Some people live with this type of aneurysm for many years without any specific treatment. Treatment is limited to surgery ( ventricular reduction ) for this defect of the heart. However, surgery is not required in most cases but, limiting the patient's physical activity levels to lower the risk of making the aneurysm bigger is advised. Also, ACE Inhibitors seem to prevent Left Ventricular remodeling and aneurysm formation. [ citation needed ]


Blood thinning agents may be given to help reduce the likelihood of blood thickening and clots forming, along with the use of drugs to correct the irregular rhythm of the heart (seen on the electrocardiogram) [ citation needed ]


Vibroacoustic disease  is a medical condition manifested in those who have had long-term exposure (≥ 10 yr) to large pressure amplitude (≥ 90 dB SPL) and  low frequency noise  (≤ 500 Hz). [ 1 ]  The disease is said to lead to  heart arrhythmia  or even death. [ 2 ] [ 3 ] [ 4 ] [ 5 ]


During  protests  over the closure of the  Roosevelt Roads Naval Base  in  Puerto Rico , it was asserted that the noise created by the Navy's testing had negatively affected the health of civilians living on Vieques. In a study conducted for Puerto Rican Governor Calderon, 48 of the 50 Vieques residents tested were diagnosed as suffering from a thickening of heart tissue caused by exposure to sonic booms. [ 2 ]  Simultaneously, the  Ponce School of Medicine  conducted an independent study and found other data to confirm the presence of vibroacoustic disease: 79% of Viequenses fishermen have thickened heart tissue, which is the main symptom of vibroacoustic disease. [ 2 ]  The federal  Agency for Toxic Substances & Disease Registry  reviewed Ponce School of Medicine study and concluded in 2001 that the Vieques heart study failed to provide any "clinically significant" evidence of heart disease. [ 6 ]


Viral cardiomyopathy  occurs when viral infections cause  myocarditis  with a resulting thickening of the myocardium and dilation of the ventricles. These viruses include Coxsackie B and adenovirus, echoviruses,  influenza H1N1 ,  Epstein–Barr virus ,  rubella (German measles virus) ,  varicella (chickenpox virus) ,  mumps ,  measles ,  parvoviruses ,  yellow fever ,  dengue fever ,  polio ,  rabies , and the viruses that cause  hepatitis A  and  C , [ 2 ] [ 3 ] [ 4 ]  as well as  COVID-19 , [ 5 ] [ 6 ]  which has been seen to cause this in persons otherwise thought to have a "low risk" of the virus's effects. [ 7 ]


Patients with  COVID-19  frequently experience  heart  issues. [ 8 ]  According to studies, people who have had previous cardiovascular conditions like  cardiomyopathy ,  hypertension ,  coronary heart disease , or  arrhythmia  are more likely to become critically ill from  SARS-CoV-2  infection.  Myocarditis  may result from a direct viral infection of the myocardium. [ 8 ]  Cardiovascular biomarkers like  troponin ,  lactate dehydrogenase , high sensitivity amino-terminal  B-type natriuretic peptide ,  creatinine kinase , and creatinine kinase myocardial band, which indicate myocardial damage, increase in concentration in response to COVID-19. [ 8 ]  Hundreds of studies have reported myocarditis/myopericarditis caused by COVID-19 infection in living patients, with a  male  predominance (58%), and a  median age  of 50 years.  [ 8 ]


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Adderall  and  Mydayis [ 11 ]  are  trade names [ note 2 ]  for a  combination drug  containing four  salts  of  amphetamine . The mixture is composed of equal parts  racemic  amphetamine and  dextroamphetamine , which produces a (3:1) ratio between dextroamphetamine and  levoamphetamine , the two  enantiomers  of amphetamine. [ 13 ]  Both enantiomers are  stimulants , but differ enough to give Adderall an  effects profile  distinct from those of racemic amphetamine or dextroamphetamine, [ 1 ] [ 2 ]  which are marketed as Evekeo and Dexedrine/Zenzedi, respectively. [ 1 ] [ 14 ] [ 15 ]  Adderall is used in the treatment of  attention deficit hyperactivity disorder  (ADHD) and  narcolepsy . It is also used illicitly as an  athletic performance enhancer ,  cognitive enhancer ,  appetite suppressant , and recreationally as a  euphoriant . It is a  central nervous system  (CNS)  stimulant  of the  phenethylamine class . [ 1 ]


At therapeutic doses, Adderall causes emotional and cognitive effects such as  euphoria , change in  sex drive , increased  wakefulness , and improved  cognitive control . At these doses, it induces physical effects such as a faster reaction time, fatigue resistance, and increased muscle strength. In contrast, much larger doses of Adderall can impair cognitive control, cause  rapid muscle breakdown , provoke  panic attacks , or induce  psychosis  (e.g.,  paranoia ,  delusions ,  hallucinations ). The side effects vary widely among individuals but most commonly include  insomnia ,  dry mouth ,  loss of appetite  and  weight loss . The risk of developing an  addiction  or  dependence  is insignificant when Adderall is used as prescribed and at fairly low daily doses, such as those used for treating ADHD. However, the routine use of Adderall in larger and daily doses poses a significant risk of addiction or dependence due to the pronounced  reinforcing effects  that are present at high doses. Recreational doses of Adderall are generally much larger than prescribed  therapeutic doses  and also carry a far greater risk of serious adverse effects. [ sources 1 ]


The two amphetamine enantiomers that compose Adderall, such as Adderall tablets/capsules (levoamphetamine and dextroamphetamine), alleviate the symptoms of ADHD and narcolepsy by increasing the activity of the  neurotransmitters   norepinephrine  and  dopamine  in the  brain , which results in part from their interactions with  human trace amine-associated receptor 1  (hTAAR1) and  vesicular monoamine transporter 2  (VMAT2) in  neurons . Dextroamphetamine is a more potent  Central nervous system  ( CNS ) stimulant than levoamphetamine, but levoamphetamine has slightly stronger cardiovascular and peripheral effects and a longer  elimination half-life  than dextroamphetamine. The levoamphetamine component of Adderall has been reported to [ weasel words ]  improve the treatment response in some individuals relative to dextroamphetamine alone [ citation needed ] . The  active ingredient  in Adderall, amphetamine, shares many chemical and pharmacological properties with the human  trace amines , particularly  phenethylamine  and  N -methylphenethylamine , the latter of which is a  positional isomer  of amphetamine. [ sources 2 ]  In 2022, Adderall was the fourteenth most commonly prescribed medication in the United States, with more than 34   million prescriptions. [ 35 ] [ 36 ]


Adderall is commonly used to treat  attention deficit hyperactivity disorder  (ADHD) and  narcolepsy  (a sleep disorder). [ 37 ] [ 17 ]


Long-term amphetamine exposure at sufficiently high doses in some animal species is known to produce abnormal  dopamine system  development or nerve damage, [ 38 ] [ 39 ]  but, in humans with ADHD, long-term use of pharmaceutical amphetamines at therapeutic doses appears to improve brain development and nerve growth. [ 40 ] [ 41 ] [ 42 ]  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 . [ 40 ] [ 41 ] [ 42 ]


Reviews of clinical stimulant research have established the safety and effectiveness of long-term continuous amphetamine use for the treatment of ADHD. [ 43 ] [ 44 ] [ 45 ]   Randomized controlled trials  of continuous stimulant therapy for the treatment of ADHD spanning 2 years have demonstrated treatment effectiveness and safety. [ 43 ] [ 44 ]  Two reviews have indicated that long-term continuous stimulant therapy for ADHD is effective for reducing the core symptoms of ADHD (i.e., hyperactivity, inattention, and impulsivity), enhancing  quality of life  and academic achievement, and producing improvements in a large number of functional outcomes [ note 3 ]  across 9 categories of outcomes related to academics,  antisocial behavior , driving, non-medicinal drug use, obesity, occupation,  self-esteem , service use (i.e., academic, occupational, health, financial, and legal services), and social function. [ 43 ] [ 45 ]  Additionally, a 2024  meta-analytic   systematic review  reported moderate improvements in quality of life when amphetamine treatment is used for ADHD. [ 47 ]  One review highlighted a nine-month randomized controlled trial of amphetamine treatment for ADHD in children that found an average increase of 4.5  IQ  points, continued increases in attention, and continued decreases in disruptive behaviors and hyperactivity. [ 44 ]  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. [ 43 ]  A 2025 meta-analytic systematic review of 113 randomized controlled trials demonstrated that stimulant medications significantly improved core ADHD symptoms in adults over a three-month period, with good acceptability compared to other pharmacological and non-pharmacological treatments. [ 48 ]


Models of ADHD suggest that it is associated with functional impairments in some of the brain's  neurotransmitter systems ; [ 49 ]  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 . [ 49 ]  Stimulants like  methylphenidate  and amphetamine are effective in treating ADHD because they increase neurotransmitter activity in these systems. [ 18 ] [ 49 ] [ 50 ]  Approximately 80% of those who use these stimulants see improvements in ADHD symptoms. [ 51 ]  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. [ 52 ] [ 53 ]  The  Cochrane  reviews [ note 4 ]  on the treatment of ADHD in children, adolescents, and adults with pharmaceutical amphetamines stated that short-term studies have demonstrated that these drugs decrease the severity of symptoms, but they have higher discontinuation rates than non-stimulant medications due to their adverse  side effects . [ 55 ] [ 56 ]  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. [ 57 ]


