In the United States lisdexamfetamine is a Schedule II controlled substance (DEA number 1205)  and the aggregate production quota for 2014 is 23,750 kilograms of anhydrous acid or base.
In the United Kingdom, Denmark, Sweden, Germany, Finland, Spain and Norway lisdexamfetamine is available and licensed under the brand name Elvanse (Tyvense in Ireland) and is available in 30 mg, 50 mg and 70 mg capsules. It was recently scheduled as a Schedule 2/Class B substance in the United Kingdom, allowing for its medical use but placing strict criminal penalties for its unauthorised production, supply, possession etc.
Lisdexamfetamine is currently in Phase II trials in Japan for ADHD, as well as under investigation for the treatment of binge eating disorder.
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 and continued improvements in attention, 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 1] on the treatment of adult ADHD with amphetamines stated that while amphetamines 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 indicated that stimulants in general do not make tics worse, but high doses of dextroamphetamine in such people should be avoided. 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.
Individuals over the age of 65 were not commonly tested in clinical trials of lisdexamfetamine. Therefore, there is insufficient data to determine how older individuals respond. People over the age of 65 should start on the low end of dosing schedules due to the prevalence of decreased hepatic function, decreased renal function, and comorbidities in this population.
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, performance-enhancing use, rather than abuse as a recreational drug, is the primary reason that students use stimulants. 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. Like the psychostimulants methylphenidate and bupropion, amphetamine increases stamina and endurance in humans 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.
Lisdexamfetamine dimesylate is a white to off-white powder that is soluble in water (792 mg/mL). Vyvanse capsules contain 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, and 70 mg of lisdexamfetamine dimesylate and the following inactive ingredients: microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. The capsule shells contain gelatin, titanium dioxide, and one or more of the following: FD&C Red #3, FD&C Yellow #6, FD&C Blue #1, Black Iron Oxide, and Yellow Iron Oxide.
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 1]
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, 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. The most important transcription factors that produce these alterations are ΔFosB, cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), and nuclear factor kappa B (NFκB). ΔFosB is the most significant factor in drug addiction, since its overexpression in the nucleus accumbens is necessary and sufficient for many of the associated neural adaptations that occur; it has been implicated in addictions to alcohol, cannabinoids, cocaine, nicotine, opiates, phenylcyclidine, and substituted amphetamines.ΔJunD is the transcription factor which directly opposes ΔFosB. An increase in the expression of ΔJunD in the nucleus accumbens can reduce the neural alternations seen in chronic drug abuse (i.e., the alterations mediated by ΔFosB), and a large enough increase can even block most of these alternations. ΔFosB also plays an important role in regulating behavioral responses to natural rewards, such as palatable food, sex, and exercise. Since natural rewards induce expression ΔFosB just like drugs of abuse do, chronic acquisition of these rewards can result in a similar pathological state of addiction. Consequently, ΔFosB is the key transcription factor involved in amphetamine addiction and amphetamine-induced sex addictions.
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.
Abuse of amphetamine can result in a stimulant psychosis that may present with a variety of symptoms (e.g., paranoia, hallucinations, delusions). A Cochrane Collaboration review on treatment for amphetamine, dextroamphetamine, and methamphetamine abuse-induced 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.
In rodents and primates, sufficiently high doses of amphetamine cause dopaminergic neurotoxicity, or damage to dopamine neurons, which is characterized as reduced transporter and receptor function. There is no evidence that amphetamine is directly neurotoxic in humans. High-dose amphetamine can cause indirect neurotoxicity as a result of increased oxidative stress from reactive oxygen species and autoxidation of dopamine.
According to another Cochrane Collaboration review on withdrawal in highly addicted amphetamine and methamphetamine abusers, "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 suggested 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.
Acidifying Agents: Drugs that acidify the urine, such as ascorbic acid, increase urinary excretion of amphetamines thus decreasing the half-life time of lisdexamfetamine in the body.
Alkalinizing Agents: Drugs that alkalinize the urine, such as sodium bicarbonate, decrease urinary excretion of amphetamines thus increasing the half-life time of lisdexamfetamine in the body.
