex, VTA, caudate, and putamen, but not the medial preoptic nucleus.... these findings support a critical role for DeltaFosB expression in the NAc in the reinforcing effects of sexual behavior and sexual experience-induced facilitation of sexual performance.... both drug addiction and sexual addiction represent pathological forms of neuroplasticity along with the emergence of aberrant behaviors involving a cascade of neurochemical changes mainly in the brain's rewarding circuitry.
Malenka RC, Nestler EJ, Hyman SE, Holtzman DM (2015). "Chapter 16: Reinforcement and Addictive Disorders". Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (3rded.). New York: McGraw-Hill Medical. ISBN9780071827706. 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.
Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 5: Excitatory and Inhibitory Amino Acids". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nded.). New York, US: McGraw-Hill Medical. pp.124–125. ISBN9780071481274.
Carroll ME, Smethells JR (February 2016). "Sex Differences in Behavioral Dyscontrol: Role in Drug Addiction and Novel Treatments". Frontiers in Psychiatry. 6: 175. doi:10.3389/fpsyt.2015.00175. PMC4745113. PMID26903885. 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.
Shoptaw SJ, Kao U, Heinzerling K, Ling W (April 2009). Shoptaw SJ (ed.). "Treatment for amphetamine withdrawal". Cochrane Database of Systematic Reviews. 2009 (2): CD003021. doi:10.1002/14651858.CD003021.pub2. PMC7138250. PMID19370579. The prevalence of this withdrawal syndrome is extremely common (Cantwell 1998; Gossop 1982) with 87.6% of 647 individuals with amphetamine dependence reporting six or more signs of amphetamine withdrawal listed in the DSM when the drug is not available (Schuckit 1999)... The severity of withdrawal symptoms is greater in amphetamine dependent individuals who are older and who have more extensive amphetamine use disorders (McGregor 2005). Withdrawal symptoms typically present within 24hours of the last use of amphetamine, with a withdrawal syndrome involving two general phases that can last 3 weeks or more. The first phase of this syndrome is the initial "crash" that resolves within about a week (Gossop 1982;McGregor 2005)...
Advokat C (July 2007). "Update on amphetamine neurotoxicity and its relevance to the treatment of ADHD". Journal of Attention Disorders. 11 (1): 8–16. doi:10.1177/1087054706295605. PMID17606768. S2CID7582744.
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. 1 (3): 172–182. doi:10.4161/23328940.2014.982049. PMC5008711. PMID27626044. 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 (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nded.). New York, US: McGraw-Hill Medical. p.370. ISBN9780071481274. Unlike cocaine and amphetamine, methamphetamine is directly toxic to midbrain dopamine neurons.
Hasenhuetl PS, Bhat S, Freissmuth M, Sandtner W (March 2019). "Functional Selectivity and Partial Efficacy at the Monoamine Transporters: A Unified Model of Allosteric Modulation and Amphetamine-Induced Substrate Release". Molecular Pharmacology. 95 (3): 303–312. doi:10.1124/mol.118.114793. PMID30567955. S2CID58557130. Although the monoamine transport cycle has been resolved in considerable detail, kinetic knowledge on the molecular actions of synthetic allosteric modulators is still scarce. Fortunately, the DAT catalytic cycle is allosterically modulated by an endogenous ligand (namely, Zn2+; Norregaard et al., 1998). It is worth consulting Zn2+ as an instructive example, because its action on the DAT catalytic cycle has been deciphered to a large extent... Zn+ binding stabilizes the outward-facing conformation of DAT... This potentiates both the forward-transport mode (i.e., DA uptake; Li et al., 2015) and the substrate-exchange mode (i.e., amphetamine-induced DA release; Meinild et al., 2004; Li et al., 2015). Importantly, the potentiating effect on substrate uptake is only evident when internal Na+ concentrations are low... If internal Na+ concentrations rise during the experiment, the substrate-exchange mode dominates and the net effect of Zn2+ on uptake is inhibitory. Conversely, Zn2+ accelerates amphetamine-induced substrate release via DAT.... t is important to emphasize that Zn2+ has been shown to reduce dopamine uptake under conditions that favor intracellular Na+ accumulation —Fig. 3. Functional selectivity by conformational selection.
