The amphetamine molecule exists as two enantiomers,[note 1]levoamphetamine and dextroamphetamine. Dextroamphetamine is thedextrorotatory, or 'right-handed', enantiomer and exhibits more pronounced effects on the central nervous system than levoamphetamine. Pharmaceutical dextroamphetamine sulfate is available as both abrand name andgeneric drug in a variety ofdosage forms. Dextroamphetamine is sometimes prescribed as theinactive prodruglisdexamfetamine.
Dextroamphetamine is also used recreationally as a euphoriant and aphrodisiac, and, like otheramphetamines, is used as aclub drug for its energetic and euphoric high. Dextroamphetamine is considered to have a high potential for misuse in arecreational manner since individuals typically report feelingeuphoric, more alert, and more energetic after taking the drug.[87][88][89] Dextroamphetamine'sdopaminergic (rewarding) properties affect themesocorticolimbic circuit; a group of neural structures responsible forincentive salience (i.e., "wanting"; desire or craving for a reward and motivation),positive reinforcement andpositively-valenced emotions, particularly ones involvingpleasure.[90] Large recreational doses of dextroamphetamine may producesymptoms of dextroamphetamine overdose.[89] 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.[89] 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).[91][92]
The reason for using crushedspansules for insufflation and injectionmethods is evidently due to the instant-release forms of the drug seen in tablet preparations often containing a sizable amount of inactive binders and fillers alongside theactive d-amphetamine, such asdextrose.[93] Injection into the bloodstream can be dangerous because insoluble fillers within the tablets can block small blood vessels.[89] Chronic overuse of dextroamphetamine can lead to severedrug dependence, resulting in withdrawal symptoms when drug use stops.[89]
Amphetamine enters the presynaptic neuron across the neuronal membrane or throughDAT.[31] Once inside, it binds toTAAR1 or enters synaptic vesicles throughVMAT2.[31][32][182] When amphetamine enters synaptic vesicles through VMAT2, it collapses the vesicular pH gradient, which in turn causes dopamine to be released into thecytosol (light tan-colored area) through VMAT2.[32][183] When amphetamine binds to TAAR1, it reduces thefiring rate of the dopamine neuron viaG protein-coupled inwardly rectifying potassium channels (GIRKs) and activatesprotein kinase A (PKA) andprotein kinase C (PKC), which subsequently phosphorylate DAT.[31][184][185]PKA phosphorylation causes DAT to withdraw into the presynaptic neuron (internalize) and cease transport.[31]PKC-phosphorylated DAT may either operate in reverse or, likePKA-phosphorylated DAT, internalize and cease transport.[31][182] Amphetamine is also known to increase intracellular calcium, an effect which is associated with DAT phosphorylation through aCAMKIIα-dependent pathway, in turn producing dopamine efflux.[186][187]
Amphetamine and its enantiomers have been identified as potentfull agonists oftrace amine-associated receptor 1 (TAAR1), aGPCR, discovered in 2001, that is important for regulation ofmonoaminergic systems in the brain.[188][189] Activation of TAAR1 increasescAMP production viaadenylyl cyclase activation and inhibits the function of thedopamine transporter,norepinephrine transporter, andserotonin transporter, as well as inducing the release of these monoamine neurotransmitters (effluxion).[31][188][190] Amphetamine enantiomers are also substrates for a specific neuronal synaptic vesicle uptake transporter calledVMAT2.[32] When amphetamine is taken up by VMAT2, the vesicle releases (effluxes) dopamine, norepinephrine, and serotonin, among other monoamines, into the cytosol in exchange.[32]
Dextroamphetamine (thedextrorotaryenantiomer) andlevoamphetamine (thelevorotary enantiomer) have identical pharmacodynamics, but their binding affinities to their biomolecular targets vary.[189][191] Dextroamphetamine is a more potent agonist of TAAR1 than levoamphetamine.[189] Consequently, dextroamphetamine produces roughly three to four times morecentral nervous system (CNS) stimulation than levoamphetamine;[189][191] however, levoamphetamine has slightly greater cardiovascular and peripheral effects.[191]
Racemic amphetamine was firstsynthesized under the chemical name "phenylisopropylamine" inBerlin, 1887 by the Romanian chemistLazăr Edeleanu. It was not widely marketed until 1932, when the pharmaceutical companySmith, Kline & French (now known asGlaxoSmithKline) introduced it in the form of theBenzedrine inhaler for use as abronchodilator. Notably, the amphetamine contained in the Benzedrine inhaler was the liquid free-base,[note 15] not a chloride or sulfate salt.
Three years later, in 1935, the medical community became aware of the stimulant properties of amphetamine, specifically the dextroamphetamine isomer, and in 1937 Smith, Kline, and French introduced tablets under the brand nameDexedrine.[208] In the United States, Dexedrine was approved to treatnarcolepsy andattention deficit hyperactivity disorder (ADHD).[10] In Canadaindications once included epilepsy and parkinsonism.[209] Dextroamphetamine was marketed in various other forms in the following decades, primarily by Smith, Kline, and French, such as several combination medications including a mixture of dextroamphetamine andamobarbital (abarbiturate) sold under the brand nameDexamyl and, in the 1950s, an extended release capsule (the "Spansule").[210] Preparations containing dextroamphetamine were also used inWorld War II as a treatment againstfatigue.[27]
It quickly became apparent that dextroamphetamine and other amphetamines had a high potential formisuse, although they were not heavilycontrolled until 1970, when theComprehensive Drug Abuse Prevention and Control Act was passed by the United States Congress. Dextroamphetamine, along with other sympathomimetics, was eventually classified as Schedule II, the most restrictive category possible for a drug with a government-sanctioned, recognized medical use.[211] Internationally, it has been available under the names AmfeDyn (Italy), Curban (US), Obetrol (Switzerland), Simpamina (Italy), Dexedrine/GSK (US & Canada), Dexedrine/UCB (United Kingdom), Dextropa (Portugal), and Stild (Spain).[212] It became popular on themod scene in England in the early 1960s, and carried through to theNorthern Soul scene in the north of England to the end of the 1970s.
In October 2010,GlaxoSmithKline sold the rights for Dexedrine Spansule to Amedra Pharmaceuticals (a subsidiary of CorePharma).[213]
The U.S. Air Force uses dextroamphetamine as one of its "go pills", given to pilots on long missions to help them remain focused and alert. Conversely, "no-go pills" are used after the mission is completed, to combat the effects of the mission and "go-pills".[214][215][216] TheTarnak Farm incident was linked by media reports to the use of this drug on long term fatigued pilots. The military did not accept this explanation, citing the lack of similar incidents. Newerstimulant medications or awakeness promoting agents with different side effect profiles, such asmodafinil, are being investigated and sometimes issued for this reason.[215]
In the United States,immediate release (IR) formulations of dextroamphetaminesulfate are available generically as 5 mg and 10 mg tablets, marketed by Barr (Teva Pharmaceutical Industries),Mallinckrodt Pharmaceuticals, Wilshire Pharmaceuticals,Aurobindo Pharmaceutical USA and CorePharma. Previous IR tablets sold under the brand names Dexedrine and Dextrostat have been discontinued but in 2015, IR tablets became available by the brand name Zenzedi, offered as 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg and 30 mg tablets.[229] Dextroamphetamine sulfate is also available as acontrolled-release (CR) capsule preparation in strengths of 5 mg, 10 mg, and 15 mg under the brand name Dexedrine Spansule, with generic versions marketed by Barr and Mallinckrodt. A bubblegum flavored oral solution is available under the brand name ProCentra, manufactured by FSC Pediatrics, which is designed to be an easier method of administration in children who have difficulty swallowing tablets, each 5 mL contains 5 mg dextroamphetamine.[230] The conversion rate between dextroamphetamine sulfate to amphetamine free base is .728.[231]
In Australia, dexamfetamine is available in bottles of 100 instant release 5 mg tablets as ageneric drug[232] or slow release dextroamphetamine preparations may be compounded by individual chemists.[233] In the United Kingdom, it is available in 5 mg instant release sulfate tablets under the generic name dexamfetamine sulfate as well as 10 mg and 20 mg strength tablets under the brand name Amfexa. It is also available in generic dexamfetamine sulfate 5 mg/ml oral sugar-free syrup.[234] The brand name Dexedrine was available in the United Kingdom prior toUCB Pharma disinvesting the product to another pharmaceutical company (Auden Mckenzie).[235]
Dextroamphetamine is the activemetabolite of theprodrug lisdexamfetamine (L-lysine-dextroamphetamine), available by the brand nameVyvanse (Elvanse in the European market) (Venvanse in the Brazil market) (lisdexamfetamine dimesylate). Dextroamphetamine is liberated from lisdexamfetamine enzymatically following contact with red blood cells. The conversion is rate-limited by the enzyme, which prevents high blood concentrations of dextroamphetamine and reduces lisdexamfetamine's drug liking andabuse potential at clinical doses.[236][237] Vyvanse is marketed as once-a-day dosing as it provides a slow release of dextroamphetamine into the body. Vyvanse is available ascapsules, and chewable tablets, and in seven strengths; 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, and 70 mg. The conversion rate between lisdexamfetamine dimesylate (Vyvanse) to dextroamphetamine base is 29.5%.[238][239][240]
Adderall 20 mg tablets, some broken in half, with a lengthwise-folded US dollar bill along the bottom
Another pharmaceutical that contains dextroamphetamine is commonly known by the brand name Adderall.[166][30] It is available as immediate release (IR) tablets and extended release (XR) capsules.[166][30] Adderall contains equal amounts of four amphetamine salts:[166][30]
Adderall has a total amphetamine base equivalence of 63%.[166][30] While the enantiomer ratio by dextroamphetamine salts to levoamphetamine salts is 3:1, the amphetamine base content is 75.9% dextroamphetamine, 24.1% levoamphetamine.[note 17]
Amphetamine base in marketed amphetamine medications
Dextroamphetamine reduces thenegative symptoms ofschizophrenia, and has been shown to enhance the effects of auditory discrimination training in schizophrenic patients.[247][248][249]
^abEnantiomers are molecules that are mirror images of one another; they are structurally identical, but of the opposite orientation.[28]
^The ADHD-related outcome domains with the greatest proportion of significantly improved outcomes from long-term continuous stimulant therapy include academics (≈55% of academic outcomes improved), driving (100% of driving outcomes improved), non-medical drug use (47% of addiction-related outcomes improved), obesity (≈65% of obesity-related outcomes improved), self-esteem (50% of self-esteem outcomes improved), and social function (67% of social function outcomes improved).[42]
The largesteffect sizes for outcome improvements from long-term stimulant therapy occur in the domains involving academics (e.g.,grade point average, achievement test scores, length of education, and education level), self-esteem (e.g., self-esteem questionnaire assessments, number of suicide attempts, and suicide rates), and social function (e.g., peer nomination scores, social skills, and quality of peer, family, and romantic relationships).[42]
Long-term combination therapy for ADHD (i.e., treatment with both a stimulant and behavioral therapy) produces even larger effect sizes for outcome improvements and improves a larger proportion of outcomes across each domain compared to long-term stimulant therapy alone.[42] These findings were further supported by a 2025 review of interventions for adolescents, which concluded that medications and cognitive-behavioral treatments (CBT) provide complementary benefits. Medications demonstrated strong short-term efficacy on core symptoms, while CBT contributed modest to strong, and sometimes long-lasting, improvements in functional impairments and executive skills when used as part of combination therapy.[43]
^Cochrane reviews are high quality meta-analytic systematic reviews of randomized controlled trials.[51]
^In contrast to the Cochrane reviews that observed higher treatment discontinuation from adverse effects alone, this figure representsany cause of discontinuation (e.g., insufficient perceived treatment benefit).[54]
^The statements supported by the USFDA come from prescribing information, which is the copyrighted intellectual property of the manufacturer and approved by the USFDA. USFDA contraindications are not necessarily intended to limit medical practice but limit claims by pharmaceutical companies.[94]
^According to one review, amphetamine can be prescribed to individuals with a history of abuse provided that appropriate medication controls are employed, such as requiring daily pick-ups of the medication from the prescribing physician.[27]
^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.[40][41][99] The average reduction in final adult height from 3 years of continuous stimulant therapy is 2 cm.[99]
^Transcription factors are proteins that increase or decrease theexpression of specific genes.[134]
^In simpler terms, thisnecessary and sufficient relationship means that ΔFosB overexpression in the nucleus accumbens and addiction-related behavioral and neural adaptations always occur together and never occur alone.