Amphetamine enters the presynaptic neuron across the neuronal membrane or through DAT. Once inside, it binds to TAAR1 or enters synaptic vesicles through VMAT2. When amphetamine enters the synaptic vesicles through VMAT2, dopamine is released into the cytosol (yellow-orange area). When amphetamine binds to TAAR1, it reduces dopamine receptor firing rate via potassium channels and triggers protein kinase A (PKA) and protein kinase C (PKC) signaling, resulting in DAT phosphorylation. PKA-phosphorylation causes DAT to withdraw into the presynaptic neuron (internalize) and cease transport. PKC-phosphorylated DAT may either operate in reverse or, like PKA-phosphorylated DAT, internalize and cease transport.
Lisdexamfetamine is an inactive prodrug that is converted in the body to dextroamphetamine, a pharmacologically active compound which is responsible for the drug’s activity. After oral ingestion, lisdexamfetamine is broken down by enzymes in red blood cells to form L-lysine, a naturally occurring essential amino acid, and dextroamphetamine. The conversion of lisdexamfetamine to dextroamphetamine is not affected by gastrointestinal pH and is unlikely to be affected by alterations in normal gastrointestinal transit times.
Lisdexamfetamine was developed with the goal of providing a long duration of effect that is consistent throughout the day, with reduced potential for abuse. The attachment of the amino acid lysine slows down the relative amount of dextroamphetamine available to the blood stream. Because no free dextroamphetamine is present in lisdexamfetamine capsules, dextroamphetamine does not become available through mechanical manipulation, such as crushing or simple extraction. A relatively sophisticated biochemical process is needed to produce dextroamphetamine from lisdexamfetamine. As opposed to Adderall, which contains roughly equal parts of racemic amphetamine and dextroamphetamic salts, lisdexamfetamine is a single-enantiomer dextroamphetamine formula. Studies conducted show that lisdexamfetamine dimesylate may have less abuse potential than dextroamphetamine and an abuse profile similar to diethylpropion at dosages that are FDA-approved for treatment of ADHD, but still has a high abuse potential when this dosage is exceeded by over 100%.
Lisdexamfetamine was developed by New River Pharmaceuticals, who were bought by Shire Pharmaceuticals shortly before lisdexamfetamine began being marketed. It was developed for the intention of creating a longer-lasting and less-easily abused version of dextroamphetamine, as the requirement of conversion into dextroamphetamine via enzymes in the red blood cells increases its duration of action, regardless of the route of ingestion. The drug lisdexamfetamine dimesylate is the first prodrug of its kind.
On April 23, 2008, Vyvanse received FDA approval for the adult population. In a randomized, double-blind, four-week phase III trial in adult patients with ADHD, dosages of 30, 50 or 70 mg/day of oral lisdexamfetamine caused a significantly greater improvement in ADHD-Rating Scale total score than placebo. On February 19, 2009, Health Canada approved 30 mg and 50 mg capsules of lisdexamfetamine for treatment of ADHD. On February 8, 2012, Vyvanse received FDA approval for maintenance treatment of adult ADHD. In February 2014, Shire announced that two late-stage clinical trials had shown that Vyvanse was not an effective treatment for depression.
Lisdexamfetamine is sold as Tyvense (IE), Elvanse (UK), Venvanse (BR), Vyvanse (CA, US).
^Cochrane Collaboration reviews are high quality meta-analytic systematic reviews of randomized controlled trials.
^During short-term treatment, fluoxetine may decrease drug craving.
^During "medium-term treatment," imipramine may extend the duration of adherence to addiction treatment.
^ abHart H, Radua J, Nakao T, Mataix-Cols D, Rubia K (February 2013). "Meta-analysis of functional magnetic resonance imaging studies of inhibition and attention in attention-deficit/hyperactivity disorder: exploring task-specific, stimulant medication, and age effects". JAMA Psychiatry70 (2): 185–198. doi:10.1001/jamapsychiatry.2013.277. PMID23247506.
