|amphetamine aspartate monohydrate||(25%) stimulant|
|amphetamine sulfate||(25%) stimulant|
|dextroamphetamine saccharate||(25%) stimulant|
|dextroamphetamine sulfate||(25%) stimulant|
|Trade names||Adderall, Adderall XR|
|Licence data||US FDA:|
|Routes||Oral, insufflation, rectal, sublingual|
|ATC code||N06 N06|
|(what is this?)|
Adderall[note 1] is a psychostimulant drug of the phenethylamine class used in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. Adderall is also used as a performance and cognitive enhancer, and recreationally as an aphrodisiac and euphoriant. The medication is a mixture of various salts of the two amphetamine stereoisomers and inactive ingredients; by salt content, the active ingredients are 75% dextroamphetamine salts (the dextrorotary or "right-handed" enantiomer) and 25% levoamphetamine salts (the levorotary or "left-handed" enantiomer).[note 2][sources 1]
Adderall works by increasing the activity of the neurotransmitters norepinephrine and dopamine in the brain, which results from its interactions with trace amine associated receptor 1 (TAAR1) and vesicular monoamine transporter 2 (VMAT2). Adderall shares many chemical and pharmacological properties with the human trace amine neurotransmitters, especially phenethylamine and N-methylphenethylamine, the latter being an isomer of amphetamine that is produced within the human body.[sources 2]
Adderall is generally well-tolerated and effective in treating the symptoms of ADHD. The most common side effects are cardiovascular, such as irregular heartbeat (usually as a fast heartbeat), and psychological, such as euphoria or anxiety. Much larger doses of Adderall are likely to impair cognitive function and induce rapid muscle breakdown. Drug addiction is a serious risk of Adderall abuse, but only rarely arises from medical use. Very high doses can result in a psychosis (e.g., delusions and paranoia) which rarely occurs at therapeutic doses even during long-term use. Recreational doses are generally much larger than prescribed therapeutic doses, and carry a far greater risk of serious side effects.[sources 3]
- 1 Uses
- 2 Contraindications
- 3 Side effects
- 4 Overdose
- 5 Interactions
- 6 Pharmacology
- 7 History, society, and culture
- 8 Notes
- 9 Reference notes
- 10 References
Adderall is used to treat attention deficit hyperactivity disorder (ADHD) and narcolepsy (a sleep disorder). Long-term amphetamine exposure in some animal species is known to produce abnormal dopamine system development or nerve damage, but, in humans with ADHD, pharmaceutical amphetamines appear to improve brain development and nerve growth. Magnetic resonance imaging (MRI) studies suggest that long-term treatment with amphetamine decreases abnormalities in brain structure and function found in subjects with ADHD, and improves function in several parts of the brain, such as the right caudate nucleus of the basal ganglia.
Reviews of clinical stimulant research have established the safety and effectiveness of long-term amphetamine use for ADHD. Controlled trials spanning two years have demonstrated treatment effectiveness and safety. One review highlighted a nine-month randomized controlled trial in children with ADHD that found an average increase of 4.5 IQ points, continued increases in attention, and continued decreases in disruptive behaviors and hyperactivity.
Current models of ADHD suggest that it is associated with functional impairments in some of the brain's neurotransmitter systems; these functional impairments involve impaired dopamine neurotransmission in the mesocorticolimbic projection and norepinephrine neurotransmission in the locus coeruleus and prefrontal cortex. Psychostimulants like methylphenidate and amphetamine are effective in treating ADHD because they increase neurotransmitter activity in these systems. Approximately 70% of those who use these stimulants see improvements in ADHD symptoms. Children with ADHD who use stimulant medications generally have better relationships with peers and family members, perform better in school, are less distractible and impulsive, and have longer attention spans. The Cochrane Collaboration's review[note 3] on the treatment of adult ADHD with pharmaceutical amphetamines stated that while these drugs improve short-term symptoms, they have higher discontinuation rates than non-stimulant medications due to their adverse side effects.
A Cochrane Collaboration review on the treatment of ADHD in children with tic disorders such as Tourette syndrome indicated that stimulants in general do not make tics worse, but high doses of dextroamphetamine could exacerbate tics in some individuals. Other Cochrane reviews on the use of amphetamine following stroke or acute brain injury indicated that it may improve recovery, but further research is needed to confirm this.
Dosing and administration
Adderall is available as immediate release tablets or extended-release capsules. The extended release capsule is generally used in the morning. The extended release formulation available under the brand Adderall XR is designed to provide therapeutic effect and plasma concentrations identical to taking two doses 4 hours apart.
Therapeutic doses of amphetamine improve cortical network efficiency, resulting in higher performance on working memory tests in all individuals. Amphetamine and other ADHD stimulants also improve task saliency (motivation to perform a task) and increase arousal (wakefulness), in turn promoting goal-directed behavior. Stimulants such as amphetamine can improve performance on difficult and boring tasks and are used by some students as a study and test-taking aid. Based upon studies of self-reported illicit stimulant use, students primarily use stimulants such as amphetamine for performance enhancement rather than abusing them as recreational drugs. However, high amphetamine doses that are above the therapeutic range can interfere with working memory and cognitive control.