^4-Hydroxyamphetamine has been shown to be metabolized into4-hydroxynorephedrine by dopamine beta-hydroxylase (DBH)in vitro and it is presumed to be metabolized similarlyin vivo.[200][203] Evidence from studies that measured the effect of serum DBH concentrations on4-hydroxyamphetamine metabolism in humans suggests that a different enzyme may mediate the conversion of4-hydroxyamphetamine to4-hydroxynorephedrine;[203][205] however, other evidence from animal studies suggests that this reaction is catalyzed by DBH insynaptic vesicles within noradrenergic neurons in the brain.[206][207]
^Free-base form amphetamine is a volatile oil, hence the efficacy of the inhalers.
^These represent the current brands in the United States, except Dexedrine instant release tablets. Dexedrine tablets, introduced in 1937, is discontinued but available as Zenzedi and generically;[27][217] Dexedrine listed here represents the extended release "Spansule" capsule which was approved in 1976.[218][219] Amphetamine sulfate tablets, now sold as Evekeo (brand), were originally sold as Benzedrine (brand) sulfate in 1935[220][27] and discontinued sometime after 1982.[27][221]
^Calculated by dextroamphetamine base percent / total amphetamine base percent = 47.49/62.57 = 75.90% from table: Amphetamine base in marketed amphetamine medications. The remainder is levoamphetamine.
^For uniformity, molar masses were calculated using the Lenntech Molecular Weight Calculator[241] and were within 0.01 g/mol of published pharmaceutical values.
^Amphetamine base percentage = molecular massbase / molecular masstotal. Amphetamine base percentage for Adderall = sum of component percentages / 4.
^dose = (1 / amphetamine base percentage) × scaling factor = (molecular masstotal / molecular massbase) × scaling factor. The values in this column were scaled to a 30 mg dose of dextroamphetamine sulfate.Due to pharmacological differences between these medications (e.g., differences in the release, absorption, conversion, concentration, differing effects of enantiomers, half-life, etc.), the listed values should not be considered equipotent doses.
^abcdefgStahl SM (March 2017)."Amphetamine (D,L)".Prescriber's Guide: Stahl's Essential Psychopharmacology (6th ed.). Cambridge, United Kingdom: Cambridge University Press. pp. 45–51.ISBN9781108228749. Retrieved5 August 2017.
^Cite error: The named referenceVitiello2008 was invoked but never defined (see thehelp page).
^Cite error: The named referenceGrahamGrahamBanaschewski2010 was invoked but never defined (see thehelp page).
^Cite error: The named referenceKociancicReedFindling2004 was invoked but never defined (see thehelp page).
^Cite error: The named referenceClemowWalker2014 was invoked but never defined (see thehelp page).
^abPatel VB, Preedy VR, eds. (2022).Handbook of Substance Misuse and Addictions. Cham: Springer International Publishing. p. 2006.doi:10.1007/978-3-030-92392-1.ISBN978-3-030-92391-4.Amphetamine is usually consumed via inhalation or orally, either in the form of a racemic mixture (levoamphetamine and dextroamphetamine) or dextroamphetamine alone (Childress et al. 2019). In general, all amphetamines have high bioavailability when consumed orally, and in the specific case of amphetamine, 90% of the consumed dose is absorbed in the gastrointestinal tract, with no significant differences in the rate and extent of absorption between the two enantiomers (Carvalho et al. 2012; Childress et al. 2019). The onset of action occurs approximately 30 to 45 minutes after consumption, depending on the ingested dose and on the degree of purity or on the concomitant consumption of certain foods (European Monitoring Centre for Drugs and Drug Addiction 2021a; Steingard et al. 2019). It is described that those substances that promote acidification of the gastrointestinal tract cause a decrease in amphetamine absorption, while gastrointestinal alkalinization may be related to an increase in the compound's absorption (Markowitz and Patrick 2017).
^Green-Hernandez C, Singleton JK, Aronzon DZ (1 January 2001).Primary Care Pediatrics. Lippincott Williams & Wilkins. p. 243.ISBN978-0-7817-2008-3.|quote = Table 21.2 Medications for ADHD ... D-amphetamine ... Onset: 30 min.
^abcMillichap JG (2010). "Chapter 9: Medications for ADHD". In Millichap JG (ed.).Attention Deficit Hyperactivity Disorder Handbook: A Physician's Guide to ADHD (2nd ed.). New York, USA: Springer. p. 112.ISBN978-1-4419-1396-8. Table 9.2 Dextroamphetamine formulations of stimulant medication Dexedrine [Peak:2–3 h] [Duration:5–6 h] ... Adderall [Peak:2–3 h] [Duration:5–7 h] Dexedrine spansules [Peak:7–8 h] [Duration:12 h] ... Adderall XR [Peak:7–8 h] [Duration:12 h] Vyvanse [Peak:3–4 h] [Duration:12 h]
^Brams M, Mao AR, Doyle RL (September 2008). "Onset of efficacy of long-acting psychostimulants in pediatric attention-deficit/hyperactivity disorder".Postgrad. Med.120 (3):69–88.doi:10.3810/pgm.2008.09.1909.PMID18824827.S2CID31791162.Onset of efficacy was earliest for d-MPH-ER at 0.5 hours, followed by d, l-MPH-LA at 1 to 2 hours, MCD at 1.5 hours, d, l-MPH-OR at 1 to 2 hours, MAS-XR at 1.5 to 2 hours, MTS at 2 hours, and LDX at approximately 2 hours. ... MAS-XR, and LDX have a long duration of action at 12 hours postdose
^abcdef"Metabolism/Pharmacokinetics".Amphetamine. Hazardous Substances Data Bank. United States National Library of Medicine – Toxicology Data Network. Archived fromthe original on 2 October 2017. Retrieved2 October 2017.Duration of effect varies depending on agent and urine pH. Excretion is enhanced in more acidic urine. Half-life is 7 to 34 hours and is, in part, dependent on urine pH (half-life is longer with alkaline urine). ... Amphetamines are distributed into most body tissues with high concentrations occurring in the brain and CSF. Amphetamine appears in the urine within about 3 hours following oral administration. ... Three days after a dose of (+ or -)-amphetamine, human subjects had excreted 91% of the (14)C in the urine
^Stahl SM (March 2017)."Amphetamine (D)".Prescriber's Guide: Stahl's Essential Psychopharmacology (6th ed.). Cambridge, United Kingdom: Cambridge University Press. pp. 39–44.ISBN978-1-108-22874-9. Retrieved8 August 2017.
^Lemke TL, Williams DA, Roche VF, Zito W (2013).Foye's Principles of Medicinal Chemistry (7th ed.). Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins. p. 648.ISBN978-1-60913-345-0.Alternatively, direct oxidation of amphetamine by DA β-hydroxylase can afford norephedrine.