Narcolepsy is a chronic sleep-wake disorder that is associated with excessive daytime sleepiness,  cataplexy , and  sleep paralysis . [ 58 ]  Patients with narcolepsy are diagnosed as either type 1 or type 2, with only the former presenting cataplexy symptoms. [ 59 ]  Type 1 narcolepsy results from the loss of approximately 70,000  orexin -releasing neurons in the  lateral hypothalamus , leading to significantly reduced  cerebrospinal  orexin levels; [ 60 ] [ 61 ]  this reduction is a  diagnostic biomarker  for type 1 narcolepsy. [ 59 ]  Lateral hypothalamic orexin neurons innervate every component of the  ascending reticular activating system  (ARAS), which includes  noradrenergic ,  dopaminergic ,  histaminergic , and  serotonergic  nuclei that promote  wakefulness . [ 61 ] [ 62 ]


Amphetamine’s therapeutic mode of action in narcolepsy primarily involves increasing  monoamine  neurotransmitter activity in the ARAS. [ 60 ] [ 63 ] [ 64 ]  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 . [ 62 ] [ 64 ]  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. [ 60 ]  In contrast, levoamphetamine may have a greater effect on cataplexy, a symptom more sensitive to the effects of norepinephrine and serotonin. [ 60 ]  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. [ 60 ] [ 59 ] [ 62 ]


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. [ 65 ]  Treatment with pharmaceutical amphetamines is generally less preferred relative to other stimulants (e.g.,  modafinil ) and is considered a  third-line treatment  option. [ 66 ] [ 67 ] [ 68 ]  Medical reviews indicate that amphetamine is safe and effective for the treatment of narcolepsy. [ 60 ] [ 66 ] [ 65 ]  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. [ 60 ] [ 66 ] [ 65 ]  Additionally, these reviews suggest that amphetamine may dose-dependently improve cataplexy symptoms. [ 60 ] [ 66 ] [ 65 ]  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. [ 65 ]


Adderall is available as  immediate-release  (IR) tablets and  extended-release  (XR) capsules. [ 17 ] [ 69 ]  Mydayis is only available as an extended-release formulation. [ 70 ]  Adderall XR is approved to treat ADHD for up to 12 hours in individuals 6 years and older and uses a  double-bead formulation . The capsule can be swallowed like a tablet, or it can be opened and the beads sprinkled over applesauce for comparable absorption. [ 69 ]  Upon ingestion, half of the beads provide immediate administration of medication, while the other half are enveloped in a coating that must dissolve, delaying absorption of its contents. It is designed to provide a therapeutic effect and plasma concentrations identical to taking two doses of Adderall IR four hours apart. [ 69 ]  Mydayis uses a longer-lasting triple-bead formulation and is approved to treat ADHD for up to 16 hours in individuals 13 years and older. [ 70 ]  In the United States, the immediate and extended-release formulations of Adderall are both available as  generic drugs . [ 71 ] [ 72 ]  Generic formulations of Mydayis became available in the US in October 2023. [ 73 ]


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; [ 74 ] [ 75 ]  these cognition-enhancing effects of amphetamine are known to be partially mediated through the  indirect activation  of both  dopamine D 1  receptor  and  α 2 -adrenergic receptor  in the  prefrontal cortex . [ 18 ] [ 74 ]  A systematic review from 2014 found that low doses of amphetamine also improve  memory consolidation , in turn leading to improved  recall of information . [ 76 ]  Therapeutic doses of amphetamine also enhance cortical network efficiency, an effect which mediates improvements in working memory in all individuals. [ 18 ] [ 77 ]  Amphetamine and other ADHD stimulants also improve  task saliency  (motivation to perform a task) and increase  arousal  (wakefulness), in turn promoting goal-directed behavior. [ 18 ] [ 78 ] [ 79 ]  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. [ 18 ] [ 79 ] [ 80 ]  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. [ 81 ] [ 82 ] [ 83 ]  However, high amphetamine doses that are above the therapeutic range can interfere with working memory and other aspects of cognitive control. [ 18 ] [ 79 ]


Amphetamine is used by some athletes for its psychological and  athletic performance-enhancing effects , such as increased endurance and alertness; [ 19 ] [ 31 ]  however, non-medical amphetamine use is prohibited at sporting events that are regulated by collegiate, national, and international anti-doping agencies. [ 84 ] [ 85 ]  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 . [ 19 ] [ 86 ] [ 87 ]  Amphetamine improves endurance and reaction time primarily through  reuptake inhibition  and  release  of dopamine in the central nervous system. [ 86 ] [ 87 ] [ 88 ]  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. [ 87 ] [ 89 ] [ 90 ]  At therapeutic doses, the adverse effects of amphetamine do not impede athletic performance; [ 19 ] [ 86 ]  however, at much higher doses, amphetamine can induce effects that severely impair performance, such as  rapid muscle breakdown  and  elevated body temperature . [ 20 ] [ 86 ]


Adderall has been banned in the  National Football League  (NFL),  Major League Baseball  (MLB),  National Basketball Association  (NBA), and the National Collegiate Athletics Association (NCAA). [ 91 ]  In leagues such as the NFL, there is a very rigorous process required to obtain an exemption to this rule even when the athlete has been medically prescribed the drug by their physician. [ 91 ]


Adderall has a high potential for misuse as a  recreational drug . [ 92 ] [ 93 ] [ 94 ]  Adderall tablets can either be swallowed, crushed and snorted, or dissolved in water and injected. [ 95 ]  Injection into the bloodstream can be dangerous because  insoluble fillers within the tablets  can block small blood vessels. [ 95 ]


Many postsecondary students have reported using Adderall for study purposes in different parts of the developed world. [ 94 ]  Among these students, some of the  risk factors  for misusing ADHD stimulants recreationally include: possessing  deviant personality  characteristics (i.e., exhibiting delinquent or deviant behavior), inadequate accommodation of disability, basing one's  self-worth  on external validation, low  self-efficacy , earning poor grades, and having an untreated  mental health disorder . [ 94 ]


The  adverse side effects  of Adderall are many and varied, but the amount of substance consumed is the primary factor in determining the likelihood and severity of side effects. [ 20 ] [ 31 ]  Adderall is currently approved for long-term therapeutic use by the USFDA. [ 20 ]   Recreational use  of Adderall generally involves far larger doses and is therefore significantly more dangerous, involving a much greater risk of serious adverse drug effects than dosages used for therapeutic purposes. [ 31 ]


Cardiovascular  side effects can include  hypertension  or  hypotension  from a  vasovagal response ,  Raynaud's phenomenon  (reduced blood flow to the hands and feet), and  tachycardia  (increased heart rate). [ 20 ] [ 31 ] [ 106 ]  Sexual side effects in males may include  erectile dysfunction , frequent erections, or  prolonged erections . [ 20 ]  Gastrointestinal side effects may include  abdominal pain ,  constipation ,  diarrhea , and  nausea . [ 7 ] [ 20 ] [ 107 ]  Other potential physical side effects include  appetite loss ,  blurred vision ,  dry mouth ,  excessive grinding of the teeth , nosebleed, profuse sweating,  rhinitis medicamentosa  (drug-induced nasal congestion), reduced  seizure threshold ,  tics  (a type of movement disorder), and  weight loss . [ sources 3 ]  Dangerous physical side effects are rare at typical pharmaceutical doses. [ 31 ]


Amphetamine stimulates the  medullary respiratory centers , producing faster and deeper breaths. [ 31 ]  In a normal person at therapeutic doses, this effect is usually not noticeable, but when respiration is already compromised, it may be evident. [ 31 ]  Amphetamine also induces  contraction  in the urinary  bladder sphincter , the muscle which controls urination, which can result in difficulty urinating. [ 31 ]  This effect can be useful in treating  bed wetting  and  loss of bladder control . [ 31 ]  The effects of amphetamine on the gastrointestinal tract are unpredictable. [ 31 ]  If intestinal activity is high, amphetamine may reduce  gastrointestinal motility  (the rate at which content moves through the digestive system); [ 31 ]  however, amphetamine may increase motility when the  smooth muscle  of the tract is relaxed. [ 31 ]  Amphetamine also has a slight  analgesic  effect and can enhance the pain relieving effects of  opioids . [ 7 ] [ 31 ]


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 4 ]  However, amphetamine pharmaceuticals are  contraindicated  in individuals with  cardiovascular disease . [ sources 5 ]


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. [ 20 ] [ 31 ]  Less common side effects include  anxiety , change in  libido ,  grandiosity ,  irritability , repetitive or  obsessive  behaviors, and restlessness; [ sources 6 ]  these effects depend on the user's personality and current mental state. [ 31 ]   Amphetamine psychosis  (e.g.,  delusions  and  paranoia ) can occur in heavy users. [ 20 ] [ 21 ] [ 115 ]  Although very rare, this psychosis can also occur at therapeutic doses during long-term therapy. [ 20 ] [ 115 ] [ 22 ]  According to the FDA, "there is no systematic evidence" that stimulants produce aggressive behavior or hostility. [ 20 ]


Amphetamine has also been shown to produce a  conditioned place preference  in humans taking therapeutic doses, [ 55 ] [ 116 ]  meaning that individuals acquire a preference for spending time in places where they have previously used amphetamine. [ 116 ] [ 117 ]


Addiction  is a serious risk with heavy recreational amphetamine use, but is unlikely to occur from long-term medical use at therapeutic doses; [ 23 ] [ 24 ] [ 66 ]  in fact, lifetime stimulant therapy for ADHD that begins during childhood reduces the risk of developing  substance use disorders  as an adult. [ 43 ]   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. [ 127 ] [ 128 ]  Individuals who frequently  self-administer  high doses of amphetamine have a high risk of developing an amphetamine addiction, since chronic use at high doses gradually increases the level of  accumbal   ΔFosB , a "molecular switch" and "master control protein" for addiction. [ 118 ] [ 129 ] [ 130 ]  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. [ 129 ] [ 131 ]  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. [ 132 ] [ 133 ]  Exercise therapy improves  clinical  treatment outcomes and may be used as an  adjunct therapy  with behavioral therapies for addiction. [ 132 ] [ 134 ] [ sources 7 ]