Amphetamine is used by some athletes for its psychological and performance-enhancing effects, such as increased stamina and alertness; however, its use is prohibited at sporting events regulated by collegiate, national, and international anti-doping agencies. In healthy people at oral therapeutic doses, amphetamine has been shown to increase physical strength, acceleration, stamina, and endurance, while reducing reaction time. Amphetamine improves stamina, endurance, and reaction time primarily through reuptake inhibition and effluxion of dopamine in the central nervous system. At therapeutic doses, the adverse effects of amphetamine do not impede athletic performance; however, at much higher doses, amphetamine can induce effects that severely impair performance, such as rapid muscle breakdown and elevated body temperature.
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). 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.
Adderall is considered to have a high potential to be used recreationally. Adderall tablets can be crushed and snorted, or dissolved in water and injected. Injection into the bloodstream can be dangerous because insoluble fillers within the tablets can block small blood vessels.
According to the International Programme on Chemical Safety (IPCS) and United States Food and Drug Administration (USFDA),[note 4] amphetamine is contraindicated in people with a history of drug abuse, heart disease, severe agitation, or severe anxiety. It is also contraindicated in people currently experiencing arteriosclerosis (hardening of the arteries), glaucoma (increased eye pressure), hyperthyroidism (excessive production of thyroid hormone), or hypertension. People who have experienced allergic reactions to other stimulants in the past or who are taking monoamine oxidase inhibitors (MAOIs) are advised not to take amphetamine. These agencies also state that anyone with anorexia nervosa, bipolar disorder, depression, hypertension, liver or kidney problems, mania, psychosis, Raynaud's phenomenon, seizures, thyroid problems, tics, or Tourette syndrome should monitor their symptoms while taking amphetamine. Evidence from human studies indicates that therapeutic amphetamine use does not cause developmental abnormalities in the fetus or newborns (i.e., it is not a human teratogen), but amphetamine abuse does pose risks to the fetus. Amphetamine has also been shown to pass into breast milk, so the IPCS and USFDA advise mothers to avoid breastfeeding when using it. Due to the potential for reversible growth impairments,[note 5] the USFDA advises monitoring the height and weight of children and adolescents prescribed an amphetamine pharmaceutical.
The 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. Adderall is currently approved for long-term therapeutic use by the USFDA. Recreational use of Adderall generally involves far larger doses and is therefore significantly more dangerous, involving a much greater risk of serious side effects.
At normal therapeutic doses, the physical side effects of amphetamine vary widely by age and from person to person. Cardiovascular side effects can include hypertension or hypotension from a vasovagal response, Raynaud's phenomenon (reduced blood flow to extremities), and tachycardia (increased heart rate). Sexual side effects in males may include erectile dysfunction, frequent erections, or prolonged erections. Abdominal side effects may include stomach pain, loss of appetite, nausea, and weight loss. Other potential side effects include dry mouth, excessive grinding of the teeth, acne, profuse sweating, blurred vision, reduced seizure threshold, and tics (a type of movement disorder). Dangerous physical side effects are rare at typical pharmaceutical doses.
Amphetamine stimulates the medullary respiratory centers, producing faster and deeper breaths. In a normal person at therapeutic doses, this effect is usually not noticeable, but when respiration is already compromised, it may be evident. Amphetamine also induces contraction in the urinary bladder sphincter, the muscle which controls urination, which can result in difficulty urinating. This effect can be useful in treating bed wetting and loss of bladder control. The effects of amphetamine on the gastrointestinal tract are unpredictable. If intestinal activity is high, amphetamine may reduce gastrointestinal motility (the rate at which content moves through the digestive system); however, amphetamine may increase motility when the smooth muscle of the tract is relaxed. Amphetamine also has a slight analgesic effect and can enhance the pain relieving effects of opiates.
USFDA commissioned studies from 2011 indicate that in children, young adults, and adults there is no association between serious adverse cardiovascular events (sudden death, heart attack, and stroke) and the medical use of amphetamine or other ADHD stimulants.[sources 4]
Common psychological effects of therapeutic doses can include increased alertness, apprehension, concentration, decreased sense of fatigue, mood swings (elated mood followed by mildly depressed mood), increased initiative, insomnia or wakefulness, self-confidence, and sociability. Less common side effects include anxiety, change in libido, grandiosity, irritability, repetitive or obsessive behaviors, and restlessness;[sources 5] these effects depend on the user's personality and current mental state. Amphetamine psychosis (e.g., delusions and paranoia) can occur in heavy users. Although very rare, this psychosis can also occur at therapeutic doses during long-term therapy. According to the USFDA, "there is no systematic evidence" that stimulants produce aggressive behavior or hostility.
An amphetamine overdose can lead to many different symptoms, but is rarely fatal with appropriate care. The severity of overdose symptoms increases with dosage and decreases with drug tolerance to amphetamine. Tolerant individuals have been known to take as much as 5 grams of amphetamine in a day, which is roughly 100 times the maximum daily therapeutic dose. Symptoms of a moderate and extremely large overdose are listed below; fatal amphetamine poisoning usually also involves convulsions and coma.