^abcdefHuang YS, Tsai MH (July 2011). "Long-term outcomes with medications for attention-deficit hyperactivity disorder: current status of knowledge".CNS Drugs.25 (7):539–554.doi:10.2165/11589380-000000000-00000.PMID21699268.S2CID3449435.Several other studies,[97-101] including a meta-analytic review[98] and a retrospective study,[97] suggested that stimulant therapy in childhood is associated with a reduced risk of subsequent substance use, cigarette smoking and alcohol use disorders. ... Recent studies have demonstrated that stimulants, along with the non-stimulants atomoxetine and extended-release guanfacine, are continuously effective for more than 2-year treatment periods with few and tolerable adverse effects. The effectiveness of long-term therapy includes not only the core symptoms of ADHD, but also improvedquality of life and academic achievements. The most concerning short-term adverse effects of stimulants, such as elevated blood pressure and heart rate, waned in long-term follow-up studies. ... The current data do not support the potential impact of stimulants on the worsening or development of tics or substance abuse into adulthood. In the longest follow-up study (of more than 10 years), lifetime stimulant treatment for ADHD was effective and protective against the development of adverse psychiatric disorders.
^abcdMillichap JG (2010). "Chapter 9: Medications for ADHD". In Millichap JG (ed.).Attention Deficit Hyperactivity Disorder Handbook: A Physician's Guide to ADHD (2nd ed.). New York, US: Springer. pp. 121–123,125–127.ISBN9781441913968.Ongoing research has provided answers to many of the parents' concerns, and has confirmed the effectiveness and safety of the long-term use of medication.
^Sibley MH, Flores S, Murphy M, Basu H, Stein MA, Evans SW, et al. (January 2025). "Research Review: Pharmacological and non-pharmacological treatments for adolescents with attention deficit/hyperactivity disorder - a systematic review of the literature".Journal of Child Psychology and Psychiatry, and Allied Disciplines.66 (1):132–149.doi:10.1111/jcpp.14056.PMID39370392.The main efficacy-related conclusions of this review are: (a) medications demonstrated the strongest and most consistent effects on core ADHD symptoms (especially inattention), (b) heterogeneous C/BTs demonstrated inconsistent effects on ADHD symptoms, strong consistent effects on impairment and executive function skills, and modest consistent effects on internalizing symptoms and analogue note-taking performance, (c) C/BTs demonstrated consistent maintenance effects for executive function skills and impairment up to 6 months and possibly 3 years post-treatment, (d) though comparing the efficacy of two C/BTs rarely led to significant differences, which C/BT worked best for whom could be reliably predicted from patient- and provider-level moderators ... Thus, maximal therapeutic benefit (in terms of breadth of response and maintenance of effects) might be achieved by combining medication and C/BTs, a recommendation generally reflected in current practice parameters (AACAP, 2007; AADPA, 2022; NICE, 2018; Wolraich et al., 2019).
^Bellato A, Perrott NJ, Marzulli L, Parlatini V, Coghill D, Cortese S (30 May 2024)."Systematic Review and Meta-Analysis: Effects of Pharmacological Treatment for Attention-Deficit/Hyperactivity Disorder on Quality of Life".Journal of the American Academy of Child and Adolescent Psychiatry.64 (3): S0890–8567(24)00304–6.doi:10.1016/j.jaac.2024.05.023.hdl:11586/524122.PMID38823477.We conducted the first systematic review and meta-analysis investigating the effects of medication for ADHD on quality of life (QoL) in parallel or crossover RCTs. Overall, we found that methylphenidate, amphetamines, and atomoxetine were significantly more efficacious than placebo in improving QoL in people with ADHD. ... Four studies on amphetamines (950 participants with ADHD in total; 45% adults) reported relevant data for effect sizes to be computed. The meta-analysis on 14 effect sizes showed that amphetamines led to better QoL than placebo in individuals with ADHD.
^abcMalenka RC, Nestler EJ, Hyman SE (2009). "Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin". In Sydor A, Brown RY (eds.).Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York, US: McGraw-Hill Medical. pp. 154–157.ISBN9780071481274.
^abcdefMalenka RC, Nestler EJ, Hyman SE (2009). "Chapter 13: Higher Cognitive Function and Behavioral Control". In Sydor A, Brown RY (eds.).Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York, US: McGraw-Hill Medical. pp. 318, 321.ISBN9780071481274.Therapeutic (relatively low) doses of psychostimulants, such as methylphenidate and amphetamine, improve performance on working memory tasks both in normal subjects and those with ADHD. ... stimulants act not only on working memory function, but also on general levels of arousal and, within the nucleus accumbens, improve the saliency of tasks. Thus, stimulants improve performance on effortful but tedious tasks ... through indirect stimulation of dopamine and norepinephrine receptors. ... Beyond these general permissive effects, dopamine (acting via D1 receptors) and norepinephrine (acting at several receptors) can, at optimal levels, enhance working memory and aspects of attention.
^Millichap JG (2010). "Chapter 9: Medications for ADHD". In Millichap JG (ed.).Attention Deficit Hyperactivity Disorder Handbook: A Physician's Guide to ADHD (2nd ed.). New York, US: Springer. pp. 111–113.ISBN9781441913968.
^abcBarateau L, Pizza F, Plazzi G, Dauvilliers Y (August 2022). "Narcolepsy".Journal of Sleep Research.31 (4): e13631.doi:10.1111/jsr.13631.PMID35624073.Narcolepsy type 1 was called "narcolepsy with cataplexy" before 2014 (AASM, 2005), but was renamed NT1 in the third and last international classification of sleep disorders (AASM, 2014). ... A low level of Hcrt-1 in the CSF is very sensitive and specific for the diagnosis of NT1. ... All patients with low CSF Hcrt-1 levels are considered as NT1 patients, even if they report no cataplexy (in about 10–20% of cases), and all patients with normal CSF Hcrt-1 levels (or without cataplexy when the lumbar puncture is not performed) as NT2 patients (Baumann et al., 2014). ... In patients with NT1, the absence of Hcrt leads to the inhibition of regions that suppress REM sleep, thus allowing the activation of descending pathways inhibiting motoneurons, leading to cataplexy.
^abcdefghMignot EJ (October 2012)."A practical guide to the therapy of narcolepsy and hypersomnia syndromes".Neurotherapeutics.9 (4):739–752.doi:10.1007/s13311-012-0150-9.PMC3480574.PMID23065655.At the pathophysiological level, it is now clear that most narcolepsy cases with cataplexy, and a minority of cases (5–30 %) without cataplexy or with atypical cataplexy-like symptoms, are caused by a lack of hypocretin (orexin) of likely an autoimmune origin. In these cases, once the disease is established, the majority of the 70,000 hypocretin-producing cells have been destroyed, and the disorder is irreversible. ... Amphetamines are exceptionally wake-promoting, and at high doses also reduce cataplexy in narcoleptic patients, an effect best explained by its action on adrenergic and serotoninergic synapses. ... The D-isomer is more specific for DA transmission and is a better stimulant compound. Some effects on cataplexy (especially for the L-isomer), secondary to adrenergic effects, occur at higher doses. ... Numerous studies have shown that increased dopamine release is the main property explaining wake-promotion, although norepinephrine effects also contribute.
^abMalenka RC, Nestler EJ, Hyman SE, Holtzman DM (2015). "Chapter 10: Neural and Neuroendocrine Control of the Internal Milieu".Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (3rd ed.). New York: McGraw-Hill Medical. pp. 456–457.ISBN9780071827706.More recently, the lateral hypothalamus was also found to play a central role in arousal. Neurons in this region contain cell bodies that produce the orexin (also called hypocretin) peptides (Chapter 6). These neurons project widely throughout the brain and are involved in sleep, arousal, feeding, reward, aspects of emotion, and learning. In fact, orexin is thought to promote feeding primarily by promoting arousal. Mutations in orexin receptors are responsible for narcolepsy in a canine model, knockout of the orexin gene produces narcolepsy in mice, and humans with narcolepsy have low or absent levels of orexin peptides in cerebrospinal fluid (Chapter 13). Lateral hypothalamus neurons have reciprocal connections with neurons that produce monoamine neurotransmitters (Chapter 6).
^abcMalenka RC, Nestler EJ, Hyman SE, Holtzman DM (2015). "Chapter 13: Sleep and Arousal".Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (3rd ed.). McGraw-Hill Medical. p. 521.ISBN9780071827706.The ARAS consists of several different circuits including the four main monoaminergic pathways discussed in Chapter 6. The norepinephrine pathway originates from the LC and related brainstem nuclei; the serotonergic neurons originate from the RN within the brainstem as well; the dopaminergic neurons originate in the ventral tegmental area (VTA); and the histaminergic pathway originates from neurons in the tuberomammillary nucleus (TMN) of the posterior hypothalamus. As discussed in Chapter 6, these neurons project widely throughout the brain from restricted collections of cell bodies. Norepinephrine, serotonin, dopamine, and histamine have complex modulatory functions and, in general, promote wakefulness. The PT in the brainstem is also an important component of the ARAS. Activity of PT cholinergic neurons (REM-on cells) promotes REM sleep, as noted earlier. During waking, REM-on cells are inhibited by a subset of ARAS norepinephrine and serotonin neurons called REM-off cells.
^Shneerson JM (2009).Sleep medicine a guide to sleep and its disorders (2nd ed.). John Wiley & Sons. p. 81.ISBN9781405178518.All the amphetamines enhance activity at dopamine, noradrenaline and 5HT synapses. They cause presynaptic release of preformed transmitters, and also inhibit the re-uptake of dopamine and noradrenaline. These actions are most prominent in the brainstem ascending reticular activating system and the cerebral cortex.