Chronic use of amphetamine at excessive doses causes alterations in  gene expression  in the  mesocorticolimbic projection , which arise through  transcriptional  and  epigenetic  mechanisms. [ 130 ] [ 135 ] [ 136 ]  The most important  transcription factors [ note 8 ]  that produce these alterations are  Delta FBJ murine osteosarcoma viral oncogene homolog B  ( ΔFosB ),  cAMP  response element binding protein  ( CREB ), and  nuclear factor-kappa B  ( NF-κB ). [ 130 ]  ΔFosB is the most significant biomolecular mechanism in addiction because ΔFosB  overexpression  (i.e., an abnormally high level of gene expression which produces a pronounced gene-related  phenotype ) in the  D1-type   medium spiny neurons  in the  nucleus accumbens  is  necessary and sufficient [ note 9 ]  for many of the neural adaptations and regulates multiple behavioral effects (e.g.,  reward sensitization  and escalating drug  self-administration ) involved in addiction. [ 118 ] [ 129 ] [ 130 ]  Once ΔFosB is sufficiently overexpressed, it induces an addictive state that becomes increasingly more severe with further increases in ΔFosB expression. [ 118 ] [ 129 ]  It has been implicated in addictions to  alcohol ,  cannabinoids ,  cocaine ,  methylphenidate ,  nicotine ,  opioids ,  phencyclidine ,  propofol , and  substituted amphetamines , among others. [ sources 8 ]


ΔJunD , a transcription factor, and  G9a , a  histone methyltransferase  enzyme, both oppose the function of ΔFosB and inhibit increases in its expression. [ 118 ] [ 130 ] [ 140 ]  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). [ 130 ]  Similarly, accumbal G9a hyperexpression results in markedly increased  histone  3  lysine   residue  9  dimethylation  ( H3K9me2 ) and blocks the induction of ΔFosB-mediated  neural  and  behavioral plasticity  by chronic drug use, [ sources 9 ]  which occurs via  H3K9me2 -mediated  repression  of  transcription factors  for ΔFosB and H3K9me2-mediated repression of various ΔFosB transcriptional targets (e.g.,  CDK5 ). [ 130 ] [ 140 ] [ 141 ]  ΔFosB also plays an important role in regulating behavioral responses to  natural rewards , such as palatable food, sex, and exercise. [ 131 ] [ 130 ] [ 144 ]  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. [ 131 ] [ 130 ]  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. [ 131 ] [ 145 ] [ 146 ]  These sexual addictions are associated with a  dopamine dysregulation syndrome  which occurs in some patients taking  dopaminergic drugs . [ 131 ] [ 144 ]


The effects of amphetamine on gene regulation are both dose- and route-dependent. [ 136 ]  Most of the research on gene regulation and addiction is based upon animal studies with intravenous amphetamine administration at very high doses. [ 136 ]  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. [ 136 ]  This suggests that medical use of amphetamine does not significantly affect gene regulation. [ 136 ]


As of December 2019, [update]  there is no effective  pharmacotherapy  for amphetamine addiction. [ 147 ] [ 148 ] [ 149 ]  Reviews from 2015 and 2016 indicated that  TAAR1 -selective agonists have significant therapeutic potential as a treatment for psychostimulant addictions; [ 150 ] [ 151 ]  however, as of February 2016, [update]  the only compounds which are known to function as TAAR1-selective agonists are  experimental drugs . [ 150 ] [ 151 ]  Amphetamine addiction is largely mediated through increased activation of  dopamine receptors  and  co-localized   NMDA receptors [ note 10 ]  in the nucleus accumbens; [ 128 ]   magnesium ions  inhibit NMDA receptors by blocking the receptor  calcium channel . [ 128 ] [ 152 ]  One review suggested that, based upon animal testing, pathological (addiction-inducing) psychostimulant use significantly reduces the level of intracellular magnesium throughout the brain. [ 128 ]   Supplemental magnesium [ note 11 ]  treatment has been shown to reduce amphetamine  self-administration  (i.e., doses given to oneself) in humans, but it is not an effective  monotherapy  for amphetamine addiction. [ 128 ]


A systematic review and meta-analysis from 2019 assessed the efficacy of 17 different pharmacotherapies used in  randomized controlled trials  (RCTs) for amphetamine and methamphetamine addiction; [ 148 ]  it found only low-strength evidence that methylphenidate might reduce amphetamine or methamphetamine self-administration. [ 148 ]  There was low- to moderate-strength evidence of no benefit for most of the other medications used in RCTs, which included antidepressants (bupropion,  mirtazapine ,  sertraline ), antipsychotics ( aripiprazole ), anticonvulsants ( topiramate ,  baclofen ,  gabapentin ),  naltrexone ,  varenicline ,  citicoline ,  ondansetron ,  prometa ,  riluzole ,  atomoxetine , dextroamphetamine, and  modafinil . [ 148 ]


A 2018 systematic review and  network meta-analysis  of 50 trials involving 12 different psychosocial interventions for amphetamine, methamphetamine, or cocaine addiction found that  combination therapy  with both  contingency management  and  community reinforcement approach  had the highest efficacy (i.e., abstinence rate) and acceptability (i.e., lowest dropout rate). [ 153 ]  Other treatment modalities examined in the analysis included  monotherapy  with contingency management or community reinforcement approach,  cognitive behavioral therapy ,  12-step programs , non-contingent reward-based therapies,  psychodynamic therapy , and other combination therapies involving these. [ 153 ]


Additionally, research on the  neurobiological effects of physical exercise  suggests that daily aerobic exercise, especially endurance exercise (e.g.,  marathon running ), prevents the development of drug addiction and is an effective  adjunct therapy  (i.e., a supplemental treatment) for amphetamine addiction. [ sources 7 ]  Exercise leads to better treatment outcomes when used as an adjunct treatment, particularly for psychostimulant addictions. [ 132 ] [ 134 ] [ 154 ]  In particular,  aerobic exercise  decreases psychostimulant self-administration, reduces the  reinstatement  (i.e., relapse) of drug-seeking, and induces increased  dopamine receptor D 2  (DRD2) density in the  striatum . [ 131 ] [ 154 ]  This is the opposite of pathological stimulant use, which induces decreased striatal DRD2 density. [ 131 ]  One review noted that exercise may also prevent the development of a drug addiction by altering ΔFosB or  c-Fos   immunoreactivity  in the striatum or other parts of the  reward system . [ 133 ]


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. [ 155 ] [ 156 ]
According to a Cochrane review on  withdrawal  in individuals who compulsively use amphetamine and methamphetamine, "when chronic heavy users abruptly discontinue amphetamine use, many report a time-limited withdrawal syndrome that occurs within 24 hours of their last dose." [ 157 ]  This review noted that withdrawal symptoms in chronic, high-dose users are frequent, occurring in roughly 88% of cases, and persist for  3–4  weeks with a marked "crash" phase occurring during the first week. [ 157 ]  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 . [ 157 ]  The review indicated that the severity of withdrawal symptoms is positively correlated with the age of the individual and the extent of their dependence. [ 157 ]  Mild withdrawal symptoms from the discontinuation of amphetamine treatment at therapeutic doses can be avoided by tapering the dose. [ 7 ]


An amphetamine overdose can lead to many different symptoms, but is rarely fatal with appropriate care. [ 158 ] [ 100 ] [ 159 ]  The severity of overdose symptoms increases with dosage and decreases with  drug tolerance  to amphetamine. [ 160 ] [ 100 ]  Tolerant individuals have been known to take as much as 5 grams of amphetamine in a day, which is roughly 100 times the maximum daily therapeutic dose. [ 100 ]  Symptoms of a moderate and extremely large overdose are listed below; fatal amphetamine poisoning usually also involves convulsions and  coma . [ 99 ] [ 160 ]  In 2013, overdose on amphetamine, methamphetamine, and other compounds implicated in an " amphetamine use disorder " resulted in an estimated 3,788 deaths worldwide ( 3,425–4,145  deaths,  95% confidence ). [ note 12 ] [ 161 ]


Amphetamine, the active ingredient of Adderall, works primarily by increasing the activity of the  neurotransmitters   dopamine  and  norepinephrine  in the brain. [ 27 ] [ 50 ]  It also triggers the release of several other hormones (e.g.,  epinephrine ) and neurotransmitters (e.g.,  serotonin  and  histamine ) as well as the synthesis of certain  neuropeptides  (e.g.,  cocaine and amphetamine regulated transcript  (CART) peptides). [ 29 ] [ 187 ]  Both active ingredients of Adderall,  dextroamphetamine  and  levoamphetamine , bind to the same  biological targets , [ 31 ] [ 32 ]  but their  binding affinities  (that is,  potency ) differ somewhat. [ 31 ] [ 32 ]  Dextroamphetamine and levoamphetamine are both potent  full agonists  (activating compounds) of  trace amine-associated receptor 1  (TAAR1) and interact with  vesicular monoamine transporter 2  (VMAT2), with dextroamphetamine being the more potent agonist of TAAR1. [ 32 ]  Consequently, dextroamphetamine produces more  CNS  stimulation than levoamphetamine; [ 32 ] [ 188 ]  however, levoamphetamine has slightly greater cardiovascular and peripheral effects. [ 31 ]  It has been reported that certain children have a better clinical response to levoamphetamine. [ 33 ] [ 34 ]