Pathological overactivation of the mesolimbic pathway, a dopamine pathway that connects the ventral tegmental area to the nucleus accumbens, plays a central role in amphetamine addiction. Individuals who frequently overdose on amphetamine during recreational use have a high risk of developing an amphetamine addiction, since repeated overdoses gradually increase the level of accumbal ΔFosB, a "molecular switch" and "master control protein" for addiction. Once nucleus accumbens ΔFosB is sufficiently overexpressed, it begins to increase the severity of addictive behavior (e.g., compulsive drug-seeking). While there are currently no effective drugs for treating amphetamine addiction, regularly engaging in sustained aerobic exercise appears to reduce the risk of developing such an addiction. Sustained aerobic exercise on a regular basis also appears to be an effective treatment for amphetamine addiction; exercise therapy improves clinical treatment outcomes and may be used as a combination therapy with cognitive behavioral therapy, which is currently the best clinical treatment available.
|System||Minor or moderate overdose||Severe overdose[sources 6]|
|• addiction – a state characterized by compulsive engagement in rewarding stimuli, despite adverse consequences|
|• reinforcing stimuli – stimuli that increase the probability of repeating behaviors paired with them|
|• rewarding stimuli – stimuli that the brain interprets as intrinsically positive or as something to be approached|
|• addictive drug – a drug that is both rewarding and reinforcing|
|• addictive behavior – a behavior that is both rewarding and reinforcing|
|• sensitization – an amplified response to a stimulus resulting from repeated exposure to it|
|• drug tolerance – the diminishing effect of a drug resulting from repeated administration at a given dose|
|• drug sensitization or reverse tolerance – the escalating effect of a drug resulting from repeated administration at a given dose|
|• drug dependence – an adaptive state associated with a withdrawal syndrome upon cessation of repeated drug intake|
|• physical dependence – dependence that involves persistent physical–somatic withdrawal symptoms (e.g., fatigue)|
|• psychological dependence – dependence that involves emotional–motivational withdrawal symptoms (e.g., dysphoria and anhedonia)|
|(edit | history)|
Addiction is a serious risk with heavy recreational amphetamine use but is unlikely to arise from typical medical use at therapeutic doses. Tolerance develops rapidly in amphetamine abuse (i.e., a recreational amphetamine overdose), so periods of extended use require increasingly larger doses of the drug in order to achieve the same effect.
Current models of addiction from chronic drug use involve alterations in gene expression in certain parts of the brain, particularly the nucleus accumbens. The most important transcription factors[note 6] that produce these alterations are ΔFosB, cAMP response element binding protein (CREB), and nuclear factor kappa B (NFκB). ΔFosB plays a crucial role in the development of drug addictions, since its overexpression in the nucleus accumbens is necessary and sufficient[note 7] for most of the behavioral and neural adaptations that arise from addiction. Once ΔFosB is sufficiently overexpressed, it induces an addictive state that becomes increasingly more severe with further increases in ΔFosB expression. It has been implicated in addictions to alcohol, cannabinoids, cocaine, nicotine, opiates, phencyclidine, and substituted amphetamines.
ΔJunD is the transcription factor which directly opposes ΔFosB. 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). ΔFosB also plays an important role in regulating behavioral responses to natural rewards, such as palatable food, sex, and exercise. Since both natural rewards and addictive drugs induce expression of ΔFosB (i.e., they cause the brain to produce more of it), chronic acquisition of these rewards can result in a similar pathological state of addiction. Consequently, ΔFosB is the most significant factor involved in both amphetamine addiction and amphetamine-induced sex addictions, which are compulsive sexual behaviors that result from excessive amphetamine use. These sex addictions are caused by dopamine dysregulation syndrome, an addictive disorder which has been observed in some patients taking dopaminergic drugs, like amphetamine, for an extended period.
The effects of amphetamine on gene regulation are both dose- and route-dependent. Most of the research on gene regulation and addiction is based upon animal studies with intravenous amphetamine administration at very high doses. The few studies that have used equivalent (weight-adjusted) human therapeutic doses and oral administration show that these changes, if they occur, are relatively minor. This suggests that medical use of amphetamine does not significantly affect gene regulation.
A Cochrane Collaboration review on amphetamine and methamphetamine addiction indicates that the current evidence on pharmacological treatments (i.e., drugs) is extremely limited. Fluoxetine[note 8] and imipramine[note 9] have some limited benefits but neither drug is an effective monotherapy for amphetamine addiction. A corroborating review indicated that amphetamine addiction is mediated through increased activation of dopamine receptors and co-localized NMDA receptors in the mesolimbic pathway (i.e., the nucleus accumbens). This review also noted that magnesium ions and serotonin inhibit NMDA receptors and that the magnesium ions do so by blocking the receptor's calcium channels. It also suggested that, based upon animal testing, pathological (addiction-inducing) amphetamine use significantly reduces the level of intracellular magnesium throughout the brain. Supplemental magnesium,[note 10] like fluoxetine treatment, has been shown to reduce amphetamine self-administration (doses given to oneself) in both humans and lab animals.
Cognitive behavioral therapy is currently the most effective clinical treatment for psychostimulant addiction. 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 (supplemental) treatment for amphetamine addiction. Exercise leads to better treatment outcomes when used as an adjunct treatment, particularly for psychostimulant addictions. In particular, aerobic exercise decreases psychostimulant self-administration, reduces the reinstatement (i.e., relapse) of drug-seeking, and induces increased dopamine receptor D2 (DRD2) density in the striatum. This is the opposite of pathological stimulant use, which induces decreased striatal DRD2 density.