^ abFrodl T, Skokauskas N (February 2012). "Meta-analysis of structural MRI studies in children and adults with attention deficit hyperactivity disorder indicates treatment effects.". Acta psychiatrica Scand.125 (2): 114–126. doi:10.1111/j.1600-0447.2011.01786.x. PMID22118249. "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."
^ abMillichap JG (2010). "Chapter 3: Medications for ADHD". In Millichap JG. Attention Deficit Hyperactivity Disorder Handbook: A Physician's Guide to ADHD (2nd ed.). New York: Springer. pp. 111–113. ISBN9781441913968.
^ abMillichap JG (2010). "Chapter 3: Medications for ADHD". In Millichap JG. Attention Deficit Hyperactivity Disorder Handbook: A Physician's Guide to ADHD (2nd ed.). New York: Springer. pp. 121–123, 125–127. ISBN9781441913968.
^ abcMalenka 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: McGraw-Hill Medical. pp. 154–157. ISBN9780071481274.
^ abcdeMalenka 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: McGraw-Hill Medical. p. 318. ISBN9780071481274. "Therapeutic (relatively low) doses of psychostimulants, such as methylphenidate and amphetamine, improve performance on working memory tasks both in 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."
^Greenhill LL, Pliszka S, Dulcan MK, Bernet W, Arnold V, Beitchman J, Benson RS, Bukstein O, Kinlan J, McClellan J, Rue D, Shaw JA, Stock S (February 2002). "Practice parameter for the use of stimulant medications in the treatment of children, adolescents, and adults". J. Am. Acad. Child Adolesc. Psychiatry41 (2 Suppl): 26S–49S. doi:10.1097/00004583-200202001-00003. PMID11833633.
^Castells X, Ramos-Quiroga JA, Bosch R, Nogueira M, Casas M (2011). "Amphetamines for Attention Deficit Hyperactivity Disorder (ADHD) in adults". In Castells X. Cochrane Database Syst. Rev. (6): CD007813. doi:10.1002/14651858.CD007813.pub2. PMID21678370.
^Pringsheim T, Steeves T (April 2011). "Pharmacological treatment for Attention Deficit Hyperactivity Disorder (ADHD) in children with comorbid tic disorders". In Pringsheim T. Cochrane Database Syst. Rev. (4): CD007990. doi:10.1002/14651858.CD007990.pub2. PMID21491404.
^Harbeck-Seu A, Brunk I, Platz T, Vajkoczy P, Endres M, Spies C (April 2011). "A speedy recovery: amphetamines and other therapeutics that might impact the recovery from brain injury". Curr. Opin. Anaesthesiol.24 (2): 144–153. doi:10.1097/ACO.0b013e328344587f. PMID21386667.
^Devous MD, Trivedi MH, Rush AJ (April 2001). "Regional cerebral blood flow response to oral amphetamine challenge in healthy volunteers". J. Nucl. Med.42 (4): 535–42. PMID11337538.
^ abcWood S, Sage JR, Shuman T, Anagnostaras SG (January 2014). "Psychostimulants and cognition: a continuum of behavioral and cognitive activation". Pharmacol. Rev.66 (1): 193–221. doi:10.1124/pr.112.007054. PMID24344115.
^Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 10: Neural and Neuroendocrine Control of the Internal Milieu". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. p. 266. ISBN9780071481274. "Dopamine acts in the nucleus accumbens to attach motivational significance to stimuli associated with reward."
^ abcLiddle DG, Connor DJ (June 2013). "Nutritional supplements and ergogenic AIDS". Prim. Care40 (2): 487–505. doi:10.1016/j.pop.2013.02.009. PMID23668655. "Amphetamines and caffeine are stimulants that increase alertness, improve focus, decrease reaction time, and delay fatigue, allowing for an increased intensity and duration of training ... Physiologic and performance effects • Amphetamines increase dopamine/norepinephrine release and inhibit their reuptake, leading to central nervous system (CNS) stimulation • Amphetamines seem to enhance athletic performance in anaerobic conditions 39 40 • Improved reaction time • Increased muscle strength and delayed muscle fatigue • Increased acceleration • Increased alertness and attention to task"
^ abcRoelands B, de Koning J, Foster C, Hettinga F, Meeusen R (May 2013). "Neurophysiological determinants of theoretical concepts and mechanisms involved in pacing". Sports Med.43 (5): 301–311. doi:10.1007/s40279-013-0030-4. PMID23456493.