Krause J (April 2008). "SPECT and PET of the dopamine transporter in attention-deficit/hyperactivity disorder". Expert Review of Neurotherapeutics. 8 (4): 611–625. doi:10.1586/14737175.8.4.611. PMID18416663. S2CID24589993. 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.
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". Journal of Biological Chemistry. 277 (24): 21505–21513. doi:10.1074/jbc.M112265200. PMID11940571. S2CID10521850. The human dopamine transporter (hDAT) contains an endogenous high affinity Zn2+ binding site with three coordinating residues on its extracellular face (His193, His375, and Glu396).... Although Zn2+ inhibited uptake, Zn2+ facilitated [3H]MPP+ release induced by amphetamine, MPP+, or K+-induced depolarization specifically at hDAT but not at the human serotonin and the norepinephrine transporter (hNET).... Surprisingly, this amphetamine-elicited efflux was markedly enhanced, rather than inhibited, by the addition of 10μM Zn2+ to the superfusion buffer (Fig. 2 A, open squares).... The concentrations of Zn2+ shown in this study, required for the stimulation of dopamine release (as well as inhibition of uptake), covered this physiologically relevant range, with maximum stimulation occurring at 3–30μM.... Thus, when Zn2+ is co-released with glutamate, it may greatly augment the efflux of dopamine.
Scassellati C, Bonvicini C, Faraone SV, Gennarelli M (October 2012). "Biomarkers and attention-deficit/hyperactivity disorder: a systematic review and meta-analyses". Journal of the American Academy of Child & Adolescent Psychiatry. 51 (10): 1003–1019.e20. doi:10.1016/j.jaac.2012.08.015. PMID23021477. With regard to zinc supplementation, a placebo controlled trial reported that doses up to 30mg/day of zinc were safe for at least 8weeks, but the clinical effect was equivocal except for the finding of a 37% reduction in amphetamine optimal dose with 30mg per day of zinc.110
Eiden LE, Weihe E (January 2011). "VMAT2: a dynamic regulator of brain monoaminergic neuronal function interacting with drugs of abuse". Annals of the New York Academy of Sciences. 1216 (1): 86–98. doi:10.1111/j.1749-6632.2010.05906.x. PMC4183197. PMID21272013. VMAT2 is the CNS vesicular transporter for not only the biogenic amines DA, NE, EPI, 5-HT, and HIS, but likely also for the trace amines TYR, PEA, and thyronamine (THYR)... [Trace aminergic] neurons in mammalian CNS would be identifiable as neurons expressing VMAT2 for storage, and the biosynthetic enzyme aromatic amino acid decarboxylase (AADC).... AMPH release of DA from synapses requires both an action at VMAT2 to release DA to the cytoplasm and a concerted release of DA from the cytoplasm via "reverse transport" through DAT.
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. PMC4850498. PMID27141430. 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 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.
Ledonne A, Berretta N, Davoli A, Rizzo GR, Bernardi G, Mercuri NB (July 2011). "Electrophysiological effects of trace amines on mesencephalic dopaminergic neurons". Frontiers in Systems Neuroscience. 5: 56. doi:10.3389/fnsys.2011.00056. PMC3131148. PMID21772817. 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.
"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)
Underhill SM, Wheeler DS, Li M, Watts SD, Ingram SL, Amara SG (July 2014). "Amphetamine modulates excitatory neurotransmission through endocytosis of the glutamate transporter EAAT3 in dopamine neurons". Neuron. 83 (2): 404–416. doi:10.1016/j.neuron.2014.05.043. PMC4159050. PMID25033183. 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
Vaughan RA, Foster JD (September 2013). "Mechanisms of dopamine transporter regulation in normal and disease states". Trends in Pharmacological Sciences. 34 (9): 489–496. doi:10.1016/j.tips.2013.07.005. PMC3831354. PMID23968642. 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].