According to another Cochrane Collaboration review on withdrawal in individuals who compulsively use amphetamine and methamphetamine, "when chronic heavy users abruptly discontinue amphetamine use, many report a time-limited withdrawal syndrome that occurs within 24 hours of their last dose." This review noted that withdrawal symptoms in chronic, high-dose users are frequent, occurring in up to 87.6% of cases, and persist for three to four weeks with a marked "crash" phase occurring during the first week. Amphetamine withdrawal symptoms can include anxiety, drug craving, depressed mood, fatigue, increased appetite, increased movement or decreased movement, lack of motivation, sleeplessness or sleepiness, and lucid dreams. The review indicated that withdrawal symptoms are associated with the degree of dependence, suggesting that therapeutic use would result in far milder discontinuation symptoms. Manufacturer prescribing information does not indicate the presence of withdrawal symptoms following discontinuation of amphetamine use after an extended period at therapeutic doses.
Toxicity and psychosis
In rodents and primates, sufficiently high doses of amphetamine cause dopaminergic neurotoxicity, or damage to dopamine neurons, which is characterized by reduced transporter and receptor function. There is no evidence that amphetamine is directly neurotoxic in humans. However, large doses of amphetamine may cause indirect neurotoxicity as a result of increased oxidative stress from reactive oxygen species and autoxidation of dopamine.
A severe amphetamine overdose can result in a stimulant psychosis that may involve a variety of symptoms, such as paranoia and delusions. A Cochrane Collaboration review on treatment for amphetamine, dextroamphetamine, and methamphetamine psychosis states that about 5–15% of users fail to recover completely. According to the same review, there is at least one trial that shows antipsychotic medications effectively resolve the symptoms of acute amphetamine psychosis. Psychosis very rarely arises from therapeutic use.
- Monoamine oxidase inhibitors (MAOIs) taken with Adderall may result in a hypertensive crisis if taken within two weeks after last use of an MAOI type drug.
- Inhibitors of enzymes that directly metabolize amphetamine (particularly FMO3 and CYP2D6) will prolong the elimination of amphetamine.
- Stimulants and antidepressants (sedatives and depressants) may increase (decrease) the drug effects of Adderall, and vice versa.
- Dietary pH affects the absorption and elimination half-life of Adderall; an alkaline diet increases the rate of absorption and decreases the rate of excretion, while acidic diets decrease absorption and increase excretion rates.
Pharmacodynamics of amphetamine enantiomers in a dopamine neuron
Mechanism of action
Amphetamine, the active ingredient of Adderall, works primarily by increasing the activity of the neurotransmitters dopamine and norepinephrine in the brain and more specifically, in the nucleus accumbens, prefrontal cortex, and locus coeruleus regions. It also triggers the release of several other neurotransmitters (e.g., serotonin, histamine, and epinephrine, among others) from neurons and also the synthesis of neuropeptides (e.g., cocaine and amphetamine regulated transcript (CART) peptides). Both active ingredients of Adderall, dextroamphetamine and levoamphetamine, bind to the same biological targets, but their binding affinities (that is, potency) differ somewhat. 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. Consequently, dextroamphetamine produces roughly two times more CNS stimulation than levoamphetamine; however, levoamphetamine has slightly greater cardiovascular and peripheral effects. Levoamphetamine provides Adderall with a quicker onset and longer-lasting effects than dextroamphetamine alone. It has been reported that certain children have a better clinical response to levoamphetamine.
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 are essentially chemical storage units inside a neuron. 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. 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 molecules altogether (via internalization) or even transport them in reverse; 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. 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).
Related endogenous compounds
Amphetamine has a very similar structure and function to the endogenous trace amines, which are naturally occurring neurotransmitter molecules produced in the human body and brain. Among this group, the most closely related compounds are phenethylamine, the parent compound of amphetamine, and N-methylphenethylamine, an isomer of amphetamine (i.e., it has an identical molecular formula). In humans, phenethylamine is produced directly from L-phenylalanine by the aromatic amino acid decarboxylase (AADC) enzyme, which converts L-DOPA into dopamine as well. In turn, N‑methylphenethylamine is metabolized from phenethylamine by phenylethanolamine N-methyltransferase, the same enzyme that metabolizes norepinephrine into epinephrine. Like amphetamine, both phenethylamine and N‑methylphenethylamine regulate monoamine neurotransmission via TAAR1; unlike amphetamine, both of these substances are broken down by monoamine oxidase B, and therefore have a shorter half-life than amphetamine.
History, society, and culture
Richwood Pharmaceuticals, which later merged with Shire plc, introduced the current Adderall brand in 1996 as an instant-release tablet. In 2006, Shire agreed to sell rights to the Adderall name for this instant-release medication to Duramed Pharmaceuticals DuraMed Pharmaceuticals was acquired by Teva Pharmaceuticals in 2008 when during their acquisition of Barr Pharmaceuticals, including Barr's Duramed division.
The first generic version of Adderall IR was introduced to market in 2002. Later on, Barr and Shire reached a settlement agreement permitting Barr to offer a generic form of the drug beginning in April 2009.