In the absence of amphetamine,  VMAT2  will normally move  monoamines  (e.g.,  dopamine ,  histamine ,  serotonin ,  norepinephrine , etc.) from the  intracellular fluid  of a monoamine  neuron  into its  synaptic vesicles , which store neurotransmitters for later release (via  exocytosis ) into the synaptic cleft. [ 29 ]  When amphetamine enters a neuron and interacts with VMAT2, the transporter reverses its direction of transport, thereby releasing stored monoamines inside synaptic vesicles back into the neuron's intracellular fluid. [ 29 ]  Meanwhile, when amphetamine activates  TAAR1 , the receptor causes the neuron's  cell membrane -bound  monoamine transporters  (i.e., the  dopamine transporter ,  norepinephrine transporter , or  serotonin transporter ) to either stop transporting monoamines altogether (via transporter  internalization ) or  transport monoamines out of the neuron ; [ 28 ]  in other words, the reversed membrane transporter will push dopamine, norepinephrine, and serotonin out of the neuron's intracellular fluid and into the  synaptic cleft . [ 28 ]  In summary, by interacting with both VMAT2 and TAAR1, amphetamine releases neurotransmitters from synaptic vesicles (the effect from VMAT2) into the intracellular fluid where they subsequently exit the neuron through the membrane-bound, reversed monoamine transporters (the effect from TAAR1). [ 28 ] [ 29 ]


The oral  bioavailability  of amphetamine varies with gastrointestinal pH; [ 20 ]  it is well  absorbed  from the gut, and bioavailability is typically 90%. [ 10 ]  Amphetamine is a weak base with a  p K a  of 9.9; [ 189 ]  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 . [ 189 ] [ 20 ]  Conversely, an acidic pH means the drug is predominantly in a water-soluble  cationic  (salt) form, and less is absorbed. [ 189 ]  Approximately  20%  of amphetamine circulating in the bloodstream is bound to  plasma proteins . [ 190 ]  Following absorption, amphetamine readily  distributes  into most tissues in the body, with high concentrations occurring in  cerebrospinal fluid  and  brain  tissue. [ 191 ]


The  half-lives  of amphetamine enantiomers differ and vary with urine pH. [ 189 ]  At normal urine pH, the half-lives of dextroamphetamine and levoamphetamine are  9–11  hours and  11–14  hours, respectively. [ 189 ]  Highly acidic urine will reduce the enantiomer half-lives to 7 hours; [ 191 ]  highly alkaline urine will increase the half-lives up to 34 hours. [ 191 ]  The immediate-release and extended release variants of salts of both isomers reach  peak plasma concentrations  at 3 hours and 7 hours post-dose respectively. [ 189 ]  Amphetamine is  eliminated  via the  kidneys , with  30–40%  of the drug being excreted unchanged at normal urinary pH. [ 189 ]  When the urinary pH is basic, amphetamine is in its free base form, so less is excreted. [ 189 ]  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. [ 189 ]  Following oral administration, amphetamine appears in urine within 3 hours. [ 191 ]  Roughly 90% of ingested amphetamine is eliminated 3 days after the last oral dose. [ 191 ]


CYP2D6 ,  dopamine β-hydroxylase  (DBH),  flavin-containing monooxygenase 3  (FMO3),  butyrate-CoA ligase  (XM-ligase), and  glycine  N -acyltransferase  (GLYAT) are the enzymes known to  metabolize  amphetamine or its metabolites in humans. [ sources 11 ]  Amphetamine has a variety of excreted metabolic products, including  4-hydroxyamphetamine ,  4-hydroxynorephedrine ,  4-hydroxyphenylacetone ,  benzoic acid ,  hippuric acid ,  norephedrine , and  phenylacetone . [ 189 ] [ 192 ]  Among these metabolites, the active  sympathomimetics  are  4-hydroxyamphetamine , [ 193 ]   4-hydroxynorephedrine , [ 194 ]  and norephedrine. [ 195 ]  The main metabolic pathways involve aromatic para-hydroxylation, aliphatic alpha- and beta-hydroxylation,  N -oxidation,  N -dealkylation, and deamination. [ 189 ] [ 196 ]  The known metabolic pathways, detectable metabolites, and metabolizing enzymes in humans include the following:


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. [ 205 ] [ 206 ]  Since the total number of microbial and viral cells in the human body (over 100 trillion) greatly outnumbers human cells (tens of trillions), [ note 15 ] [ 205 ] [ 207 ]  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. [ 205 ] [ 206 ] [ 208 ]  The field that studies these interactions is known as  pharmacomicrobiomics . [ 205 ]


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. [ 28 ] [ 209 ] [ 210 ]  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). [ 28 ] [ 209 ] [ 211 ]  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. [ 209 ] [ 211 ]  In turn,  N -methylphenethylamine  is metabolized from phenethylamine by  phenylethanolamine  N -methyltransferase , the same enzyme that metabolizes norepinephrine into epinephrine. [ 209 ] [ 211 ]  Like amphetamine, both phenethylamine and  N -methylphenethylamine  regulate monoamine neurotransmission via  TAAR1 ; [ 28 ] [ 210 ] [ 211 ]  unlike amphetamine, both of these substances are broken down by  monoamine oxidase B , and therefore have a shorter half-life than amphetamine. [ 209 ] [ 211 ]


The pharmaceutical company Rexar reformulated their popular weight loss drug  Obetrol  following its mandatory withdrawal from the market in 1973 under the  Kefauver Harris Amendment  to the  Federal Food, Drug, and Cosmetic Act  due to the results of the  Drug Efficacy Study Implementation (DESI)  program (which indicated a lack of efficacy). The new formulation simply replaced the two methamphetamine components with dextroamphetamine and amphetamine components of the same weight (the other two original dextroamphetamine and amphetamine components were preserved), preserved the Obetrol branding, and despite it lacking FDA approval, it still made it onto the market and was marketed and sold by Rexar for many years.


In 1994, Richwood Pharmaceuticals acquired Rexar and began promoting Obetrol as a treatment for ADHD (and later narcolepsy as well), now marketed under the new brand name of Adderall, a contraction of the phrase "A.D.D. for All" intended to convey that "it was meant to be kind of an inclusive thing" for marketing purposes. [ 212 ]  The FDA cited the company for numerous significant CGMP violations related to Obetrol discovered during routine inspections following the acquisition (including issuing a formal warning letter for the violations), then later issued a second formal warning letter to Richwood Pharmaceuticals specifically due to violations of "the new drug and misbranding provisions of the FD&C Act". Following extended discussions with Richwood Pharmaceuticals regarding the resolution of a large number of issues related to the company's numerous violations of FDA regulations, the FDA formally approved the first Obetrol labeling/sNDA revisions in 1996, including a name change to Adderall and a restoration of its status as an approved drug product. [ 213 ] [ 214 ]  In 1997 Richwood Pharmaceuticals was acquired by Shire Pharmaceuticals in a $186 million transaction. [ 212 ]


Richwood Pharmaceuticals, which later merged with  Shire plc , introduced the current Adderall brand in 1996 as an instant-release tablet. [ 215 ]  In 2006, Shire agreed to sell rights to the Adderall name for the instant-release form of the medication to  Duramed Pharmaceuticals . [ 216 ]  DuraMed Pharmaceuticals was acquired by  Teva Pharmaceuticals  in 2008 during their  acquisition  of  Barr Pharmaceuticals , including Barr's Duramed division. [ 217 ]


The first generic version of Adderall IR was introduced to the market in 2002. [ 12 ]  Later on, Barr and Shire reached a settlement agreement permitting Barr to offer a generic form of the extended-release drug beginning in April 2009. [ 12 ] [ 218 ]


Chemically, Adderall is a mixture of four amphetamine salts; specifically, it is composed of equal parts (by  mass ) of amphetamine  aspartate monohydrate , amphetamine  sulfate , dextroamphetamine sulfate, and dextroamphetamine  saccharate . [ 69 ]  This drug mixture has slightly stronger  CNS  effects than racemic amphetamine due to the higher proportion of dextroamphetamine. [ 28 ] [ 31 ]  Adderall is produced as both an immediate-release (IR) and extended-release (XR) formulation. [ 12 ] [ 17 ] [ 69 ]  As of December 2013 [update] , ten different companies produced generic Adderall IR, while  Teva Pharmaceutical Industries ,  Actavis , and  Barr Pharmaceuticals  manufactured generic Adderall XR. [ 12 ]  As of 2013 [update] ,  Shire plc , the company that held the original patent for Adderall and Adderall XR, still manufactured brand name Adderall XR, but not Adderall IR. [ 12 ]


Adderall is one of several formulations of pharmaceutical amphetamine, including singular or mixed enantiomers and as an enantiomer prodrug. The table below compares these medications (based on U.S.-approved forms):


In February 2023, news organizations began reporting on shortages of Adderall in the United States that have lasted for over five months. [ 235 ] [ 236 ]  The  Food and Drug Administration  first reported the shortage in October 2022. [ 237 ]  In May 2023, seven months into the shortage, the  Food and Drug Administration  commissioner  Robert Califf  stated that "a number of generic drugs are in shortage at any given time because there's not enough profit". He points out that Adderall is a special case because it is a  controlled substance  and the amount available for prescription is controlled by the  Drug Enforcement Administration . He also faults a "tremendous increase in prescribing" due to virtual prescribing and general overprescribing and overdiagnosing, adding that "if only the people that needed these drugs got them, there probably wouldn't be a [stimulant medication] shortage". [ 238 ] [ 239 ]  The shortage has continued into 2024. [ 240 ] [ 241 ] [ 242 ]  It has led to the creation and expansion of businesses that outsource the search for Adderall. One company charges $50 per U.S. customer to hire workers in the Philippines or another country to make phone calls to all the pharmacies located near the customer and check whether they have any Adderall.  Celebrity endorsements  have contributed to the increased demand for Adderall. [ 243 ]


(adenosine may be safe to the fetus in pregnant women)


Adenosine  ( symbol   A ) is an  organic compound  that occurs widely in nature in the form of diverse derivatives. The molecule consists of an  adenine  attached to a  ribose  via a β-N 9 - glycosidic bond . Adenosine is one of the four  nucleoside  building blocks of  RNA  (and its derivative  deoxyadenosine  is a building block of  DNA ), which are essential for all life on Earth. Its derivatives include the energy carriers  adenosine mono-, di-, and triphosphate , also known as AMP/ADP/ATP.  Cyclic adenosine monophosphate  (cAMP) is pervasive in  signal transduction . Adenosine is used as an intravenous medication for some  cardiac arrhythmias .