^Cooper WO, Habel LA, Sox CM, Chan KA, Arbogast PG, Cheetham TC, Murray KT, Quinn VP, Stein CM, Callahan ST, Fireman BH, Fish FA, Kirshner HS, O'Duffy A, Connell FA, Ray WA (November 2011). "ADHD drugs and serious cardiovascular events in children and young adults". N. Engl. J. Med.365 (20): 1896–1904. doi:10.1056/NEJMoa1110212. PMID22043968.
^O'Connor PG (February 2012). "Amphetamines". Merck Manual for Health Care Professionals. Merck. Retrieved 8 May 2012.
^ abcdShoptaw SJ, Kao U, Ling W (2009). "Treatment for amphetamine psychosis". In Shoptaw SJ, Ali R. Cochrane Database Syst. Rev. (1): CD003026. doi:10.1002/14651858.CD003026.pub3. PMID19160215. "A minority of individuals who use amphetamines develop full-blown psychosis requiring care at emergency departments or psychiatric hospitals. In such cases, symptoms of amphetamine psychosis commonly include paranoid and persecutory delusions as well as auditory and visual hallucinations in the presence of extreme agitation. More common (about 18%) is for frequent amphetamine users to report psychotic symptoms that are sub-clinical and that do not require high-intensity intervention ... About 5–15% of the users who develop an amphetamine psychosis fail to recover completely (Hofmann 1983) ... Findings from one trial indicate use of antipsychotic medications effectively resolves symptoms of acute amphetamine psychosis."
^ abSpiller HA, Hays HL, Aleguas A (June 2013). "Overdose of drugs for attention-deficit hyperactivity disorder: clinical presentation, mechanisms of toxicity, and management". CNS Drugs27 (7): 531–543. doi:10.1007/s40263-013-0084-8. PMID23757186. "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."
^Pérez-Mañá C, Castells X, Torrens M, Capellà D, Farre M (2013). "Efficacy of psychostimulant drugs for amphetamine abuse or dependence". In Pérez-Mañá C. Cochrane Database Syst. Rev.9: CD009695. doi:10.1002/14651858.CD009695.pub2. PMID23996457.
^ abcdeSrisurapanont M, Jarusuraisin N, Kittirattanapaiboon P (2001). "Treatment for amphetamine dependence and abuse". In Srisurapanont M. Cochrane Database Syst. Rev. (4): CD003022. doi:10.1002/14651858.CD003022. PMID11687171. "Although there are a variety of amphetamines and amphetamine derivatives, the word "amphetamines" in this review stands for amphetamine, dextroamphetamine and methamphetamine only."
^ abcdeNechifor M (March 2008). "Magnesium in drug dependences". Magnes. Res.21 (1): 5–15. PMID18557129.
^Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and Addictive Disorders". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. p. 386. ISBN9780071481274. "Currently, cognitive–behavioral therapies are the most successful treatment available for preventing the relapse of psychostimulant use."
^ abcdefOlsen CM (December 2011). "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology61 (7): 1109–1122. doi:10.1016/j.neuropharm.2011.03.010. PMC3139704. PMID21459101. "Similar to environmental enrichment, studies have found that exercise reduces self-administration and relapse to drugs of abuse (Cosgrove et al., 2002; Zlebnik et al., 2010). There is also some evidence that these preclinical findings translate to human populations, as exercise reduces withdrawal symptoms and relapse in abstinent smokers (Daniel et al, 2006; Prochaska et al, 2008), and one drug recovery program has seen success in participants that train for and compete in a marathon as part of the program (Butler, 2005)."