Chemically, Adderall is a mixture of several amphetamine salts; specifically, it is composed of equal parts (by mass) of amphetamine aspartate monohydrate, amphetamine sulfate, dextroamphetamine sulfate, and dextroamphetamine saccharate. This drug mixture has slightly stronger CNS effects than racemic amphetamine due to the higher proportion of dextroamphetamine. Adderall is produced as both an immediate release (IR) and extended release (XR) formulation. As of December 2013[update], ten different companies have produced generic Adderall IR at one point, while Teva Pharmaceutical Industries, Actavis, and Barr Pharmaceuticals currently manufacture generic Adderall XR. Shire plc, the company that held the original patent for Adderall and Adderall XR, still manufactures brand name Adderall XR, but not Adderall IR.
Rexar, a pharmaceutical company, reformulated another drug, branded as Obetrol, and continued to sell this new formulation under the same brand name. This new unapproved formulation was later rebranded and sold as Adderall by Richwood after it acquired Rexar resulting in FDA warning in 1994. Richwood submitted this formulation as NDA 11-522 and Adderall gained FDA approval for the treatment of attention-deficit/hyperactivity disorder therapy on 13 February 1996.
- In Canada, amphetamines are in Schedule I of the Controlled Drugs and Substances Act, and can only be obtained by prescription.
- In Japan, the use, production, and import of any medicine containing amphetamine are prohibited.
- In South Korea, amphetamines are prohibited.
- In Thailand, Amphetamines are classified as Type 1 Narcotics.
- In the United Kingdom, amphetamines are regarded as Class B drugs. The maximum penalty for unauthorized possession is five years in prison and an unlimited fine. The maximum penalty for illegal supply is 14 years in prison and an unlimited fine.
- In the United States, amphetamine is a Schedule II prescription drug, classified as a CNS stimulant.
- Internationally (United Nations), amphetamine is in Schedule II of the Convention on Psychotropic Substances.
- The US nonproprietary name of Adderall is dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine sulfate and amphetamine aspartate. It is sometimes referred to as amphetamine mixed salts and other variants thereof.
- Enantiomers are molecules that are "mirror images" of one another; they are structurally identical but of the opposite orientation, like left and right hands. The compound "amphetamine" (racemic amphetamine) refers to equal parts of the enantiomers, i.e. 50% levoamphetamine and 50% dextroamphetamine.
- Cochrane Collaboration reviews are high quality meta-analytic systematic reviews of randomized controlled trials.
- The statements supported by the USFDA come from prescribing information, which is the copyrighted intellectual property of the manufacturer and approved by the USFDA.
- In individuals who experience sub-normal height and weight gains, a rebound to normal levels is expected to occur if stimulant therapy is briefly interrupted. The average reduction in final adult height from continuous stimulant therapy over a 3 year period is 2 cm.
- Transcription factors are proteins that increase or decrease the expression of specific genes.
- In simpler terms, this necessary and sufficient relationship means that ΔFosB overexpression in the nucleus accumbens and addiction-related behavioral and neural adaptations always occur together and never occur alone.
- During short-term treatment, fluoxetine may decrease drug craving.
- During "medium-term treatment," imipramine may extend the duration of adherence to addiction treatment.
- The review indicated that magnesium L-aspartate and magnesium chloride produce significant changes in addictive behavior; other forms of magnesium were not mentioned.
- Heal DJ, Smith SL, Gosden J, Nutt DJ (June 2013). "Amphetamine, past and present – a pharmacological and clinical perspective". J. Psychopharmacol. 27 (6): 479–496. doi:10.1177/0269881113482532. PMC 3666194. PMID 23539642.
Mixed enantiomers/mixed salts amphetamine (3:1 d:l isomers)
- "National Drug Code Amphetamine Search Results". National Drug Code Directory. United States Food and Drug Administration. Archived from the original on 7 February 2014. Retrieved 16 December 2013.
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- Wilens TE, Adler LA, Adams J, Sgambati S, Rotrosen J, Sawtelle R, Utzinger L, Fusillo S (January 2008). "Misuse and diversion of stimulants prescribed for ADHD: a systematic review of the literature". J. Am. Acad. Child Adolesc. Psychiatry 47 (1): 21–31. doi:10.1097/chi.0b013e31815a56f1. PMID 18174822.
Stimulant misuse appears to occur both for performance enhancement and their euphorogenic effects, the latter being related to the intrinsic properties of the stimulants (e.g., IR versus ER profile) ...
Although useful in the treatment of ADHD, stimulants are controlled II substances with a history of preclinical and human studies showing potential abuse liability.
- Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York, USA: McGraw-Hill Medical. pp. 154–157. ISBN 9780071481274.
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- Eiden LE, Weihe E (January 2011). "VMAT2: a dynamic regulator of brain monoaminergic neuronal function interacting with drugs of abuse". Ann. N. Y. Acad. Sci. 1216: 86–98. doi:10.1111/j.1749-6632.2010.05906.x. PMID 21272013.
VMAT2 is the CNS vesicular transporter for not only the biogenic amines DA, NE, EPI, 5-HT, and HIS, but likely also for the trace amines TYR, PEA, and thyronamine (THYR) ... [Trace aminergic] neurons in mammalian CNS would be identiﬁable as neurons expressing VMAT2 for storage, and the biosynthetic enzyme aromatic amino acid decarboxylase (AADC).
- Broadley KJ (March 2010). "The vascular effects of trace amines and amphetamines". Pharmacol. Ther. 125 (3): 363–375. doi:10.1016/j.pharmthera.2009.11.005. PMID 19948186.