^abSchwartz JR, Roth T (2008)."Neurophysiology of sleep and wakefulness: basic science and clinical implications".Current Neuropharmacology.6 (4):367–378.doi:10.2174/157015908787386050.PMC2701283.PMID19587857.Alertness and associated forebrain and cortical arousal are mediated by several ascending pathways with distinct neuronal components that project from the upper brain stem near the junction of the pons and the midbrain. ... Key cell populations of the ascending arousal pathway include cholinergic, noradrenergic, serotoninergic, dopaminergic, and histaminergic neurons located in the pedunculopontine and laterodorsal tegmental nucleus (PPT/LDT), locus coeruleus, dorsal and median raphe nucleus, and tuberomammillary nucleus (TMN), respectively. ... The mechanism of action of sympathomimetic alerting drugs (eg, dextro- and methamphetamine, methylphenidate) is direct or indirect stimulation of dopaminergic and noradrenergic nuclei, which in turn heightens the efficacy of the ventral periaqueductal grey area and locus coeruleus, both components of the secondary branch of the ascending arousal system. ... Sympathomimetic drugs have long been used to treat narcolepsy
^abcdeBarateau L, Lopez R, Dauvilliers Y (October 2016). "Management of Narcolepsy".Current Treatment Options in Neurology.18 (10): 43.doi:10.1007/s11940-016-0429-y.PMID27549768.The usefulness of amphetamines is limited by a potential risk of abuse, and their cardiovascular adverse effects (Table 1). That is why, even though they are cheaper than other drugs, and efficient, they remain third-line therapy in narcolepsy. Three class II studies showed an improvement of EDS in that disease. ... Despite the potential for drug abuse or tolerance using stimulants, patients with narcolepsy rarely exhibit addiction to their medication. ... Some stimulants, such as mazindol, amphetamines, and pitolisant, may also have some anticataplectic effects.
^Dauvilliers Y, Barateau L (August 2017). "Narcolepsy and Other Central Hypersomnias".Continuum.23 (4, Sleep Neurology):989–1004.doi:10.1212/CON.0000000000000492.PMID28777172.Recent clinical trials and practice guidelines have confirmed that stimulants such as modafinil, armodafinil, or sodium oxybate (as first line); methylphenidate and pitolisant (as second line [pitolisant is currently only available in Europe]); and amphetamines (as third line) are appropriate medications for excessive daytime sleepiness.
^Thorpy MJ, Bogan RK (April 2020). "Update on the pharmacologic management of narcolepsy: mechanisms of action and clinical implications".Sleep Medicine.68:97–109.doi:10.1016/j.sleep.2019.09.001.PMID32032921.The first agents used to treat EDS (ie, amphetamines, methylphenidate) are now considered second- or third-line options because newer medications have been developed with improved tolerability and lower abuse potential (eg, modafinil/armodafinil, solriamfetol, pitolisant)
^abSpencer RC, Devilbiss DM, Berridge CW (June 2015)."The Cognition-Enhancing Effects of Psychostimulants Involve Direct Action in the Prefrontal Cortex".Biological Psychiatry.77 (11):940–950.doi:10.1016/j.biopsych.2014.09.013.PMC4377121.PMID25499957.The procognitive actions of psychostimulants are only associated with low doses. Surprisingly, despite nearly 80 years of clinical use, the neurobiology of the procognitive actions of psychostimulants has only recently been systematically investigated. Findings from this research unambiguously demonstrate that the cognition-enhancing effects of psychostimulants involve the preferential elevation of catecholamines in the PFC and the subsequent activation of norepinephrine α2 and dopamine D1 receptors. ... This differential modulation of PFC-dependent processes across dose appears to be associated with the differential involvement of noradrenergic α2 versus α1 receptors. Collectively, this evidence indicates that at low, clinically relevant doses, psychostimulants are devoid of the behavioral and neurochemical actions that define this class of drugs and instead act largely as cognitive enhancers (improving PFC-dependent function). ... In particular, in both animals and humans, lower doses maximally improve performance in tests of working memory and response inhibition, whereas maximal suppression of overt behavior and facilitation of attentional processes occurs at higher doses.
^Devous MD, Trivedi MH, Rush AJ (April 2001). "Regional cerebral blood flow response to oral amphetamine challenge in healthy volunteers".Journal of Nuclear Medicine.42 (4):535–542.PMID11337538.
^Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 10: Neural and Neuroendocrine Control of the Internal Milieu". In Sydor A, Brown RY (eds.).Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York, US: McGraw-Hill Medical. p. 266.ISBN9780071481274.Dopamine acts in the nucleus accumbens to attach motivational significance to stimuli associated with reward.
^Clemow DB, Walker DJ (September 2014). "The potential for misuse and abuse of medications in ADHD: a review".Postgraduate Medicine.126 (5):64–81.doi:10.3810/pgm.2014.09.2801.PMID25295651.S2CID207580823.Overall, the data suggest that ADHD medication misuse and diversion are common health care problems for stimulant medications, with the prevalence believed to be approximately 5% to 10% of high school students and 5% to 35% of college students, depending on the study.
^abcLiddle DG, Connor DJ (June 2013). "Nutritional supplements and ergogenic AIDS".Primary Care: Clinics in Office Practice.40 (2):487–505.doi:10.1016/j.pop.2013.02.009.PMID23668655.Amphetamines and caffeine are stimulants that increase alertness, improve focus, decrease reaction time, and delay fatigue, allowing for an increased intensity and duration of training ... Physiologic and performance effects • Amphetamines increase dopamine/norepinephrine release and inhibit their reuptake, leading to central nervous system (CNS) stimulation • Amphetamines seem to enhance athletic performance in anaerobic conditions 39 40 • Improved reaction time • Increased muscle strength and delayed muscle fatigue • Increased acceleration • Increased alertness and attention to task
^abcdefghijklmnopqrsWestfall DP, Westfall TC (2010). "Miscellaneous Sympathomimetic Agonists". In Brunton LL, Chabner BA, Knollmann BC (eds.).Goodman & Gilman's Pharmacological Basis of Therapeutics (12th ed.). New York, US: McGraw-Hill.ISBN9780071624428.
^abcdParr JW (July 2011). "Attention-deficit hyperactivity disorder and the athlete: new advances and understanding".Clinics in Sports Medicine.30 (3):591–610.doi:10.1016/j.csm.2011.03.007.PMID21658550.In 1980, Chandler and Blair47 showed significant increases in knee extension strength, acceleration, anaerobic capacity, time to exhaustion during exercise, pre-exercise and maximum heart rates, and time to exhaustion during maximal oxygen consumption (VO2 max) testing after administration of 15 mg of dextroamphetamine versus placebo. Most of the information to answer this question has been obtained in the past decade through studies of fatigue rather than an attempt to systematically investigate the effect of ADHD drugs on exercise.
^abcRoelands B, de Koning J, Foster C, Hettinga F, Meeusen R (May 2013). "Neurophysiological determinants of theoretical concepts and mechanisms involved in pacing".Sports Medicine.43 (5):301–311.doi:10.1007/s40279-013-0030-4.PMID23456493.S2CID30392999.In high-ambient temperatures, dopaminergic manipulations clearly improve performance. The distribution of the power output reveals that after dopamine reuptake inhibition, subjects are able to maintain a higher power output compared with placebo. ... Dopaminergic drugs appear to override a safety switch and allow athletes to use a reserve capacity that is 'off-limits' in a normal (placebo) situation.
^Parker KL, Lamichhane D, Caetano MS, Narayanan NS (October 2013)."Executive dysfunction in Parkinson's disease and timing deficits".Frontiers in Integrative Neuroscience.7: 75.doi:10.3389/fnint.2013.00075.PMC3813949.PMID24198770.Manipulations of dopaminergic signaling profoundly influence interval timing, leading to the hypothesis that dopamine influences internal pacemaker, or "clock," activity. For instance, amphetamine, which increases concentrations of dopamine at the synaptic cleft advances the start of responding during interval timing, whereas antagonists of D2 type dopamine receptors typically slow timing;... Depletion of dopamine in healthy volunteers impairs timing, while amphetamine releases synaptic dopamine and speeds up timing.
^Rattray B, Argus C, Martin K, Northey J, Driller M (March 2015)."Is it time to turn our attention toward central mechanisms for post-exertional recovery strategies and performance?".Frontiers in Physiology.6: 79.doi:10.3389/fphys.2015.00079.PMC4362407.PMID25852568.Aside from accounting for the reduced performance of mentally fatigued participants, this model rationalizes the reduced RPE and hence improved cycling time trial performance of athletes using a glucose mouthwash (Chambers et al., 2009) and the greater power output during a RPE matched cycling time trial following amphetamine ingestion (Swart, 2009). ... Dopamine stimulating drugs are known to enhance aspects of exercise performance (Roelands et al., 2008)
^Roelands B, De Pauw K, Meeusen R (June 2015)."Neurophysiological effects of exercise in the heat".Scandinavian Journal of Medicine & Science in Sports.25 (Suppl 1):65–78.doi:10.1111/sms.12350.PMID25943657.S2CID22782401.This indicates that subjects did not feel they were producing more power and consequently more heat. The authors concluded that the "safety switch" or the mechanisms existing in the body to prevent harmful effects are overridden by the drug administration (Roelands et al., 2008b). Taken together, these data indicate strong ergogenic effects of an increased DA concentration in the brain, without any change in the perception of effort.