Adenosyl  (abbreviated  Ado  or  5'-dAdo ) is the chemical group formed by removal of the 5′-hydroxy (OH) group. It is found in  adenosylcobalamin  (an active form of  vitamin B12 [ 1 ] ) and as a radical in the  radical SAM  enzymes. [ 2 ]


In individuals with  supraventricular tachycardia  (SVT), adenosine is used to help identify and convert the rhythm. [ 3 ] [ 4 ] [ 5 ]


Certain SVTs can be successfully terminated with adenosine. [ 6 ]  This includes any  re-entrant arrhythmias  that require the AV node for the re-entry, e.g.,  AV reentrant tachycardia  (AVRT) and  AV nodal reentrant tachycardia  (AVNRT). In addition,  atrial tachycardia  can sometimes be terminated with adenosine. [ 7 ]


Fast rhythms of the heart that are confined to the  atria  (e.g.,  atrial fibrillation  and  atrial flutter ) or  ventricles  (e.g.,  monomorphic ventricular tachycardia ), and do not involve the AV node as part of the re-entrant circuit, are not typically converted by adenosine. However, the ventricular response rate is temporarily slowed with adenosine in such cases. [ 7 ]


Because of the effects of adenosine on AV node-dependent SVTs, adenosine is considered a class V  antiarrhythmic agent . When adenosine is used to  cardiovert  an abnormal rhythm, it is normal for the heart to enter ventricular  asystole  for a few seconds. This can be disconcerting to a normally conscious patient, and is associated with angina-like sensations in the chest. [ 8 ]


Adenosine is used as an adjunct to  thallium  (TI 201) or  technetium (Tc99m)   myocardial perfusion scintigraphy  (nuclear stress test) in patients unable to undergo adequate stress testing with exercise. [ 9 ]


When given for the evaluation or treatment of a  supraventricular tachycardia  (SVT), the initial dose is 6 mg to 12 mg, depending on standing orders or provider preference, [ 10 ]  given as a rapid  parenteral infusion . Due to adenosine's extremely short half-life, the IV line is started as proximal (near) to the heart as possible, such as the  antecubital fossa . The IV push is often followed with a flush of 10–20 mL of normal saline. If this has no effect (i.e., no evidence of transient AV block), a dose of 12 mg can be given 1–2 minutes after the first dose. When given to dilate the arteries, such as in a "stress test", the dosage is typically 0.14 mg/kg/min, administered for 4 or 6 minutes, depending on the protocol.


The recommended dose may be increased in patients on theophylline since methylxanthines prevent binding of adenosine at receptor sites. The dose is often decreased in patients on  dipyridamole  (Persantine) and  diazepam  (Valium) because adenosine potentiates the effects of these drugs. The recommended dose is also reduced by half in patients presenting  congestive heart failure ,  myocardial infarction ,  shock ,  hypoxia , and/or chronic liver disease or  chronic kidney disease , and in  elderly  patients.


Dipyridamole  potentiates the action of adenosine, requiring the use of lower doses.


Methylxanthines  (e.g.  caffeine  found in coffee,  theophylline  found in tea, or  theobromine  found in chocolate) have a  purine  structure and bind to some of the same receptors as adenosine. [ 12 ]  Methylxanthines act as competitive antagonists of adenosine and can blunt its pharmacological effects. [ 13 ]  Individuals taking large quantities of methylxanthines may require increased doses of adenosine.


Caffeine  acts by blocking binding of adenosine to the  adenosine A 1  receptor , which enhances release of the neurotransmitter  acetylcholine . [ 14 ]  Caffeine also increases cyclic AMP levels through nonselective inhibition of phosphodiesterase. [ 15 ]  "Caffeine has a three-dimensional structure similar to that of adenosine," which allows it to bind and block its receptors. [ 16 ]


Common  contraindications  for adenosine include


Adenosine is an endogenous purine nucleoside that modulates many physiological processes. Cellular signaling by adenosine occurs through four known adenosine receptor subtypes ( A 1 ,  A 2A ,  A 2B , and  A 3 ). [ 18 ]


Extracellular adenosine concentrations from normal cells are approximately 300 nM; however, in response to cellular damage (e.g., in inflammatory or  ischemic  tissue), these concentrations are quickly elevated (600–1,200 nM). Thus, in regard to stress or injury, the function of adenosine is primarily that of cytoprotection preventing tissue damage during instances of  hypoxia ,  ischemia , and seizure activity. Activation of A 2A  receptors produces a constellation of responses that in general can be classified as anti-inflammatory. [ 19 ]  Enzymatic production of adenosine can be anti- inflammatory  or  immunosuppressive . [ 20 ] [ 21 ] [ 22 ]


All adenosine receptor subtypes (A 1 , A 2A , A 2B , and A 3 ) are  G-protein-coupled receptors . The four receptor subtypes are further classified based on their ability to either stimulate or inhibit  adenylate cyclase  activity. The A 1  receptors couple to G i/o  and decrease cAMP levels, while the A 2  adenosine receptors couple to G s , which stimulates adenylate cyclase activity. In addition, A 1  receptors couple to G o , which has been reported to mediate adenosine inhibition of Ca 2+  conductance, whereas A 2B  and A 3  receptors also couple to G q  and stimulate  phospholipase  activity.
Researchers at Cornell University have recently shown adenosine receptors to be key in opening the blood-brain barrier (BBB).
Mice dosed with adenosine have shown increased transport across the BBB of amyloid plaque antibodies and prodrugs associated with Parkinson's disease, Alzheimer's, multiple sclerosis, and cancers of the central nervous system. [ 23 ]


Adenosine is an  endogenous   agonist  of the  ghrelin/growth hormone secretagogue receptor . [ 24 ]  However, while it is able to increase  appetite , unlike other agonists of this receptor, adenosine is unable to induce the secretion of  growth hormone  and increase its plasma levels. [ 24 ]


When it is administered intravenously, adenosine causes transient  heart block  in the  atrioventricular (AV) node . This is mediated via the  A 1  receptor , inhibiting adenylyl cyclase, reducing cAMP and so causing cell hyperpolarization by increasing K +  efflux via  inward rectifier K +  channels , subsequently inhibiting Ca 2+  current. [ 25 ] [ 26 ]  It also causes endothelial-dependent relaxation of smooth muscle as is found inside the artery walls. This causes dilation of the "normal" segments of arteries, i.e. where the  endothelium  is not separated from the tunica media by  atherosclerotic plaque . This feature allows physicians to use adenosine to test for blockages in the coronary arteries, by exaggerating the difference between the normal and abnormal segments.


The administration of adenosine also reduces blood flow to coronary arteries past the occlusion. Other coronary arteries dilate when adenosine is administered while the segment past the occlusion is already maximally dilated, which is a process called  coronary steal . This leads to less blood reaching the ischemic tissue, which in turn produces the characteristic chest pain.


Adenosine used as a  second messenger  can be the result of  de novo   purine biosynthesis  via  adenosine monophosphate  (AMP), though it is possible other pathways exist. [ 27 ]


When adenosine enters the circulation, it is broken down by  adenosine deaminase , which is present in  red blood cells  and the vessel wall.


Dipyridamole , an inhibitor of  adenosine nucleoside transporter , allows adenosine to accumulate in the blood stream. This causes an increase in coronary  vasodilatation .


Adenosine deaminase deficiency  is a known cause of immunodeficiency.


The adenosine analog  NITD008  has been reported to directly inhibit the recombinant RNA-dependent  RNA polymerase  of the  dengue virus  by terminating its RNA chain synthesis. This interaction suppresses peak  viremia  and rise in  cytokines  and prevents lethality in infected animals, raising the possibility of a new treatment for this  flavivirus . [ 28 ]  The 7-deaza-adenosine analog has been shown to inhibit the replication of the  hepatitis C virus . [ 29 ]   BCX4430  is protective against  Ebola  and  Marburg  viruses. [ 30 ]  Such adenosine analogs are potentially clinically useful since they can be taken orally.


Adenosine is believed to be an  anti-inflammatory  agent at the A 2A  receptor. [ 31 ] [ 32 ]  Topical treatment of adenosine to foot wounds in  diabetes mellitus  has been shown in lab animals to drastically increase tissue repair and reconstruction. Topical administration of adenosine for use in wound-healing deficiencies and diabetes mellitus in humans is currently under clinical investigation.