Fig. 2. Synthetic and metabolic pathways for endogenous and exogenously administered trace amines and sympathomimetic amines ...
Trace amines are metabolized in the mammalian body via monoamine oxidase (MAO; EC 188.8.131.52) (Berry, 2004) (Fig. 2) ... It deaminates primary and secondary amines that are free in the neuronal cytoplasm but not those bound in storage vesicles of the sympathetic neurone ...
Thus, MAO inhibitors potentiate the peripheral effects of indirectly acting sympathomimetic amines ... this potentiation occurs irrespective of whether the amine is a substrate for MAO. An α-methyl group on the side chain, as in amphetamine and ephedrine, renders the amine immune to deamination so that they are not metabolized in the gut. Similarly, β-PEA would not be deaminated in the gut as it is a selective substrate for MAO-B which is not found in the gut ...
Brain levels of endogenous trace amines are several hundred-fold below those for the classical neurotransmitters noradrenaline, dopamine and serotonin but their rates of synthesis are equivalent to those of noradrenaline and dopamine and they have a very rapid turnover rate (Berry, 2004). Endogenous extracellular tissue levels of trace amines measured in the brain are in the low nanomolar range. These low concentrations arise because of their very short half-life ...
- "Adderall XR Prescribing Information". United States Food and Drug Administration. December 2013. p. 11. Retrieved 30 December 2013.
- "Adderall XR Prescribing Information". United States Food and Drug Administration. December 2013. pp. 4–8. Retrieved 30 December 2013.
- Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 13: Higher Cognitive Function and Behavioral Control". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York, USA: McGraw-Hill Medical. p. 318. ISBN 9780071481274.
Therapeutic (relatively low) doses of psychostimulants, such as methylphenidate and amphetamine, improve performance on working memory tasks both in normal subjects and those with ADHD. Positron emission tomography (PET) demonstrates that methylphenidate decreases regional cerebral blood flow in the doroslateral prefrontal cortex and posterior parietal cortex while improving performance of a spacial working memory task. This suggests that cortical networks that normally process spatial working memory become more efficient in response to the drug. ... [It] is now believed that dopamine and norepinephrine, but not serotonin, produce the beneficial effects of stimulants on working memory. At abused (relatively high) doses, stimulants can interfere with working memory and cognitive control ... stimulants act not only on working memory function, but also on general levels of arousal and, within the nucleus accumbens, improve the saliency of tasks. Thus, stimulants improve performance on effortful but tedious tasks ... through indirect stimulation of dopamine and norepinephrine receptors.
- Shoptaw SJ, Kao U, Ling W (2009). Shoptaw SJ, Ali R, ed. "Treatment for amphetamine psychosis". Cochrane Database Syst. Rev. (1): CD003026. doi:10.1002/14651858.CD003026.pub3. PMID 19160215.
A minority of individuals who use amphetamines develop full-blown psychosis requiring care at emergency departments or psychiatric hospitals. In such cases, symptoms of amphetamine psychosis commonly include paranoid and persecutory delusions as well as auditory and visual hallucinations in the presence of extreme agitation. More common (about 18%) is for frequent amphetamine users to report psychotic symptoms that are sub-clinical and that do not require high-intensity intervention ...
About 5–15% of the users who develop an amphetamine psychosis fail to recover completely (Hofmann 1983) ...
Findings from one trial indicate use of antipsychotic medications effectively resolves symptoms of acute amphetamine psychosis.
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Basal ganglia regions like the right globus pallidus, the right putamen, and the nucleus caudatus are structurally affected in children with ADHD. These changes and alterations in limbic regions like ACC and amygdala are more pronounced in non-treated populations and seem to diminish over time from child to adulthood. Treatment seems to have positive effects on brain structure.
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Dopamine acts in the nucleus accumbens to attach motivational significance to stimuli associated with reward.
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Amphetamines and caffeine are stimulants that increase alertness, improve focus, decrease reaction time, and delay fatigue, allowing for an increased intensity and duration of training ...
Physiologic and performance effects
• Amphetamines increase dopamine/norepinephrine release and inhibit their reuptake, leading to central nervous system (CNS) stimulation
• Amphetamines seem to enhance athletic performance in anaerobic conditions 39 40
• Improved reaction time
• Increased muscle strength and delayed muscle fatigue
• Increased acceleration
• Increased alertness and attention to task
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The neurotransmitter dopamine is released from projections originating in the midbrain. Manipulations of dopaminergic signaling profoundly influence interval timing, leading to the hypothesis that dopamine influences internal pacemaker, or “clock,” activity (Maricq and Church, 1983; Buhusi and Meck, 2005, 2009; Lake and Meck, 2013). For instance, amphetamine, which increases concentrations of dopamine at the synaptic cleft (Maricq and Church, 1983; Zetterström et al., 1983) advances the start of responding during interval timing (Taylor et al., 2007), whereas antagonists of D2 type dopamine receptors typically slow timing (Drew et al., 2003; Lake and Meck, 2013). ... Depletion of dopamine in healthy volunteers impairs timing (Coull et al., 2012), while amphetamine releases synaptic dopamine and speeds up timing (Taylor et al., 2007).