^ abcdefghRobison AJ, Nestler EJ (November 2011). "Transcriptional and epigenetic mechanisms of addiction". Nat. Rev. Neurosci.12 (11): 623–637. doi:10.1038/nrn3111. PMC3272277. PMID21989194. "ΔFosB has been linked directly to several addiction-related behaviors ... Importantly, genetic or viral overexpression of ΔJunD, a dominant negative mutant of JunD which antagonizes ΔFosB- and other AP-1-mediated transcriptional activity, in the NAc or OFC blocks these key effects of drug exposure14,22–24. This indicates that ΔFosB is both necessary and sufficient for many of the changes wrought in the brain by chronic drug exposure. ΔFosB is also induced in D1-type NAc MSNs by chronic consumption of several natural rewards, including sucrose, high fat food, sex, wheel running, where it promotes that consumption14,26–30. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states."
^ abBlum K, Werner T, Carnes S, Carnes P, Bowirrat A, Giordano J, Oscar-Berman M, Gold M (2012). "Sex, drugs, and rock 'n' roll: hypothesizing common mesolimbic activation as a function of reward gene polymorphisms". J. Psychoactive Drugs44 (1): 38–55. doi:10.1080/02791072.2012.662112. PMC4040958. PMID22641964. "It has been found that deltaFosB gene in the NAc is critical for reinforcing effects of sexual reward. Pitchers and colleagues (2010) reported that sexual experience was shown to cause DeltaFosB accumulation in several limbic brain regions including the NAc, medial pre-frontal cortex, VTA, caudate, and putamen, but not the medial preoptic nucleus. ...these findings support a critical role for DeltaFosB expression in the NAc in the reinforcing effects of sexual behavior and sexual experience-induced facilitation of sexual performance. ... both drug addiction and sexual addiction represent pathological forms of neuroplasticity along with the emergence of aberrant behaviors involving a cascade of neurochemical changes mainly in the brain's rewarding circuitry."
^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. PMC3865508. PMID23426671. "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"
^Hofmann FG (1983). A Handbook on Drug and Alcohol Abuse: The Biomedical Aspects (2nd ed.). New York: Oxford University Press. p. 329. ISBN9780195030570.
^"Amphetamine". Hazardous Substances Data Bank. National Library of Medicine. Retrieved 26 February 2014. "Direct toxic damage to vessels seems unlikely because of the dilution that occurs before the drug reaches the cerebral circulation."
^Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and addictive disorders". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. p. 370. ISBN9780071481274. "Unlike cocaine and amphetamine, methamphetamine is directly toxic to midbrain dopamine neurons."
^Miyazaki I, Asanuma M (June 2008). "Dopaminergic neuron-specific oxidative stress caused by dopamine itself". Acta Med. Okayama62 (3): 141–150. PMID18596830.
^ abcdShoptaw SJ, Kao U, Heinzerling K, Ling W (2009). "Treatment for amphetamine withdrawal". In Shoptaw SJ. Cochrane Database Syst. Rev. (2): CD003021. doi:10.1002/14651858.CD003021.pub2. PMID19370579. " The prevalence of this withdrawal syndrome is extremely common (Cantwell 1998; Gossop 1982) with 87.6% of 647 individuals with amphetamine dependence reporting six or more signs of amphetamine withdrawal listed in the DSM when the drug is not available (Schuckit 1999) ... 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) ..."
^ abIdentification. "Lisdexamfetamine". DrugBank. University of Alberta. 16 September 2013. Retrieved 13 June 2014.
^ abcJasinski DR, Krishnan S (June 2009). "Abuse liability and safety of oral lisdexamfetamine dimesylate in individuals with a history of stimulant abuse". J. Psychopharmacol. (Oxford)23 (4): 419–427. doi:10.1177/0269881109103113. PMID19329547.
^ abEiden 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. PMID21272013. "VMAT2 is the CNS vesicular transporter for not only the biogenic amines DA, NE, EPI, 5-HT, and HIS, but likely also for the trace amines TYR, PEA, and thyronamine (THYR) ... [Trace aminergic] neurons in mammalian CNS would be identiﬁable as neurons expressing VMAT2 for storage, and the biosynthetic enzyme aromatic amino acid decarboxylase (AADC)."