Methotrexate 's anti-inflammatory effect may be due to its stimulation of adenosine release. [ 33 ]


In general, adenosine has an inhibitory effect in the  central nervous system  (CNS).
 Caffeine 's stimulatory effects are credited primarily (although not entirely) to its capacity to block adenosine receptors, thereby reducing the inhibitory tonus of adenosine in the CNS. This reduction in adenosine activity leads to increased activity of the  neurotransmitters   dopamine  and  glutamate . [ 34 ]  Experimental evidence suggests that adenosine and adenosine agonists can activate  Trk receptor  phosphorylation through a mechanism that requires the adenosine A 2A  receptor. [ 35 ]


Adenosine has been shown to promote thickening of hair on people with thinning hair. [ 36 ] [ 37 ]   A 2013 study compared topical adenosine with  minoxidil  in male  androgenetic alopecia , finding it was as potent as minoxidil (in overall treatment outcomes) but with higher satisfaction rate with patients due to “faster prevention of hair loss and appearance of the newly grown hairs” (further trials were called for to clarify the findings). [ 38 ]


Adenosine is a key factor in regulating the body's  sleep-wake cycle . [ 39 ]  Adenosine levels rise during periods of wakefulness and lowers during sleep. Higher adenosine levels correlate with a stronger feeling of  sleepiness , also known as sleep drive or sleep pressure. [ 40 ]   Cognitive behavioral therapy for insomnia  (CBT-I), which is considered one of the most effective treatments for  insomnia , utilizes short-term  sleep deprivation  to raise and regulate adenosine levels in the body, for the intended promotion of consistent and sustained sleep in the long term. [ 41 ]


A principal component of  cannabis   delta-9-tetrahydrocannabinol  (THC) and the  endocannabinoid   anandamide  (AEA) induces  sleep  in  rats  by increasing adenosine levels in the  basal forebrain . These components also significantly increase  slow-wave sleep  during the  sleep cycle , mediated by  CB1 receptor   activation . These findings identify a potential  therapeutic use  of  cannabinoids  to induce sleep in conditions where sleep may be severely attenuated. [ 42 ]


It also plays a role in regulation of blood flow to various organs through  vasodilation . [ 43 ] [ 44 ] [ 45 ]


Alifedrine  ( INN Tooltip International Nonproprietary Name ; developmental code name  D-13625 ) is a drug described as a  sympathomimetic  and  cardiotonic  or  positive inotropic agent  which was never marketed. [ 3 ] [ 4 ] [ 5 ] [ 6 ]  It is a  β-adrenergic receptor   partial agonist  and was studied in the treatment of  heart failure . [ 4 ] [ 1 ] [ 2 ] [ 7 ]  The drug is taken  by mouth  or  intravenously . [ 1 ] [ 2 ]  It is a β- hydroxylated   substituted amphetamine   derivative . [ 8 ]


This  drug  article relating to the  cardiovascular system  is a  stub . You can help Wikipedia by  expanding it .


Amphetamine [ note 2 ]  (contracted from  a lpha - m ethyl ph en et hyl amine ) is a  central nervous system  (CNS)  stimulant  that is used in the treatment of  attention deficit hyperactivity disorder  (ADHD),  narcolepsy , and  obesity ; it is also used to treat  binge eating disorder  in the form of its inactive  prodrug   lisdexamfetamine . Amphetamine was discovered as a chemical in 1887 by  Lazăr Edeleanu , and then as a drug in the late 1920s. It exists as two  enantiomers : [ note 3 ]   levoamphetamine  and  dextroamphetamine .  Amphetamine  properly refers to a specific chemical, the  racemic   free base , which is equal parts of the two enantiomers in their pure  amine  forms. The term is frequently used informally to refer to any combination of the enantiomers, or to either of them alone. Historically, it has been used to treat nasal congestion and depression. Amphetamine is also used as an  athletic performance enhancer  and  cognitive enhancer , and recreationally as an  aphrodisiac  and  euphoriant . It is a  prescription drug  in many countries, and unauthorized possession and distribution of amphetamine are often tightly controlled due to the significant health risks associated with recreational use. [ sources 1 ]


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


At therapeutic doses, amphetamine causes emotional and cognitive effects such as  euphoria , change in  desire for sex , increased  wakefulness , and improved  cognitive control . It induces physical effects such as improved reaction time, fatigue resistance,  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 ]


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


Amphetamine is used to treat  attention deficit hyperactivity disorder  (ADHD),  narcolepsy ,  obesity , and, in the form of  lisdexamfetamine ,  binge eating disorder . [ 1 ] [ 36 ] [ 37 ]  It is sometimes prescribed  off-label  for its past  medical indications , particularly for  depression  and  chronic pain . [ 1 ] [ 52 ]


Long-term amphetamine exposure at sufficiently high doses in some animal species is known to produce abnormal  dopamine system  development or nerve damage, [ 53 ] [ 54 ]  but, in humans with ADHD, long-term use of pharmaceutical amphetamines at therapeutic doses appears to improve brain development and nerve growth. [ 55 ] [ 56 ] [ 57 ]  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 . [ 55 ] [ 56 ] [ 57 ]


Reviews of clinical stimulant research have established the safety and effectiveness of long-term continuous amphetamine use for the treatment of ADHD. [ 45 ] [ 58 ] [ 59 ]   Randomized controlled trials  of continuous stimulant therapy for the treatment of ADHD spanning 2 years have demonstrated treatment effectiveness and safety. [ 45 ] [ 58 ]  Two reviews have indicated that long-term continuous stimulant therapy for ADHD is effective for reducing the core symptoms of ADHD (i.e., hyperactivity, inattention, and impulsivity), enhancing  quality of life  and academic achievement, and producing improvements in a large number of functional outcomes [ note 6 ]  across 9 categories of outcomes related to academics,  antisocial behavior , driving, non-medicinal drug use, obesity, occupation,  self-esteem , service use (i.e., academic, occupational, health, financial, and legal services), and social function. [ 45 ] [ 59 ]  Additionally, a 2024  meta-analytic   systematic review  reported moderate improvements in quality of life when amphetamine treatment is used for ADHD. [ 61 ]  One review highlighted a nine-month randomized controlled trial of amphetamine treatment for ADHD in children that found an average increase of 4.5  IQ  points, continued increases in attention, and continued decreases in disruptive behaviors and hyperactivity. [ 58 ]  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. [ 45 ]  A 2025 meta-analytic systematic review of 113 randomized controlled trials demonstrated that stimulant medications significantly improved core ADHD symptoms in adults over a three-month period, with good acceptability compared to other pharmacological and non-pharmacological treatments. [ 62 ]


Models of ADHD suggest that it is associated with functional impairments in some of the brain's  neurotransmitter systems ; [ 63 ]  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 . [ 63 ]  Stimulants like  methylphenidate  and amphetamine are effective in treating ADHD because they increase neurotransmitter activity in these systems. [ 27 ] [ 63 ] [ 64 ]  Approximately 80% of those who use these stimulants see improvements in ADHD symptoms. [ 65 ]  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. [ 66 ] [ 67 ]  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 . [ 69 ] [ 70 ]  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. [ 71 ]


Binge eating disorder  (BED) is characterized by recurrent and persistent episodes of compulsive binge eating. [ 72 ]  These episodes are often accompanied by marked distress and a feeling of loss of control over eating. [ 72 ]  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 . [ 73 ] [ 74 ]  As of July 2024, lisdexamfetamine is the only  USFDA - and  TGA -approved  pharmacotherapy  for BED. [ 37 ] [ 75 ]  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. [ 73 ] [ 74 ]


Lisdexamfetamine's therapeutic effects for BED primarily involve direct action in the  central nervous system  after conversion to its pharmacologically active metabolite, dextroamphetamine. [ 75 ]  Centrally, dextroamphetamine increases neurotransmitter activity of dopamine and norepinephrine in prefrontal cortical regions that regulate cognitive control of behavior. [ 73 ] [ 75 ]  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. [ 73 ] [ 77 ] [ 78 ]  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. [ 74 ] [ 79 ]  Dextroamphetamine also activates  TAAR1  in peripheral organs along the  gastrointestinal tract  that are involved in the regulation of food intake and body weight. [ 76 ]  Together, these actions confer an  anorexigenic  effect that promotes  satiety  in response to feeding and may decrease binge eating as a secondary effect. [ 78 ] [ 76 ]


Medical reviews of randomized controlled trials have demonstrated that lisdexamfetamine, at doses between 50–70 mg, 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. [ 78 ]  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. [ 74 ] [ 78 ]  Lisdexamfetamine, like all pharmaceutical amphetamines, has direct appetite suppressant effects that may be therapeutically useful in both BED and its comorbidities. [ 37 ] [ 78 ]  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. [ 37 ] [ 75 ] [ 78 ]


Narcolepsy is a chronic sleep-wake disorder that is associated with excessive daytime sleepiness,  cataplexy , and  sleep paralysis . [ 81 ]  Patients with narcolepsy are diagnosed as either type 1 or type 2, with only the former presenting cataplexy symptoms. [ 82 ]  Type 1 narcolepsy results from the loss of approximately 70,000  orexin -releasing neurons in the  lateral hypothalamus , leading to significantly reduced  cerebrospinal  orexin levels; [ 18 ] [ 83 ]  this reduction is a  diagnostic biomarker  for type 1 narcolepsy. [ 82 ]  Lateral hypothalamic orexin neurons innervate every component of the  ascending reticular activating system  (ARAS), which includes  noradrenergic ,  dopaminergic ,  histaminergic , and  serotonergic  nuclei that promote  wakefulness . [ 83 ] [ 84 ]