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Amphetamine, dextroamphetamine, and methylphenidate act as substrates for the cellular monoamine transporter, especially the dopamine transporter (DAT) and less so the norepinephrine (NET) and serotonin transporter. The mechanism of toxicity is primarily related to excessive extracellular dopamine, norepinephrine, and serotonin.
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ΔFosB as a therapeutic biomarker
The strong correlation between chronic drug exposure and ΔFosB provides novel opportunities for targeted therapies in addiction (118), and suggests methods to analyze their efficacy (119). Over the past two decades, research has progressed from identifying ΔFosB induction to investigating its subsequent action (38). It is likely that ΔFosB research will now progress into a new era – the use of ΔFosB as a biomarker. If ΔFosB detection is indicative of chronic drug exposure (and is at least partly responsible for dependence of the substance), then its monitoring for therapeutic efficacy in interventional studies is a suitable biomarker (Figure 2). Examples of therapeutic avenues are discussed herein. ...
ΔFosB is an essential transcription factor implicated in the molecular and behavioral pathways of addiction following repeated drug exposure. The formation of ΔFosB in multiple brain regions, and the molecular pathway leading to the formation of AP-1 complexes is well understood. The establishment of a functional purpose for ΔFosB has allowed further determination as to some of the key aspects of its molecular cascades, involving effectors such as GluR2 (87,88), Cdk5 (93) and NFkB (100). Moreover, many of these molecular changes identified are now directly linked to the structural, physiological and behavioral changes observed following chronic drug exposure (60,95,97,102). New frontiers of research investigating the molecular roles of ΔFosB have been opened by epigenetic studies, and recent advances have illustrated the role of ΔFosB acting on DNA and histones, truly as a ‘‘molecular switch’’ (34). As a consequence of our improved understanding of ΔFosB in addiction, it is possible to evaluate the addictive potential of current medications (119), as well as use it as a biomarker for assessing the efficacy of therapeutic interventions (121,122,124). Some of these proposed interventions have limitations (125) or are in their infancy (75). However, it is hoped that some of these preliminary findings may lead to innovative treatments, which are much needed in addiction.
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DESPITE THE IMPORTANCE OF NUMEROUS PSYCHOSOCIAL FACTORS, AT ITS CORE, DRUG ADDICTION INVOLVES A BIOLOGICAL PROCESS: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. ... A large body of literature has demonstrated that such ΔFosB induction in D1-type NAc neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement
- Robison AJ, Nestler EJ (November 2011). "Transcriptional and epigenetic mechanisms of addiction". Nat. Rev. Neurosci. 12 (11): 623–637. doi:10.1038/nrn3111. PMC 3272277. PMID 21989194.
ΔFosB serves as one of the master control proteins governing this structural plasticity.
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Similar to environmental enrichment, studies have found that exercise reduces self-administration and relapse to drugs of abuse (Cosgrove et al., 2002; Zlebnik et al., 2010). There is also some evidence that these preclinical findings translate to human populations, as exercise reduces withdrawal symptoms and relapse in abstinent smokers (Daniel et al., 2006; Prochaska et al., 2008), and one drug recovery program has seen success in participants that train for and compete in a marathon as part of the program (Butler, 2005). ... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some patients taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al., 2006; Aiken, 2007; Lader, 2008).
- Lynch WJ, Peterson AB, Sanchez V, Abel J, Smith MA (September 2013). "Exercise as a novel treatment for drug addiction: a neurobiological and stage-dependent hypothesis". Neurosci Biobehav Rev 37 (8): 1622–44. doi:10.1016/j.neubiorev.2013.06.011. PMC 3788047. PMID 23806439.
these data show that exercise can affect dopaminergic signaling at many different levels, which may underlie its ability to modify vulnerability during drug use initiation. Exercise also produces neuroadaptations that may influence an individual's vulnerability to initiate drug use. Consistent with this idea, chronic moderate levels of forced treadmill running blocks not only subsequent methamphetamine-induced conditioned place preference, but also stimulant-induced increases in dopamine release in the NAc (Chen et al., 2008) and striatum (Marques et al., 2008). ... [These] findings indicate the efficacy of exercise at reducing drug intake in drug-dependent individuals ... wheel running [reduces] methamphetamine self-administration under extended access conditions (Engelmann et al., 2013) ... These findings suggest that exercise may "magnitude"-dependently prevent the development of an addicted phenotype possibly by blocking/reversing behavioral and neuro-adaptive changes that develop during and following extended access to the drug. ... Exercise has been proposed as a treatment for drug addiction that may reduce drug craving and risk of relapse. Although few clinical studies have investigated the efficacy of exercise for preventing relapse, the few studies that have been conducted generally report a reduction in drug craving and better treatment outcomes (see Table 4). ... Taken together, these data suggest that the potential benefits of exercise during relapse, particularly for relapse to psychostimulants, may be mediated via chromatin remodeling and possibly lead to greater treatment outcomes.
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Currently, cognitive–behavioral therapies are the most successful treatment available for preventing the relapse of psychostimulant use.
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ΔFosB has been linked directly to several addiction-related behaviors ... Importantly, genetic or viral overexpression of ΔJunD, a dominant negative mutant of JunD which antagonizes ΔFosB- and other AP-1-mediated transcriptional activity, in the NAc or OFC blocks these key effects of drug exposure14,22–24. This indicates that ΔFosB is both necessary and sufficient for many of the changes wrought in the brain by chronic drug exposure. ΔFosB is also induced in D1-type NAc MSNs by chronic consumption of several natural rewards, including sucrose, high fat food, sex, wheel running, where it promotes that consumption14,26–30. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states.