Maguire JJ, Davenport AP (2 December 2014). "TA1 receptor". IUPHAR database. International Union of Basic and Clinical Pharmacology. Archived from the original on 29 June 2015. Retrieved 8 December 2014.
"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 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.
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. PMID13677912.
Vicentic A, Jones DC (February 2007). "The CART (cocaine- and amphetamine-regulated transcript) system in appetite and drug addiction". Journal of Pharmacology and Experimental Therapeutics. 320 (2): 499–506. doi:10.1124/jpet.105.091512. PMID16840648. S2CID14212763. 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". Clinical and Experimental Pharmacology and Physiology. 39 (6): 586–592. doi:10.1111/j.1440-1681.2011.05642.x. PMID22077697. S2CID25134612. 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
Rogge G, Jones D, Hubert GW, Lin Y, Kuhar MJ (October 2008). "CART peptides: regulators of body weight, reward and other functions". Nature Reviews Neuroscience. 9 (10): 747–758. doi:10.1038/nrn2493. PMC4418456. PMID18802445. 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...
Finnema SJ, Scheinin M, Shahid M, Lehto J, Borroni E, Bang-Andersen B, etal. (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. PMC4600473. PMID25921033. 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 of d-amphetamine, 0.5mg/kg, 3h 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, 0.3mg/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).
Colasanti A, Searle GE, Long CJ, Hill SP, Reiley RR, Quelch D, etal. (September 2012). "Endogenous opioid release in the human brain reward system induced by acute amphetamine administration". Biological Psychiatry. 72 (5): 371–377. doi:10.1016/j.biopsych.2012.01.027. PMID22386378. S2CID18555036.
Angeli A, Vaiano F, Mari F, Bertol E, Supuran CT (December 2017). "Psychoactive substances belonging to the amphetamine class potently activate brain carbonic anhydrase isoforms VA, VB, VII, and XII". Journal of Enzyme Inhibition and Medicinal Chemistry. 32 (1): 1253–1259. doi:10.1080/14756366.2017.1375485. PMC6009978. PMID28936885. Here, we report the first such study, showing that amphetamine, methamphetamine, phentermine, mephentermine, and chlorphenteramine, potently activate several CA isoforms, some of which are highly abundant in the brain, where they play important functions connected to cognition and memory, among others26,27.... We investigated psychotropic amines based on the phenethylamine scaffold, such as amphetamine 5, methamphetamine 6, phentermine 7, mephentermine 8, and the structurally diverse chlorphenteramine 9, for their activating effects on 11 CA isoforms of human origin... The widespread hCA I and II, the secreted hCA VI, as well as the cytosolic hCA XIII and membrane-bound hCA IX and XIV were poorly activated by these amines, whereas the extracellular hCA IV, the mitochondrial enzymes hCA VA/VB, the cytosolic hCA VII, and the transmembrane isoform hCA XII were potently activated. Some of these enzymes (hCA VII, VA, VB, XII) are abundant in the brain, raising the possibility that some of the cognitive effects of such psychoactive substances might be related to the activation of these enzymes.... CAAs started to be considered only recently for possible pharmacologic applications in memory/cognition therapy27. This work may bring new lights on the intricate relationship between CA activation by this type of compounds and the multitude of pharmacologic actions that they can elicit. —Table 1: CA activation of isoforms hCA I, II, IV, VII, and XIII [5: amphetamine] —Table 2: CA activation of isoforms hCA VA, VB, VI, IX, XII, and XIV [5: amphetamine]
"Amphetamine: Biological activity". IUPHAR/BPS Guide to Pharmacology. International Union of Basic and Clinical Pharmacology. Retrieved 31 December 2019.