Amphetamine’s therapeutic mode of action in narcolepsy primarily involves increasing  monoamine  neurotransmitter activity in the ARAS. [ 18 ] [ 85 ] [ 86 ]  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 . [ 84 ] [ 86 ]  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. [ 18 ]  In contrast, levoamphetamine may have a greater effect on cataplexy, a symptom more sensitive to the effects of norepinephrine and serotonin. [ 18 ]  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. [ 18 ] [ 82 ] [ 84 ]


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. [ 87 ]  Treatment with pharmaceutical amphetamines is generally less preferred relative to other stimulants (e.g.,  modafinil ) and is considered a  third-line treatment  option. [ 48 ] [ 88 ] [ 89 ]  Medical reviews indicate that amphetamine is safe and effective for the treatment of narcolepsy. [ 18 ] [ 48 ] [ 87 ]  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. [ 18 ] [ 48 ] [ 87 ]  Additionally, these reviews suggest that amphetamine may dose-dependently improve cataplexy symptoms. [ 18 ] [ 48 ] [ 87 ]  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. [ 87 ]


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; [ 90 ] [ 91 ]  these cognition-enhancing effects of amphetamine are known to be partially mediated through the  indirect activation  of both  dopamine D 1  receptor  and  α 2 -adrenergic receptor  in the  prefrontal cortex . [ 27 ] [ 90 ]  A systematic review from 2014 found that low doses of amphetamine also improve  memory consolidation , in turn leading to improved  recall of information . [ 92 ]  Therapeutic doses of amphetamine also enhance cortical network efficiency, an effect which mediates improvements in working memory in all individuals. [ 27 ] [ 93 ]  Amphetamine and other ADHD stimulants also improve  task saliency  (motivation to perform a task) and increase  arousal  (wakefulness), in turn promoting goal-directed behavior. [ 27 ] [ 94 ] [ 95 ]  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. [ 27 ] [ 95 ] [ 96 ]  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. [ 97 ] [ 98 ] [ 99 ]  However, high amphetamine doses that are above the therapeutic range can interfere with working memory and other aspects of cognitive control. [ 27 ] [ 95 ]


Amphetamine is used by some athletes for its psychological and  athletic performance-enhancing effects , such as increased endurance and alertness; [ 28 ] [ 41 ]  however, non-medical amphetamine use is prohibited at sporting events that are regulated by collegiate, national, and international anti-doping agencies. [ 100 ] [ 101 ]  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 . [ 28 ] [ 102 ] [ 103 ]  Amphetamine improves endurance and reaction time primarily through  reuptake inhibition  and  release  of dopamine in the central nervous system. [ 102 ] [ 103 ] [ 104 ]  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. [ 103 ] [ 105 ] [ 106 ]  At therapeutic doses, the adverse effects of amphetamine do not impede athletic performance; [ 28 ] [ 102 ]  however, at much higher doses, amphetamine can induce effects that severely impair performance, such as  rapid muscle breakdown  and  elevated body temperature . [ 29 ] [ 102 ]


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. [ 107 ] [ 108 ] [ 109 ]  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. [ 110 ]  Mods used the drug for  stimulation  and  alertness , which they viewed as different from the  intoxication  caused by alcohol and other drugs. [ 110 ]  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." [ 110 ]  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 . [ 111 ]  Large recreational doses of dextroamphetamine may produce  symptoms of dextroamphetamine overdose . [ 109 ]  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. [ 109 ]  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). [ 112 ] [ 113 ]  Injection into the bloodstream can be dangerous because insoluble fillers within the tablets can block small blood vessels. [ 109 ]  Chronic overuse of dextroamphetamine can lead to severe  drug dependence , resulting in withdrawal symptoms when drug use stops. [ 109 ]


According to the  International Programme on Chemical Safety  (IPCS) and the U.S.  Food and Drug Administration  (FDA), [ note 8 ]  amphetamine is  contraindicated  in people with a history of  drug abuse , [ note 9 ]   cardiovascular disease , severe  agitation , or severe anxiety. [ 36 ] [ 29 ] [ 115 ]  It is also contraindicated in individuals with advanced  arteriosclerosis  (hardening of the arteries),  glaucoma  (increased eye pressure),  hyperthyroidism  (excessive production of thyroid hormone), or moderate to severe  hypertension . [ 36 ] [ 29 ] [ 115 ]  These agencies indicate that people who have experienced  allergic reactions  to other stimulants or who are taking  monoamine oxidase inhibitors  (MAOIs) should not take amphetamine, [ 36 ] [ 29 ] [ 115 ]  although safe concurrent use of amphetamine and monoamine oxidase inhibitors has been documented. [ 116 ] [ 117 ]  These agencies also state that anyone with  anorexia nervosa ,  bipolar disorder , depression, hypertension, liver or kidney problems,  mania ,  psychosis ,  Raynaud's phenomenon ,  seizures ,  thyroid  problems,  tics , or  Tourette syndrome  should monitor their symptoms while taking amphetamine. [ 29 ] [ 115 ]  Evidence from human studies indicates that therapeutic amphetamine use does not cause developmental abnormalities in the fetus or newborns (i.e., it is not a human  teratogen ), but amphetamine abuse does pose risks to the fetus. [ 115 ]  Amphetamine has also been shown to pass into breast milk, so the IPCS and the FDA advise mothers to avoid breastfeeding when using it. [ 29 ] [ 115 ]  Due to the potential for reversible growth impairments, [ note 10 ]  the FDA advises monitoring the height and weight of children and adolescents prescribed an amphetamine pharmaceutical. [ 29 ]


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. [ 29 ] [ 41 ]  Amphetamine products such as  Adderall , Dexedrine, and their generic equivalents are currently approved by the U.S. FDA for long-term therapeutic use. [ 38 ] [ 29 ]   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. [ 41 ]


Cardiovascular  side effects can include  hypertension  or  hypotension  from a  vasovagal response ,  Raynaud's phenomenon  (reduced blood flow to the hands and feet), and  tachycardia  (increased heart rate). [ 29 ] [ 41 ] [ 118 ]  Sexual side effects in males may include  erectile dysfunction , frequent erections, or  prolonged erections . [ 29 ]  Gastrointestinal side effects may include  abdominal pain ,  constipation ,  diarrhea , and  nausea . [ 1 ] [ 29 ] [ 119 ]  Other potential physical side effects include  appetite loss ,  blurred vision ,  dry mouth ,  excessive grinding of the teeth , nosebleed, profuse sweating,  rhinitis medicamentosa  (drug-induced nasal congestion), reduced  seizure threshold ,  tics  (a type of movement disorder), and  weight loss . [ sources 6 ]  Dangerous physical side effects are rare at typical pharmaceutical doses. [ 41 ]


Amphetamine stimulates the  medullary respiratory centers , producing faster and deeper breaths. [ 41 ]  In a normal person at therapeutic doses, this effect is usually not noticeable, but when respiration is already compromised, it may be evident. [ 41 ]  Amphetamine also induces  contraction  in the urinary  bladder sphincter , the muscle which controls urination, which can result in difficulty urinating. [ 41 ]  This effect can be useful in treating  bed wetting  and  loss of bladder control . [ 41 ]  The effects of amphetamine on the gastrointestinal tract are unpredictable. [ 41 ]  If intestinal activity is high, amphetamine may reduce  gastrointestinal motility  (the rate at which content moves through the digestive system); [ 41 ]  however, amphetamine may increase motility when the  smooth muscle  of the tract is relaxed. [ 41 ]  Amphetamine also has a slight  analgesic  effect and can enhance the pain relieving effects of  opioids . [ 1 ] [ 41 ]


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 ]


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. [ 29 ] [ 41 ]  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. [ 41 ]   Amphetamine psychosis  (e.g.,  delusions  and  paranoia ) can occur in heavy users. [ 29 ] [ 42 ] [ 43 ]  Although very rare, this psychosis can also occur at therapeutic doses during long-term therapy. [ 29 ] [ 43 ] [ 44 ]  According to the FDA, "there is no systematic evidence" that stimulants produce aggressive behavior or hostility. [ 29 ]


Amphetamine has also been shown to produce a  conditioned place preference  in humans taking therapeutic doses, [ 69 ] [ 126 ]  meaning that individuals acquire a preference for spending time in places where they have previously used amphetamine. [ 126 ] [ 127 ]


Addiction  is a serious risk with heavy recreational amphetamine use, but is unlikely to occur from long-term medical use at therapeutic doses; [ 46 ] [ 47 ] [ 48 ]  in fact, lifetime stimulant therapy for ADHD that begins during childhood reduces the risk of developing  substance use disorders  as an adult. [ 45 ]   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. [ 136 ] [ 137 ]  Individuals who frequently  self-administer  high doses of amphetamine have a high risk of developing an amphetamine addiction, since chronic use at high doses gradually increases the level of  accumbal   ΔFosB , a "molecular switch" and "master control protein" for addiction. [ 128 ] [ 138 ] [ 139 ]  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. [ 138 ] [ 140 ]  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. [ 141 ] [ 142 ]  Exercise therapy improves  clinical  treatment outcomes and may be used as an  adjunct therapy  with behavioral therapies for addiction. [ 141 ] [ 143 ] [ sources 10 ]