^Schultz W (2015)."Neuronal reward and decision signals: from theories to data".Physiological Reviews.95 (3):853–951.doi:10.1152/physrev.00023.2014.PMC4491543.PMID26109341.Rewards in operant conditioning are positive reinforcers. ... Operant behavior gives a good definition for rewards. Anything that makes an individual come back for more is a positive reinforcer and therefore a reward. Although it provides a good definition, positive reinforcement is only one of several reward functions. ... Rewards are attractive. They are motivating and make us exert an effort. ... Rewards induce approach behavior, also called appetitive or preparatory behavior, sexual behavior, and consummatory behavior. ... Thus any stimulus, object, event, activity, or situation that has the potential to make us approach and consume it is by definition a reward. ... Rewarding stimuli, objects, events, situations, and activities consist of several major components. First, rewards have basic sensory components (visual, auditory, somatosensory, gustatory, and olfactory) ... Second, rewards are salient and thus elicit attention, which are manifested as orienting responses. The salience of rewards derives from three principal factors, namely, their physical intensity and impact (physical salience), their novelty and surprise (novelty/surprise salience), and their general motivational impact shared with punishers (motivational salience). A separate form not included in this scheme, incentive salience, primarily addresses dopamine function in addiction and refers only to approach behavior (as opposed to learning) ... Third, rewards have a value component that determines the positively motivating effects of rewards and is not contained in, nor explained by, the sensory and attentional components. This component reflects behavioral preferences and thus is subjective and only partially determined by physical parameters. Only this component constitutes what we understand as a reward. It mediates the specific behavioral reinforcing, approach generating, and emotional effects of rewards that are crucial for the organism's survival and reproduction, whereas all other components are only supportive of these functions. ... Rewards can also be intrinsic to behavior. They contrast with extrinsic rewards that provide motivation for behavior and constitute the essence of operant behavior in laboratory tests. Intrinsic rewards are activities that are pleasurable on their own and are undertaken for their own sake, without being the means for getting extrinsic rewards. ... Intrinsic rewards are genuine rewards in their own right, as they induce learning, approach, and pleasure, like perfectioning, playing, and enjoying the piano. Although they can serve to condition higher order rewards, they are not conditioned, higher order rewards, as attaining their reward properties does not require pairing with an unconditioned reward. ... These emotions are also called liking (for pleasure) and wanting (for desire) in addiction research and strongly support the learning and approach generating functions of reward.
^Kessler S (January 1996). "Drug therapy in attention-deficit hyperactivity disorder".Southern Medical Journal.89 (1):33–38.doi:10.1097/00007611-199601000-00005.PMID8545689.S2CID12798818.statements on package inserts are not intended to limit medical practice. Rather they are intended to limit claims by pharmaceutical companies. ... the FDA asserts explicitly, and the courts have upheld that clinical decisions are to be made by physicians and patients in individual situations.
^Feinberg SS (November 2004). "Combining stimulants with monoamine oxidase inhibitors: a review of uses and one possible additional indication".The Journal of Clinical Psychiatry.65 (11):1520–1524.doi:10.4088/jcp.v65n1113.PMID15554766.
^Stewart JW, Deliyannides DA, McGrath PJ (June 2014). "How treatable is refractory depression?".Journal of Affective Disorders.167:148–152.doi:10.1016/j.jad.2014.05.047.PMID24972362.
^abcd"Dyanavel XR- amphetamine suspension, extended release".DailyMed. Tris Pharma, Inc. 6 February 2019. Retrieved22 December 2019.DYANAVEL XR contains d-amphetamine and l-amphetamine in a ratio of 3.2 to 1 ... The most common (≥2% in the DYANAVEL XR group and greater than placebo) adverse reactions reported in the Phase 3 controlled study conducted in 108 patients with ADHD (aged 6 to 12 years) were: epistaxis, allergic rhinitis and upper abdominal pain. ... DOSAGE FORMS AND STRENGTHS Extended-release oral suspension contains 2.5 mg amphetamine base equivalents per mL.
^Ramey JT, Bailen E, Lockey RF (2006)."Rhinitis medicamentosa"(PDF).Journal of Investigational Allergology & Clinical Immunology.16 (3):148–155.PMID16784007. Retrieved29 April 2015.Table 2. Decongestants Causing Rhinitis Medicamentosa – Nasal decongestants: – Sympathomimetic: • Amphetamine
^O'Connor PG (February 2012)."Amphetamines".Merck Manual for Health Care Professionals. Merck. Retrieved8 May 2012.
^abcdShoptaw SJ, Kao U, Ling W (January 2009). Shoptaw SJ, Ali R (eds.)."Treatment for amphetamine psychosis".Cochrane Database of Systematic Reviews.2009 (1): CD003026.doi:10.1002/14651858.CD003026.pub3.PMC7004251.PMID19160215.A minority of individuals who use amphetamines develop full-blown psychosis requiring care at emergency departments or psychiatric hospitals. In such cases, symptoms of amphetamine psychosis commonly include paranoid and persecutory delusions as well as auditory and visual hallucinations in the presence of extreme agitation. More common (about 18%) is for frequent amphetamine users to report psychotic symptoms that are sub-clinical and that do not require high-intensity intervention ... About 5–15% of the users who develop an amphetamine psychosis fail to recover completely (Hofmann 1983) ... Findings from one trial indicate use of antipsychotic medications effectively resolves symptoms of acute amphetamine psychosis. psychotic symptoms of individuals with amphetamine psychosis may be due exclusively to heavy use of the drug or heavy use of the drug may exacerbate an underlying vulnerability to schizophrenia.
^abMalenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and Addictive Disorders". In Sydor A, Brown RY (eds.).Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 364–375.ISBN9780071481274.
^abcdeNestler EJ (December 2013)."Cellular basis of memory for addiction".Dialogues in Clinical Neuroscience.15 (4):431–443.PMC3898681.PMID24459410.Despite the importance of numerous psychosocial factors, at its core, drug addiction involves a biological process: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. ... A large body of literature has demonstrated that such ΔFosB induction in D1-type [nucleus accumbens] neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement ... Another ΔFosB target is cFos: as ΔFosB accumulates with repeated drug exposure it represses c-Fos and contributes to the molecular switch whereby ΔFosB is selectively induced in the chronic drug-treated state.41. ... Moreover, there is increasing evidence that, despite a range of genetic risks for addiction across the population, exposure to sufficiently high doses of a drug for long periods of time can transform someone who has relatively lower genetic loading into an addict.
^Volkow ND, Koob GF, McLellan AT (January 2016)."Neurobiologic Advances from the Brain Disease Model of Addiction".New England Journal of Medicine.374 (4):363–371.doi:10.1056/NEJMra1511480.PMC6135257.PMID26816013.Substance-use disorder: A diagnostic term in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) referring to recurrent use of alcohol or other drugs that causes clinically and functionally significant impairment, such as health problems, disability, and failure to meet major responsibilities at work, school, or home. Depending on the level of severity, this disorder is classified as mild, moderate, or severe. Addiction: A term used to indicate the most severe, chronic stage of substance-use disorder, in which there is a substantial loss of self-control, as indicated by compulsive drug taking despite the desire to stop taking the drug. In the DSM-5, the term addiction is synonymous with the classification of severe substance-use disorder.
^abcRenthal W, Nestler EJ (September 2009)."Chromatin regulation in drug addiction and depression".Dialogues in Clinical Neuroscience.11 (3):257–268.doi:10.31887/DCNS.2009.11.3/wrenthal.PMC2834246.PMID19877494.[Psychostimulants] increase cAMP levels in striatum, which activates protein kinase A (PKA) and leads to phosphorylation of its targets. This includes the cAMP response element binding protein (CREB), the phosphorylation of which induces its association with the histone acetyltransferase, CREB binding protein (CBP) to acetylate histones and facilitate gene activation. This is known to occur on many genes including fosB andc-fos in response to psychostimulant exposure. ΔFosB is also upregulated by chronic psychostimulant treatments, and is known to activate certain genes (eg, cdk5) and repress others (eg,c-fos) where it recruits HDAC1 as a corepressor. ... Chronic exposure to psychostimulants increases glutamatergic [signaling] from the prefrontal cortex to the NAc. Glutamatergic signaling elevates Ca2+ levels in NAc postsynaptic elements where it activates CaMK (calcium/calmodulin protein kinases) signaling, which, in addition to phosphorylating CREB, also phosphorylates HDAC5. Figure 2: Psychostimulant-induced signaling events
^Broussard JI (January 2012)."Co-transmission of dopamine and glutamate".The Journal of General Physiology.139 (1):93–96.doi:10.1085/jgp.201110659.PMC3250102.PMID22200950.Coincident and convergent input often induces plasticity on a postsynaptic neuron. The NAc integrates processed information about the environment from basolateral amygdala, hippocampus, and prefrontal cortex (PFC), as well as projections from midbrain dopamine neurons. Previous studies have demonstrated how dopamine modulates this integrative process. For example, high frequency stimulation potentiates hippocampal inputs to the NAc while simultaneously depressing PFC synapses (Goto and Grace, 2005). The converse was also shown to be true; stimulation at PFC potentiates PFC–NAc synapses but depresses hippocampal–NAc synapses. In light of the new functional evidence of midbrain dopamine/glutamate co-transmission (references above), new experiments of NAc function will have to test whether midbrain glutamatergic inputs bias or filter either limbic or cortical inputs to guide goal-directed behavior.
^Kanehisa Laboratories (10 October 2014)."Amphetamine – Homo sapiens (human)".KEGG Pathway. Retrieved31 October 2014.Most addictive drugs increase extracellular concentrations of dopamine (DA) in nucleus accumbens (NAc) and medial prefrontal cortex (mPFC), projection areas of mesocorticolimbic DA neurons and key components of the "brain reward circuit". Amphetamine achieves this elevation in extracellular levels of DA by promoting efflux from synaptic terminals. ... Chronic exposure to amphetamine induces a unique transcription factor delta FosB, which plays an essential role in long-term adaptive changes in the brain.