- Steiner H, Van Waes V (January 2013). "Addiction-related gene regulation: risks of exposure to cognitive enhancers vs. other psychostimulants". Prog. Neurobiol. 100: 60–80. doi:10.1016/j.pneurobio.2012.10.001. PMC 3525776. PMID 23085425.
- Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 4: Signal Transduction in the Brain". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York, USA: McGraw-Hill Medical. p. 94. ISBN 9780071481274.
All living cells depend on the regulation of gene expression by extracellular signals for their development, homeostasis, and adaptation to the environment. Indeed, many signal transduction pathways function primarily to modify transcription factors that alter the expression of specific genes. Thus, neurotransmitters, growth factors, and drugs change patterns of gene expression in cells and in turn affect many aspects of nervous system functioning, including the formation of long-term memories. Many drugs that require prolonged administration, such as antidepressants and antipsychotics, trigger changes in gene expression that are thought to be therapeutic adaptations to the initial action of the drug.
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It has been found that deltaFosB gene in the NAc is critical for reinforcing effects of sexual reward. Pitchers and colleagues (2010) reported that sexual experience was shown to cause DeltaFosB accumulation in several limbic brain regions including the NAc, medial pre-frontal cortex, VTA, caudate, and putamen, but not the medial preoptic nucleus. ... these findings support a critical role for DeltaFosB expression in the NAc in the reinforcing effects of sexual behavior and sexual experience-induced facilitation of sexual performance. ... both drug addiction and sexual addiction represent pathological forms of neuroplasticity along with the emergence of aberrant behaviors involving a cascade of neurochemical changes mainly in the brain's rewarding circuitry.
- Pitchers KK, Vialou V, Nestler EJ, Laviolette SR, Lehman MN, Coolen LM (February 2013). "Natural and drug rewards act on common neural plasticity mechanisms with ΔFosB as a key mediator". J. Neurosci. 33 (8): 3434–3442. doi:10.1523/JNEUROSCI.4881-12.2013. PMC 3865508. PMID 23426671.
Drugs of abuse induce neuroplasticity in the natural reward pathway, specifically the nucleus accumbens (NAc), thereby causing development and expression of addictive behavior. ... Together, these findings demonstrate that drugs of abuse and natural reward behaviors act on common molecular and cellular mechanisms of plasticity that control vulnerability to drug addiction, and that this increased vulnerability is mediated by ΔFosB and its downstream transcriptional targets. ... Sexual behavior is highly rewarding (Tenk et al., 2009), and sexual experience causes sensitized drug-related behaviors, including cross-sensitization to amphetamine (Amph)-induced locomotor activity (Bradley and Meisel, 2001; Pitchers et al., 2010a) and enhanced Amph reward (Pitchers et al., 2010a). Moreover, sexual experience induces neural plasticity in the NAc similar to that induced by psychostimulant exposure, including increased dendritic spine density (Meisel and Mullins, 2006; Pitchers et al., 2010a), altered glutamate receptor trafficking, and decreased synaptic strength in prefrontal cortex-responding NAc shell neurons (Pitchers et al., 2012). Finally, periods of abstinence from sexual experience were found to be critical for enhanced Amph reward, NAc spinogenesis (Pitchers et al., 2010a), and glutamate receptor trafficking (Pitchers et al., 2012). These findings suggest that natural and drug reward experiences share common mechanisms of neural plasticity
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Although there are a variety of amphetamines and amphetamine derivatives, the word "amphetamines" in this review stands for amphetamine, dextroamphetamine and methamphetamine only.
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The prevalence of this withdrawal syndrome is extremely common (Cantwell 1998; Gossop 1982) with 87.6% of 647 individuals with amphetamine dependence reporting six or more signs of amphetamine withdrawal listed in the DSM when the drug is not available (Schuckit 1999) ... The severity of withdrawal symptoms is greater in amphetamine dependent individuals who are older and who have more extensive amphetamine use disorders (McGregor 2005). Withdrawal symptoms typically present within 24 hours of the last use of amphetamine, with a withdrawal syndrome involving two general phases that can last 3 weeks or more. The first phase of this syndrome is the initial "crash" that resolves within about a week (Gossop 1982;McGregor 2005) ...
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In addition to the main metabolic pathway, TAs can also be converted by nonspecific N-methyltransferase (NMT)  and phenylethanolamine N-methyltransferase (PNMT)  to the corresponding secondary amines (e.g. synephrine , N-methylphenylethylamine and N-methyltyramine ), which display similar activities on TAAR1 (TA1) as their primary amine precursors.
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WOODCLIFF LAKE, N.J., Aug. 14 /PRNewswire-FirstCall/ – Barr Pharmaceuticals, Inc. today announced that its subsidiary Duramed Pharmaceuticals, Inc. and Shire plc have signed a Product Acquisition Agreement for ADDERALL(R) (immediate-release mixed amphetamine salts) tablets and a Product Development Agreement for six proprietary products, and that its subsidiary Barr Laboratories, Inc. (Barr) has signed a Settlement and License Agreement relating to the resolution of two pending patent cases involving Shire's ADDERALL XR(R) ...
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