Bozdag M, Altamimi AA, Vullo D, Supuran CT, Carta F (2019). "State of the Art on Carbonic Anhydrase Modulators for Biomedical Purposes". Current Medicinal Chemistry. 26 (15): 2558–2573. doi:10.2174/0929867325666180622120625. PMID29932025. S2CID49345601. CARBONIC ANHYDRASE INHIBITORS (CAIs). The design and development of CAIs represent the most prolific area within the CA research field. Since the introduction of CAIs in the clinical use in the 40', they still are the first choice for the treatment of edema [9], altitude sickness [9], glaucoma [7] and epilepsy [31].... CARBONIC ANHYDRASE ACTIVATORS (CAAs)... The emerging class of CAAs has recently gained attraction as the enhancement of the kinetic properties in hCAs expressed in the CNS were proved in animal models to be beneficial for the treatment of both cognitive and memory impairments. Thus, CAAs have enormous potentiality in medicinal chemistry to be developed for the treatment of symptoms associated to aging, trauma or deterioration of the CNS tissues.
Dolder PC, Strajhar P, Vizeli P, Hammann F, Odermatt A, Liechti ME (2017). "Pharmacokinetics and Pharmacodynamics of Lisdexamfetamine Compared with D-Amphetamine in Healthy Subjects". Front Pharmacol. 8: 617. doi:10.3389/fphar.2017.00617. PMC5594082. PMID28936175. Inactive lisdexamfetamine is completely (>98%) converted to its active metabolite D-amphetamine in the circulation (Pennick, 2010; Sharman and Pennick, 2014). When lisdexamfetamine is misused intranasally or intravenously, the pharmacokinetics are similar to oral use (Jasinski and Krishnan, 2009b; Ermer et al., 2011), and the subjective effects are not enhanced by parenteral administration in contrast to D-amphetamine (Lile et al., 2011) thus reducing the risk of parenteral misuse of lisdexamfetamine compared with D-amphetamine. Intravenous lisdexamfetamine use also produced significantly lower increases in "drug liking" and "stimulant effects" compared with D-amphetamine in intravenous substance users (Jasinski and Krishnan, 2009a).
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Sjoerdsma A, von Studnitz W (April 1963). "Dopamine-beta-oxidase activity in man, using hydroxyamphetamine as substrate". British Journal of Pharmacology and Chemotherapy. 20 (2): 278–284. doi:10.1111/j.1476-5381.1963.tb01467.x. PMC1703637. PMID13977820. 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.
Badenhorst CP, van der Sluis R, Erasmus E, van Dijk AA (September 2013). "Glycine conjugation: importance in metabolism, the role of glycine N-acyltransferase, and factors that influence interindividual variation". Expert Opinion on Drug Metabolism & Toxicology. 9 (9): 1139–1153. doi:10.1517/17425255.2013.796929. PMID23650932. S2CID23738007. Figure 1. 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". Circulation Research. 32 (5): 594–599. doi:10.1161/01.RES.32.5.594. PMID4713201. S2CID28641000. 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. doi:10.1016/0028-3908(74)90069-0. PMID4457764. 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". Journal of Pharmacology and Experimental Therapeutics. 251 (3): 901–908. PMID2600821. 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.
ElRakaiby M, Dutilh BE, Rizkallah MR, Boleij A, Cole JN, Aziz RK (July 2014). "Pharmacomicrobiomics: the impact of human microbiome variations on systems pharmacology and personalized therapeutics". Omics. 18 (7): 402–414. doi:10.1089/omi.2014.0018. PMC4086029. PMID24785449. The hundred trillion microbes and viruses residing in every human body, which outnumber human cells and contribute at least 100 times more genes than those encoded on the human genome (Ley et al., 2006), offer an immense accessory pool for inter-individual genetic variation that has been underestimated and largely unexplored (Savage, 1977; Medini et al., 2008; Minot et al., 2011; Wylie et al., 2012).... Meanwhile, a wealth of literature has long been available about the biotransformation of xenobiotics, notably by gut bacteria (reviewed in Sousa et al., 2008; Rizkallah et al., 2010; Johnson et al., 2012; Haiser and Turnbaugh, 2013). This valuable information is predominantly about drug metabolism by unknown human-associated microbes; however, only a few cases of inter-individual microbiome variations have been documented [e.g., digoxin (Mathan et al., 1989) and acetaminophen (Clayton et al., 2009)].