^abcRobison AJ, Nestler EJ (November 2011)."Transcriptional and epigenetic mechanisms of addiction".Nature Reviews Neuroscience.12 (11):623–637.doi:10.1038/nrn3111.PMC3272277.PMID21989194.ΔFosB serves as one of the master control proteins governing this structural plasticity. ... ΔFosB also represses G9a expression, leading to reduced repressive histone methylation at the cdk5 gene. The net result is gene activation and increased CDK5 expression. ... In contrast, ΔFosB binds to thec-fos gene and recruits several co-repressors, including HDAC1 (histone deacetylase 1) and SIRT 1 (sirtuin 1). ... The net result isc-fos gene repression. Figure 4: Epigenetic basis of drug regulation of gene expression
^abcNestler EJ (December 2012)."Transcriptional mechanisms of drug addiction".Clinical Psychopharmacology and Neuroscience.10 (3):136–143.doi:10.9758/cpn.2012.10.3.136.PMC3569166.PMID23430970.The 35-37 kD ΔFosB isoforms accumulate with chronic drug exposure due to their extraordinarily long half-lives. ... As a result of its stability, the ΔFosB protein persists in neurons for at least several weeks after cessation of drug exposure. ... ΔFosB overexpression in nucleus accumbens induces NFκB ... In contrast, the ability of ΔFosB to repress thec-Fos gene occurs in concert with the recruitment of a histone deacetylase and presumably several other repressive proteins such as a repressive histone methyltransferase
^Nestler EJ (October 2008)."Transcriptional mechanisms of addiction: Role of ΔFosB".Philosophical Transactions of the Royal Society B: Biological Sciences.363 (1507):3245–3255.doi:10.1098/rstb.2008.0067.PMC2607320.PMID18640924.Recent evidence has shown that ΔFosB also represses thec-fos gene that helps create the molecular switch—from the induction of several short-lived Fos family proteins after acute drug exposure to the predominant accumulation of ΔFosB after chronic drug exposure
^Malenka RC, Nestler EJ, Hyman SE, Holtzman DM (2015). "Chapter 16: Reinforcement and Addictive Disorders".Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (3rd ed.). New York: McGraw-Hill Medical.ISBN9780071827706.Such agents also have important therapeutic uses; cocaine, for example, is used as a local anesthetic (Chapter 2), and amphetamines and methylphenidate are used in low doses to treat attention deficit hyperactivity disorder and in higher doses to treat narcolepsy (Chapter 12). Despite their clinical uses, these drugs are strongly reinforcing, and their long-term use at high doses is linked with potential addiction, especially when they are rapidly administered or when high-potency forms are given.
^Kollins SH (May 2008). "A qualitative review of issues arising in the use of psycho-stimulant medications in patients with ADHD and co-morbid substance use disorders".Current Medical Research and Opinion.24 (5):1345–1357.doi:10.1185/030079908X280707.PMID18384709.S2CID71267668.When oral formulations of psychostimulants are used at recommended doses and frequencies, they are unlikely to yield effects consistent with abuse potential in patients with ADHD.
^abcdeRuffle JK (November 2014). "Molecular neurobiology of addiction: what's all the (Δ)FosB about?".The American Journal of Drug and Alcohol Abuse.40 (6):428–437.doi:10.3109/00952990.2014.933840.PMID25083822.S2CID19157711.ΔFosB is an essential transcription factor implicated in the molecular and behavioral pathways of addiction following repeated drug exposure.
^abcdefghijkRobison AJ, Nestler EJ (November 2011)."Transcriptional and epigenetic mechanisms of addiction".Nature Reviews Neuroscience.12 (11):623–637.doi:10.1038/nrn3111.PMC3272277.PMID21989194.ΔFosB has been linked directly to several addiction-related behaviors ... Importantly, genetic or viral overexpression of ΔJunD, a dominant negative mutant of JunD which antagonizes ΔFosB- and other AP-1-mediated transcriptional activity, in the NAc or OFC blocks these key effects of drug exposure14,22–24. This indicates that ΔFosB is both necessary and sufficient for many of the changes wrought in the brain by chronic drug exposure. ΔFosB is also induced in D1-type NAc MSNs by chronic consumption of several natural rewards, including sucrose, high fat food, sex, wheel running, where it promotes that consumption14,26–30. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states. ... ΔFosB serves as one of the master control proteins governing this structural plasticity.
^abcdefghijklmnopqrstuvOlsen CM (December 2011)."Natural rewards, neuroplasticity, and non-drug addictions".Neuropharmacology.61 (7):1109–1122.doi:10.1016/j.neuropharm.2011.03.010.PMC3139704.PMID21459101.Similar to environmental enrichment, studies have found that exercise reduces self-administration and relapse to drugs of abuse (Cosgrove et al., 2002; Zlebnik et al., 2010). There is also some evidence that these preclinical findings translate to human populations, as exercise reduces withdrawal symptoms and relapse in abstinent smokers (Daniel et al., 2006; Prochaska et al., 2008), and one drug recovery program has seen success in participants that train for and compete in a marathon as part of the program (Butler, 2005). ... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some patients taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al., 2006; Aiken, 2007; Lader, 2008).
^abcdLynch WJ, Peterson AB, Sanchez V, Abel J, Smith MA (September 2013)."Exercise as a novel treatment for drug addiction: a neurobiological and stage-dependent hypothesis".Neuroscience & Biobehavioral Reviews.37 (8):1622–1644.doi:10.1016/j.neubiorev.2013.06.011.PMC3788047.PMID23806439.These findings suggest that exercise may "magnitude"-dependently prevent the development of an addicted phenotype possibly by blocking/reversing behavioral and neuroadaptive changes that develop during and following extended access to the drug. ... Exercise has been proposed as a treatment for drug addiction that may reduce drug craving and risk of relapse. Although few clinical studies have investigated the efficacy of exercise for preventing relapse, the few studies that have been conducted generally report a reduction in drug craving and better treatment outcomes ... Taken together, these data suggest that the potential benefits of exercise during relapse, particularly for relapse to psychostimulants, may be mediated via chromatin remodeling and possibly lead to greater treatment outcomes.
^abcLinke SE, Ussher M (January 2015)."Exercise-based treatments for substance use disorders: evidence, theory, and practicality".The American Journal of Drug and Alcohol Abuse.41 (1):7–15.doi:10.3109/00952990.2014.976708.PMC4831948.PMID25397661.The limited research conducted suggests that exercise may be an effective adjunctive treatment for SUDs. In contrast to the scarce intervention trials to date, a relative abundance of literature on the theoretical and practical reasons supporting the investigation of this topic has been published. ... numerous theoretical and practical reasons support exercise-based treatments for SUDs, including psychological, behavioral, neurobiological, nearly universal safety profile, and overall positive health effects.
^Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 4: Signal Transduction in the Brain". In Sydor A, Brown RY (eds.).Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York, US: McGraw-Hill Medical. p. 94.ISBN9780071481274.
^abBlum K, Werner T, Carnes S, Carnes P, Bowirrat A, Giordano J, et al. (March 2012)."Sex, drugs, and rock 'n' roll: hypothesizing common mesolimbic activation as a function of reward gene polymorphisms".Journal of Psychoactive Drugs.44 (1):38–55.doi:10.1080/02791072.2012.662112.PMC4040958.PMID22641964.It has been found that deltaFosB gene in the NAc is critical for reinforcing effects of sexual reward. Pitchers and colleagues (2010) reported that sexual experience was shown to cause DeltaFosB accumulation in several limbic brain regions including the NAc, medial pre-frontal cortex, VTA, caudate, and putamen, but not the medial preoptic nucleus. ... these findings support a critical role for DeltaFosB expression in the NAc in the reinforcing effects of sexual behavior and sexual experience-induced facilitation of sexual performance. ... both drug addiction and sexual addiction represent pathological forms of neuroplasticity along with the emergence of aberrant behaviors involving a cascade of neurochemical changes mainly in the brain's rewarding circuitry.
^Beloate LN, Weems PW, Casey GR, Webb IC, Coolen LM (February 2016). "Nucleus accumbens NMDA receptor activation regulates amphetamine cross-sensitization and deltaFosB expression following sexual experience in male rats".Neuropharmacology.101:154–164.doi:10.1016/j.neuropharm.2015.09.023.PMID26391065.S2CID25317397.
^Malenka RC, Nestler EJ, Hyman SE, Holtzman DM (2015). "Chapter 16: Reinforcement and Addictive Disorders".Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (3rd ed.). New York: McGraw-Hill Medical.ISBN9780071827706.Pharmacologic treatment for psychostimulant addiction is generally unsatisfactory. As previously discussed, cessation of cocaine use and the use of other psychostimulants in dependent individuals does not produce a physical withdrawal syndrome but may produce dysphoria, anhedonia, and an intense desire to reinitiate drug use.
^abcdChan B, Freeman M, Kondo K, Ayers C, Montgomery J, Paynter R, et al. (December 2019). "Pharmacotherapy for methamphetamine/amphetamine use disorder-a systematic review and meta-analysis".Addiction.114 (12):2122–2136.doi:10.1111/add.14755.PMID31328345.S2CID198136436.
^abMalenka RC, Nestler EJ, Hyman SE (2009). "Chapter 5: Excitatory and Inhibitory Amino Acids". In Sydor A, Brown RY (eds.).Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York, US: McGraw-Hill Medical. pp. 124–125.ISBN9780071481274.