Chronic use of amphetamine at excessive doses causes alterations in  gene expression  in the  mesocorticolimbic projection , which arise through  transcriptional  and  epigenetic  mechanisms. [ 139 ] [ 144 ] [ 145 ]  The most important  transcription factors [ note 11 ]  that produce these alterations are  Delta FBJ murine osteosarcoma viral oncogene homolog B  ( ΔFosB ),  cAMP  response element binding protein  ( CREB ), and  nuclear factor-kappa B  ( NF-κB ). [ 139 ]  ΔFosB is the most significant biomolecular mechanism in addiction because ΔFosB  overexpression  (i.e., an abnormally high level of gene expression which produces a pronounced gene-related  phenotype ) in the  D1-type   medium spiny neurons  in the  nucleus accumbens  is  necessary and sufficient [ note 12 ]  for many of the neural adaptations and regulates multiple behavioral effects (e.g.,  reward sensitization  and escalating drug  self-administration ) involved in addiction. [ 128 ] [ 138 ] [ 139 ]  Once ΔFosB is sufficiently overexpressed, it induces an addictive state that becomes increasingly more severe with further increases in ΔFosB expression. [ 128 ] [ 138 ]  It has been implicated in addictions to  alcohol ,  cannabinoids ,  cocaine ,  methylphenidate ,  nicotine ,  opioids ,  phencyclidine ,  propofol , and  substituted amphetamines , among others. [ sources 11 ]


ΔJunD , a transcription factor, and  G9a , a  histone methyltransferase  enzyme, both oppose the function of ΔFosB and inhibit increases in its expression. [ 128 ] [ 139 ] [ 149 ]  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). [ 139 ]  Similarly, accumbal G9a hyperexpression results in markedly increased  histone  3  lysine   residue  9  dimethylation  ( H3K9me2 ) and blocks the induction of ΔFosB-mediated  neural  and  behavioral plasticity  by chronic drug use, [ sources 12 ]  which occurs via  H3K9me2 -mediated  repression  of  transcription factors  for ΔFosB and H3K9me2-mediated repression of various ΔFosB transcriptional targets (e.g.,  CDK5 ). [ 139 ] [ 149 ] [ 150 ]  ΔFosB also plays an important role in regulating behavioral responses to  natural rewards , such as palatable food, sex, and exercise. [ 140 ] [ 139 ] [ 153 ]  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. [ 140 ] [ 139 ]  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. [ 140 ] [ 154 ] [ 155 ]  These sexual addictions are associated with a  dopamine dysregulation syndrome  which occurs in some patients taking  dopaminergic drugs . [ 140 ] [ 153 ]


The effects of amphetamine on gene regulation are both dose- and route-dependent. [ 145 ]  Most of the research on gene regulation and addiction is based upon animal studies with intravenous amphetamine administration at very high doses. [ 145 ]  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. [ 145 ]  This suggests that medical use of amphetamine does not significantly affect gene regulation. [ 145 ]


As of December 2019, [update]  there is no effective  pharmacotherapy  for amphetamine addiction. [ 156 ] [ 157 ] [ 158 ]  Reviews from 2015 and 2016 indicated that  TAAR1 -selective agonists have significant therapeutic potential as a treatment for psychostimulant addictions; [ 40 ] [ 159 ]  however, as of February 2016, [update]  the only compounds which are known to function as TAAR1-selective agonists are  experimental drugs . [ 40 ] [ 159 ]  Amphetamine addiction is largely mediated through increased activation of  dopamine receptors  and  co-localized   NMDA receptors [ note 13 ]  in the nucleus accumbens; [ 137 ]   magnesium ions  inhibit NMDA receptors by blocking the receptor  calcium channel . [ 137 ] [ 160 ]  One review suggested that, based upon animal testing, pathological (addiction-inducing) psychostimulant use significantly reduces the level of intracellular magnesium throughout the brain. [ 137 ]   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. [ 137 ]


A systematic review and meta-analysis from 2019 assessed the efficacy of 17 different pharmacotherapies used in  randomized controlled trials  (RCTs) for amphetamine and methamphetamine addiction; [ 157 ]  it found only low-strength evidence that methylphenidate might reduce amphetamine or methamphetamine self-administration. [ 157 ]  There was low- to moderate-strength evidence of no benefit for most of the other medications used in RCTs, which included antidepressants (bupropion,  mirtazapine ,  sertraline ), antipsychotics ( aripiprazole ), anticonvulsants ( topiramate ,  baclofen ,  gabapentin ),  naltrexone ,  varenicline ,  citicoline ,  ondansetron ,  prometa ,  riluzole ,  atomoxetine , dextroamphetamine, and  modafinil . [ 157 ]


A 2018 systematic review and  network meta-analysis  of 50 trials involving 12 different psychosocial interventions for amphetamine, methamphetamine, or cocaine addiction found that  combination therapy  with both  contingency management  and  community reinforcement approach  had the highest efficacy (i.e., abstinence rate) and acceptability (i.e., lowest dropout rate). [ 161 ]  Other treatment modalities examined in the analysis included  monotherapy  with contingency management or community reinforcement approach,  cognitive behavioral therapy ,  12-step programs , non-contingent reward-based therapies,  psychodynamic therapy , and other combination therapies involving these. [ 161 ]


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. [ 141 ] [ 143 ] [ 162 ]  In particular,  aerobic exercise  decreases psychostimulant self-administration, reduces the  reinstatement  (i.e., relapse) of drug-seeking, and induces increased  dopamine receptor D 2  (DRD2) density in the  striatum . [ 140 ] [ 162 ]  This is the opposite of pathological stimulant use, which induces decreased striatal DRD2 density. [ 140 ]  One review noted that exercise may also prevent the development of a drug addiction by altering ΔFosB or  c-Fos   immunoreactivity  in the striatum or other parts of the  reward system . [ 142 ]


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. [ 163 ] [ 164 ]
According to a Cochrane review on  withdrawal  in individuals who compulsively use amphetamine and methamphetamine, "when chronic heavy users abruptly discontinue amphetamine use, many report a time-limited withdrawal syndrome that occurs within 24 hours of their last dose." [ 165 ]  This review noted that withdrawal symptoms in chronic, high-dose users are frequent, occurring in roughly 88% of cases, and persist for  3–4  weeks with a marked "crash" phase occurring during the first week. [ 165 ]  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 . [ 165 ]  The review indicated that the severity of withdrawal symptoms is positively correlated with the age of the individual and the extent of their dependence. [ 165 ]  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 ] [ 115 ] [ 166 ]  The severity of overdose symptoms increases with dosage and decreases with  drug tolerance  to amphetamine. [ 41 ] [ 115 ]  Tolerant individuals have been known to take as much as 5 grams of amphetamine in a day, which is roughly 100 times the maximum daily therapeutic dose. [ 115 ]  Symptoms of a moderate and extremely large overdose are listed below; fatal amphetamine poisoning usually also involves convulsions and  coma . [ 29 ] [ 41 ]  In 2013, overdose on amphetamine, methamphetamine, and other compounds implicated in an " amphetamine use disorder " resulted in an estimated 3,788 deaths worldwide ( 3,425–4,145  deaths,  95% confidence ). [ note 15 ] [ 167 ]


In rodents and primates, sufficiently high doses of amphetamine cause dopaminergic  neurotoxicity , or damage to dopamine neurons, which is characterized by dopamine  terminal   degeneration  and reduced transporter and receptor function. [ 169 ] [ 170 ]  There is no evidence that amphetamine is directly neurotoxic in humans. [ 171 ] [ 172 ]  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. [ 170 ]  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. [ 170 ]


An amphetamine overdose can result in a stimulant psychosis that may involve a variety of symptoms, such as delusions and paranoia. [ 42 ] [ 43 ]  A Cochrane review on treatment for amphetamine, dextroamphetamine, and methamphetamine psychosis states that about  5–15%  of users fail to recover completely. [ 42 ] [ 175 ]  According to the same review, there is at least one trial that shows  antipsychotic  medications effectively resolve the symptoms of acute amphetamine psychosis. [ 42 ]  Psychosis rarely arises from therapeutic use. [ 29 ] [ 43 ] [ 44 ]


Many types of substances are known to  interact  with amphetamine, resulting in altered  drug action  or  metabolism  of amphetamine, the interacting substance, or both. [ 29 ]   Inhibitors of enzymes  that metabolize amphetamine (e.g.,  CYP2D6  and  FMO3 ) will prolong its  elimination half-life , meaning that its effects will last longer. [ 6 ] [ 29 ]  Amphetamine also interacts with  MAOIs , particularly  monoamine oxidase A  inhibitors, since both MAOIs and amphetamine increase  plasma  catecholamines (i.e., norepinephrine and dopamine); [ 29 ]  therefore, concurrent use of both is dangerous. [ 29 ]  Amphetamine modulates the activity of most psychoactive drugs. In particular, amphetamine may decrease the effects of  sedatives  and  depressants  and increase the effects of  stimulants  and  antidepressants . [ 29 ]  Amphetamine may also decrease the effects of  antihypertensives  and  antipsychotics  due to its effects on blood pressure and dopamine respectively. [ 29 ]   Zinc supplementation  may reduce the  minimum effective dose  of amphetamine when it is used for the treatment of ADHD. [ note 16 ] [ 180 ]   Norepinephrine reuptake inhibitors  (NRIs) like  atomoxetine  prevent  norepinephrine  release induced by amphetamines and have been found to reduce the  stimulant ,  euphoriant , and  sympathomimetic  effects of  dextroamphetamine  in humans. [ 181 ] [ 182 ] [ 183 ]


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. [ 29 ]  Acidic substances reduce the absorption of amphetamine and increase urinary excretion, and alkaline substances do the opposite. [ 29 ]  Due to the effect pH has on absorption, amphetamine also interacts with gastric acid reducers such as  proton pump inhibitors  and  H 2  antihistamines , which increase gastrointestinal pH (i.e., make it less acidic). [ 29 ]