Cho I, Blaser MJ (March 2012). "The human microbiome: at the interface of health and disease". Nature Reviews Genetics. 13 (4): 260–270. doi:10.1038/nrg3182. PMC3418802. PMID22411464. The composition of the microbiome varies by anatomical site (Figure 1). The primary determinant of community composition is anatomical location: interpersonal variation is substantial23,24 and is higher than the temporal variability seen at most sites in a single individual25.... How does the microbiome affect the pharmacology of medications? Can we "micro-type" people to improve pharmacokinetics and/or reduce toxicity? Can we manipulate the microbiome to improve pharmacokinetic stability?
Hutter T, Gimbert C, Bouchard F, Lapointe FJ (2015). "Being human is a gut feeling". Microbiome. 3: 9. doi:10.1186/s40168-015-0076-7. PMC4359430. PMID25774294. Some metagenomic studies have suggested that less than 10% of the cells that comprise our bodies are Homo sapiens cells. The remaining 90% are bacterial cells. The description of this so-called human microbiome is of great interest and importance for several reasons. For one, it helps us redefine what a biological individual is. We suggest that a human individual is now best described as a super-individual in which a large number of different species (including Homo sapiens) coexist.
Kumar K, Dhoke GV, Sharma AK, Jaiswal SK, Sharma VK (January 2019). "Mechanistic elucidation of amphetamine metabolism by tyramine oxidase from human gut microbiota using molecular dynamics simulations". Journal of Cellular Biochemistry. 120 (7): 11206–11215. doi:10.1002/jcb.28396. PMID30701587. S2CID73413138. Particularly in the case of the human gut, which harbors a large diversity of bacterial species, the differences in microbial composition can significantly alter the metabolic activity in the gut lumen.4 The differential metabolic activity due to the differences in gut microbial species has been recently linked with various metabolic disorders and diseases.5–12 In addition to the impact of gut microbial diversity or dysbiosis in various human diseases, there is an increasing amount of evidence which shows that the gut microbes can affect the bioavailability and efficacy of various orally administrated[sic] drug molecules through promiscuous enzymatic metabolism.13,14... The present study on the atomistic details of amphetamine binding and binding affinity to the tyramine oxidase along with the comparison with two natural substrates of this enzyme namely tyramine and phenylalanine provides strong evidence for the promiscuity-based metabolism of amphetamine by the tyramine oxidase enzyme of E. coli. The obtained results will be crucial in designing a surrogate molecule for amphetamine that can help either in improving the efficacy and bioavailability of the amphetamine drug via competitive inhibition or in redesigning the drug for better pharmacological effects. This study will also have useful clinical implications in reducing the gut microbiota caused variation in the drug response among different populations.
Khan MZ, Nawaz W (October 2016). "The emerging roles of human trace amines and human trace amine-associated receptors (hTAARs) in central nervous system". Biomedicine & Pharmacotherapy. 83: 439–449. doi:10.1016/j.biopha.2016.07.002. PMID27424325.
Lindemann L, Hoener MC (May 2005). "A renaissance in trace amines inspired by a novel GPCR family". Trends in Pharmacological Sciences. 26 (5): 274–281. doi:10.1016/j.tips.2005.03.007. PMID15860375.
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"Clinical Drug Testing in Primary Care"(PDF). University of Colorado Denver. Technical Assistance Publication Series 32. United States Department of Health and Human Services– Substance Abuse and Mental Health Services Administration. 2012. p.55. Archived(PDF) from the original on 14 May 2018. 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).
"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. 1 April 2019. Archived from the original on 25 December 2019. Retrieved 24 December 2019. 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.
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European Monitoring Centre for Drugs Drug Addiction (May 2014). European drug report 2014: Trends and developments(PDF) (Report). Lisbon, Portugal: European Monitoring Centre for Drugs and Drug Addiction. pp.13, 24. doi:10.2810/32306. ISSN2314-9086. Archived(PDF) from the original on 9 October 2022. Retrieved 18 August 2014. 1.2 million or 0.9% of young adults (15–34) used amphetamines in the last year
"Adzenys XR-ODT- amphetamine tablet, orally disintegrating". DailyMed. Neos Therapeutics, Inc. 9 February 2018. Retrieved 22 December 2019. 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.