^abcCarroll ME, Smethells JR (February 2016)."Sex Differences in Behavioral Dyscontrol: Role in Drug Addiction and Novel Treatments".Frontiers in Psychiatry.6: 175.doi:10.3389/fpsyt.2015.00175.PMC4745113.PMID26903885.Physical Exercise There is accelerating evidence that physical exercise is a useful treatment for preventing and reducing drug addiction ... In some individuals, exercise has its own rewarding effects, and a behavioral economic interaction may occur, such that physical and social rewards of exercise can substitute for the rewarding effects of drug abuse. ... The value of this form of treatment for drug addiction in laboratory animals and humans is that exercise, if it can substitute for the rewarding effects of drugs, could be self-maintained over an extended period of time. Work to date in [laboratory animals and humans] regarding exercise as a treatment for drug addiction supports this hypothesis. ... Animal and human research on physical exercise as a treatment for stimulant addiction indicates that this is one of the most promising treatments on the horizon.
^abcdShoptaw SJ, Kao U, Heinzerling K, Ling W (April 2009). Shoptaw SJ (ed.)."Treatment for amphetamine withdrawal".Cochrane Database of Systematic Reviews.2009 (2): CD003021.doi:10.1002/14651858.CD003021.pub2.PMC7138250.PMID19370579.The prevalence of this withdrawal syndrome is extremely common (Cantwell 1998; Gossop 1982) with 87.6% of 647 individuals with amphetamine dependence reporting six or more signs of amphetamine withdrawal listed in the DSM when the drug is not available (Schuckit 1999) ... The severity of withdrawal symptoms is greater in amphetamine dependent individuals who are older and who have more extensive amphetamine use disorders (McGregor 2005). Withdrawal symptoms typically present within 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) ...
^abcdBowyer JF, Hanig JP (November 2014)."Amphetamine- and methamphetamine-induced hyperthermia: Implications of the effects produced in brain vasculature and peripheral organs to forebrain neurotoxicity".Temperature.1 (3):172–182.doi:10.4161/23328940.2014.982049.PMC5008711.PMID27626044.Hyperthermia alone does not produce amphetamine-like neurotoxicity but AMPH and METH exposures that do not produce hyperthermia (≥40 °C) are minimally neurotoxic. Hyperthermia likely enhances AMPH and METH neurotoxicity directly through disruption of protein function, ion channels and enhanced ROS production. ... The hyperthermia and the hypertension produced by high doses amphetamines are a primary cause of transient breakdowns in the blood-brain barrier (BBB) resulting in concomitant regional neurodegeneration and neuroinflammation in laboratory animals. ... In animal models that evaluate the neurotoxicity of AMPH and METH, it is quite clear that hyperthermia is one of the essential components necessary for the production of histological signs of dopamine terminal damage and neurodegeneration in cortex, striatum, thalamus and hippocampus.
^"Amphetamine".United States National Library of Medicine – Toxicology Data Network. Hazardous Substances Data Bank. Archived fromthe original on 2 October 2017. Retrieved2 October 2017.Direct toxic damage to vessels seems unlikely because of the dilution that occurs before the drug reaches the cerebral circulation.
^Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and addictive disorders". In Sydor A, Brown RY (eds.).Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York, US: McGraw-Hill Medical. p. 370.ISBN9780071481274.Unlike cocaine and amphetamine, methamphetamine is directly toxic to midbrain dopamine neurons.
^Krause J (April 2008). "SPECT and PET of the dopamine transporter in attention-deficit/hyperactivity disorder".Expert Rev. Neurother.8 (4):611–625.doi:10.1586/14737175.8.4.611.PMID18416663.S2CID24589993.Zinc binds at ... extracellular sites of the DAT [103], serving as a DAT inhibitor. In this context, controlled double-blind studies in children are of interest, which showed positive effects of zinc [supplementation] on symptoms of ADHD [105,106]. It should be stated that at this time [supplementation] with zinc is not integrated in any ADHD treatment algorithm.
^Sulzer D (February 2011)."How addictive drugs disrupt presynaptic dopamine neurotransmission".Neuron.69 (4):628–649.doi:10.1016/j.neuron.2011.02.010.PMC3065181.PMID21338876.They did not confirm the predicted straightforward relationship between uptake and release, but rather that some compounds including AMPH were better releasers than substrates for uptake. Zinc, moreover, stimulates efflux of intracellular [3H]DA despite its concomitant inhibition of uptake (Scholze et al., 2002).
^Heal DJ, Smith SL, Findling RL (2012). "ADHD: current and future therapeutics".Behavioral Neuroscience of Attention Deficit Hyperactivity Disorder and Its Treatment. Current Topics in Behavioral Neurosciences. Vol. 9. pp. 361–390.doi:10.1007/7854_2011_125.ISBN978-3-642-24611-1.PMID21487953.Adjunctive therapy with DL-methylphenidate in atomoxetine partial responders has been successful (Wilens et al. 2009), but this also increases the rates of insomnia, irritability and loss of appetite (Hammerness et al. 2009). This combination therapy has not included amphetamine because blockade of NET by atomoxetine prevents entry of amphetamine into presynaptic noradrenergic terminals (Sofuoglu et al. 2009).
^abcRothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, et al. (January 2001). "Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin".Synapse.39 (1):32–41.doi:10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3.PMID11071707.
^abQuintero J, Gutiérrez-Casares JR, Álamo C (11 August 2022)."Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review".Neurology and Therapy.11 (4):1489–1517.doi:10.1007/s40120-022-00392-2.PMC9588136.PMID35951288.The active form of the drug has a central nervous system stimulating activity by the primary inhibition of DAT, NET, trace amine-associated receptor 1 (TAAR1) and vesicular monoamine transporter 2 (SLC18A2), among other targets, therefore regulating the reuptake and release of catecholamines (primarily NE and DA) on the synaptic cleft. ... LDX can also promote the increase of DA in the synaptic cleft by activating protein TAAR1, which produces the efflux of monoamine NTs, mainly DA, from storage sites on presynaptic neurons. TAAR1 activation leads to intracellular cAMP signalling that results in PKA and PKC phosphorylation and activation. This PKC activation decreases DAT1, NET1 and SERT cell surface expression, intensifying the direct blockage of monoamine transporters by LDX and improving the neurotransmission imbalance in ADHD.
^Sulzer D, Cragg SJ, Rice ME (August 2016)."Striatal dopamine neurotransmission: regulation of release and uptake".Basal Ganglia.6 (3):123–148.doi:10.1016/j.baga.2016.02.001.PMC4850498.PMID27141430.Despite the challenges in determining synaptic vesicle pH, the proton gradient across the vesicle membrane is of fundamental importance for its function. Exposure of isolated catecholamine vesicles to protonophores collapses the pH gradient and rapidly redistributes transmitter from inside to outside the vesicle. ... Amphetamine and its derivatives like methamphetamine are weak base compounds that are the only widely used class of drugs known to elicit transmitter release by a non-exocytic mechanism. As substrates for both DAT and VMAT, amphetamines can be taken up to the cytosol and then sequestered in vesicles, where they act to collapse the vesicular pH gradient.
^Ledonne A, Berretta N, Davoli A, Rizzo GR, Bernardi G, Mercuri NB (July 2011)."Electrophysiological effects of trace amines on mesencephalic dopaminergic neurons".Front. Syst. Neurosci.5: 56.doi:10.3389/fnsys.2011.00056.PMC3131148.PMID21772817.Three important new aspects of TAs action have recently emerged: (a) inhibition of firing due to increased release of dopamine; (b) reduction of D2 and GABAB receptor-mediated inhibitory responses (excitatory effects due to disinhibition); and (c) a direct TA1 receptor-mediated activation of GIRK channels which produce cell membrane hyperpolarization.
^"TAAR1".GenAtlas. University of Paris. 28 January 2012. Retrieved29 May 2014. • tonically activates inwardly rectifying K(+) channels, which reduces the basal firing frequency of dopamine (DA) neurons of the ventral tegmental area (VTA)
^Underhill SM, Wheeler DS, Li M, Watts SD, Ingram SL, Amara SG (July 2014)."Amphetamine modulates excitatory neurotransmission through endocytosis of the glutamate transporter EAAT3 in dopamine neurons".Neuron.83 (2):404–416.doi:10.1016/j.neuron.2014.05.043.PMC4159050.PMID25033183.AMPH also increases intracellular calcium (Gnegy et al., 2004) that is associated with calmodulin/CamKII activation (Wei et al., 2007) and modulation and trafficking of the DAT (Fog et al., 2006; Sakrikar et al., 2012). ... For example, AMPH increases extracellular glutamate in various brain regions including the striatum, VTA and NAc (Del Arco et al., 1999; Kim et al., 1981; Mora and Porras, 1993; Xue et al., 1996), but it has not been established whether this change can be explained by increased synaptic release or by reduced clearance of glutamate. ... DHK-sensitive, EAAT2 uptake was not altered by AMPH (Figure 1A). The remaining glutamate transport in these midbrain cultures is likely mediated by EAAT3 and this component was significantly decreased by AMPH
^Vaughan RA, Foster JD (September 2013)."Mechanisms of dopamine transporter regulation in normal and disease states".Trends Pharmacol. Sci.34 (9):489–496.doi:10.1016/j.tips.2013.07.005.PMC3831354.PMID23968642.AMPH and METH also stimulate DA efflux, which is thought to be a crucial element in their addictive properties [80], although the mechanisms do not appear to be identical for each drug [81]. These processes are PKCβ– and CaMK–dependent [72, 82], and PKCβ knock-out mice display decreased AMPH-induced efflux that correlates with reduced AMPH-induced locomotion [72].
^abBunzow JR, Sonders MS, Arttamangkul S, Harrison LM, Zhang G, Quigley DI, et al. (December 2001). "Amphetamine, 3,4-methylenedioxymethamphetamine, lysergic acid diethylamide, and metabolites of the catecholamine neurotransmitters are agonists of a rat trace amine receptor".Molecular Pharmacology.60 (6):1181–1188.doi:10.1124/mol.60.6.1181.PMID11723224.S2CID14140873.
^abKhan MZ, Nawaz W (October 2016). "The emerging roles of human trace amines and human trace amine-associated receptors (hTAARs) in central nervous system".Biomedicine & Pharmacotherapy.83:439–449.doi:10.1016/j.biopha.2016.07.002.PMID27424325.
^abcdeLindemann L, Hoener MC (May 2005). "A renaissance in trace amines inspired by a novel GPCR family".Trends in Pharmacological Sciences.26 (5):274–281.doi:10.1016/j.tips.2005.03.007.PMID15860375.
^abcSantagati NA, Ferrara G, Marrazzo A, Ronsisvalle G (September 2002). "Simultaneous determination of amphetamine and one of its metabolites by HPLC with electrochemical detection".Journal of Pharmaceutical and Biomedical Analysis.30 (2):247–255.doi:10.1016/S0731-7085(02)00330-8.PMID12191709.
^"Compound Summary".p-Hydroxyamphetamine. PubChem Compound Database. United States National Library of Medicine – National Center for Biotechnology Information. Retrieved15 October 2013.
^"Compound Summary".p-Hydroxynorephedrine. PubChem Compound Database. United States National Library of Medicine – National Center for Biotechnology Information. Retrieved15 October 2013.
^"Compound Summary".Phenylpropanolamine. PubChem Compound Database. United States National Library of Medicine – National Center for Biotechnology Information. Retrieved15 October 2013.
^"Pharmacology and Biochemistry".Amphetamine. Pubchem Compound Database. United States National Library of Medicine – National Center for Biotechnology Information. Retrieved12 October 2013.
^abGlennon RA (2013)."Phenylisopropylamine stimulants: amphetamine-related agents". In Lemke TL, Williams DA, Roche VF, Zito W (eds.).Foye's principles of medicinal chemistry (7th ed.). Philadelphia, US: Wolters Kluwer Health/Lippincott Williams & Wilkins. pp. 646–648.ISBN9781609133450.The simplest unsubstituted phenylisopropylamine, 1-phenyl-2-aminopropane, or amphetamine, serves as a common structural template for hallucinogens and psychostimulants. Amphetamine produces central stimulant, anorectic, and sympathomimetic actions, and it is the prototype member of this class (39). ... The phase 1 metabolism of amphetamine analogs is catalyzed by two systems: cytochrome P450 and flavin monooxygenase. ... Amphetamine can also undergo aromatic hydroxylation top-hydroxyamphetamine. ... Subsequent oxidation at the benzylic position by DA β-hydroxylase affordsp-hydroxynorephedrine. Alternatively, direct oxidation of amphetamine by DA β-hydroxylase can afford norephedrine.
^Cashman JR, Xiong YN, Xu L, Janowsky A (March 1999). "N-oxygenation of amphetamine and methamphetamine by the human flavin-containing monooxygenase (form 3): role in bioactivation and detoxication".Journal of Pharmacology and Experimental Therapeutics.288 (3):1251–1260.PMID10027866.
^abcSjoerdsma A, von Studnitz W (April 1963)."Dopamine-beta-oxidase activity in man, using hydroxyamphetamine as substrate".British Journal of Pharmacology and Chemotherapy.20 (2):278–284.doi:10.1111/j.1476-5381.1963.tb01467.x.PMC1703637.PMID13977820.Hydroxyamphetamine was administered orally to five human subjects ... Since conversion of hydroxyamphetamine to hydroxynorephedrine occurs in vitro by the action of dopamine-β-oxidase, a simple method is suggested for measuring the activity of this enzyme and the effect of its inhibitors in man. ... The lack of effect of administration of neomycin to one patient indicates that the hydroxylation occurs in body tissues. ... a major portion of the β-hydroxylation of hydroxyamphetamine occurs in non-adrenal tissue. Unfortunately, at the present time one cannot be completely certain that the hydroxylation of hydroxyamphetamine in vivo is accomplished by the same enzyme which converts dopamine to noradrenaline.
^abBadenhorst CP, van der Sluis R, Erasmus E, van Dijk AA (September 2013). "Glycine conjugation: importance in metabolism, the role of glycine N-acyltransferase, and factors that influence interindividual variation".Expert Opinion on Drug Metabolism & Toxicology.9 (9):1139–1153.doi:10.1517/17425255.2013.796929.PMID23650932.S2CID23738007.Figure 1. Glycine conjugation of benzoic acid. The glycine conjugation pathway consists of two steps. First benzoate is ligated to CoASH to form the high-energy benzoyl-CoA thioester. This reaction is catalyzed by the HXM-A and HXM-B medium-chain acid:CoA ligases and requires energy in the form of ATP. ... The benzoyl-CoA is then conjugated to glycine by GLYAT to form hippuric acid, releasing CoASH. In addition to the factors listed in the boxes, the levels of ATP, CoASH, and glycine may influence the overall rate of the glycine conjugation pathway.
^Horwitz D, Alexander RW, Lovenberg W, Keiser HR (May 1973). "Human serum dopamine-β-hydroxylase. Relationship to hypertension and sympathetic activity".Circulation Research.32 (5):594–599.doi:10.1161/01.RES.32.5.594.PMID4713201.S2CID28641000.The biologic significance of the different levels of serum DβH activity was studied in two ways. First, in vivo ability to β-hydroxylate the synthetic substrate hydroxyamphetamine was compared in two subjects with low serum DβH activity and two subjects with average activity. ... In one study, hydroxyamphetamine (Paredrine), a synthetic substrate for DβH, was administered to subjects with either low or average levels of serum DβH activity. The percent of the drug hydroxylated to hydroxynorephedrine was comparable in all subjects (6.5-9.62) (Table 3).
^Freeman JJ, Sulser F (December 1974). "Formation of p-hydroxynorephedrine in brain following intraventricular administration of p-hydroxyamphetamine".Neuropharmacology.13 (12):1187–1190.doi:10.1016/0028-3908(74)90069-0.PMID4457764.In species where aromatic hydroxylation of amphetamine is the major metabolic pathway,p-hydroxyamphetamine (POH) andp-hydroxynorephedrine (PHN) may contribute to the pharmacological profile of the parent drug. ... The location of thep-hydroxylation and β-hydroxylation reactions is important in species where aromatic hydroxylation of amphetamine is the predominant pathway of metabolism. Following systemic administration of amphetamine to rats, POH has been found in urine and in plasma. The observed lack of a significant accumulation of PHN in brain following the intraventricular administration of (+)-amphetamine and the formation of appreciable amounts of PHN from (+)-POH in brain tissue in vivo supports the view that the aromatic hydroxylation of amphetamine following its systemic administration occurs predominantly in the periphery, and that POH is then transported through the blood-brain barrier, taken up by noradrenergic neurones in brain where (+)-POH is converted in the storage vesicles by dopamine β-hydroxylase to PHN.
^Matsuda LA, Hanson GR, Gibb JW (December 1989). "Neurochemical effects of amphetamine metabolites on central dopaminergic and serotonergic systems".Journal of Pharmacology and Experimental Therapeutics.251 (3):901–908.PMID2600821.The metabolism ofp-OHA top-OHNor is well documented and dopamine-β hydroxylase present in noradrenergic neurons could easily convertp-OHA top-OHNor after intraventricular administration.
^Emonson DL, Vanderbeek RD (1995). "The use of amphetamines in U.S. Air Force tactical operations during Desert Shield and Storm".Aviation, Space, and Environmental Medicine.66 (3):260–3.PMID7661838.
^"Dexamfetamine – Prescribe Generically"(PDF).Red/Amber News (22). Interface Pharmacist Network Specialist Medicines (IPNSM): 2. November 2010. Archived fromthe original(PDF) on 18 May 2013. Retrieved20 April 2012.
^Hutson PH, Pennick M, Secker R (December 2014). "Preclinical pharmacokinetics, pharmacology and toxicology of lisdexamfetamine: a novel d-amphetamine pro-drug".Neuropharmacology.87:41–50.doi:10.1016/j.neuropharm.2014.02.014.PMID24594478.S2CID37893582.
^Heal DJ, Buckley NW, Gosden J, Slater N, France CP, Hackett D (October 2013). "A preclinical evaluation of the discriminative and reinforcing properties of lisdexamfetamine in comparison to D-amfetamine, methylphenidate and modafinil".Neuropharmacology.73:348–358.doi:10.1016/j.neuropharm.2013.05.021.PMID23748096.S2CID25343254.
^Rowley HL, Kulkarni R, Gosden J, Brammer R, Hackett D, Heal DJ (November 2012). "Lisdexamfetamine and immediate release d-amfetamine - differences in pharmacokinetic/pharmacodynamic relationships revealed by striatal microdialysis in freely-moving rats with simultaneous determination of plasma drug concentrations and locomotor activity".Neuropharmacology.63 (6):1064–1074.doi:10.1016/j.neuropharm.2012.07.008.PMID22796358.S2CID29702399.
^Lindenmayer JP, Nasrallah H, Pucci M, James S, Citrome L (July 2013). "A systematic review of psychostimulant treatment of negative symptoms of schizophrenia: challenges and therapeutic opportunities".Schizophrenia Research.147 (2–3):241–252.doi:10.1016/j.schres.2013.03.019.PMID23619055.
"PIM 178: Dexamphetamine Sulphate)".Poison Information Monograph. International Programme on Chemical Safety (IPCS) Chemical Safety Information from Intergovernmental organizations (INCHEM).
Notes: (1) TAAR1 activity of ligands varies significantly between species. Some agents that are TAAR1 ligands in some species are not in other species. This navbox includes all TAAR1 ligands regardless of species. (2) See the individual pages for references, as well as theList of trace amines,TAAR, andTAAR1 pages.See also:Receptor/signaling modulators
