Editing Amphetamine (section)

=====ADHD=====
Long-term amphetamine exposure at sufficiently high doses in some animal species is known to produce abnormal [[Dopamine receptor|dopamine system]] development or nerve damage,<ref name="pmid22392347">{{cite journal |vauthors=Carvalho M, Carmo H, Costa VM, Capela JP, Pontes H, Remião F, Carvalho F, Bastos Mde L |title=Toxicity of amphetamines: an update |journal=Archives of Toxicology|volume=86 |issue=8 |pages=1167–1231 |date=August 2012 |pmid=22392347 |doi=10.1007/s00204-012-0815-5|bibcode=2012ArTox..86.1167C |s2cid=2873101 }}</ref><ref name="AbuseAndAbnormalities">{{cite journal|vauthors=Berman S, O'Neill J, Fears S, Bartzokis G, London ED | title=Abuse of amphetamines and structural abnormalities in the brain | journal=Annals of the New York Academy of Sciences| date = October 2008 | volume= 1141 | issue=1 | pages= 195–220 | pmid=18991959 | doi=10.1196/annals.1441.031 | pmc=2769923 | bibcode=<!-- No --> }}</ref> but, in humans with ADHD, long-term use of pharmaceutical amphetamines at therapeutic doses appears to improve brain development and nerve growth.<ref name="Neuroplasticity 1">{{cite journal |vauthors=Hart H, Radua J, Nakao T, Mataix-Cols D, Rubia K |title=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 |journal=JAMA Psychiatry|volume=70 |issue=2 |pages=185–198 |date=February 2013 |pmid=23247506 |doi=10.1001/jamapsychiatry.2013.277|doi-access=free | title-link = doi }}</ref><ref name="Neuroplasticity 2">{{cite journal |vauthors=Spencer TJ, Brown A, Seidman LJ, Valera EM, Makris N, Lomedico A, Faraone SV, Biederman J |title=Effect of psychostimulants on brain structure and function in ADHD: a qualitative literature review of magnetic resonance imaging-based neuroimaging studies |journal=The Journal of Clinical Psychiatry|volume=74 |issue=9 |pages=902–917 |date=September 2013 |pmid=24107764 |doi=10.4088/JCP.12r08287 |pmc=3801446}}</ref><ref name="Neuroplasticity 3">{{cite journal | title=Meta-analysis of structural MRI studies in children and adults with attention deficit hyperactivity disorder indicates treatment effects | journal=Acta Psychiatrica Scandinavica| date=February 2012 | volume=125 | issue=2 | pages=114–126 | pmid=22118249 |vauthors=Frodl T, Skokauskas N | quote = 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. | doi=10.1111/j.1600-0447.2011.01786.x| s2cid=25954331| doi-access=free | title-link = doi }}</ref> Reviews of [[magnetic resonance imaging]] (MRI) studies suggest that long-term treatment with amphetamine decreases abnormalities in brain structure and function found in subjects with ADHD, and improves function in several parts of the brain, such as the right [[caudate nucleus]] of the [[basal ganglia]].<ref name="Neuroplasticity 1" /><ref name="Neuroplasticity 2" /><ref name="Neuroplasticity 3" />

Reviews of clinical stimulant research have established the safety and effectiveness of long-term continuous amphetamine use for the treatment of ADHD.<ref name="Long-Term Outcomes Medications">{{cite journal |vauthors=Huang YS, Tsai MH | title = Long-term outcomes with medications for attention-deficit hyperactivity disorder: current status of knowledge | journal =CNS Drugs| volume = 25 | issue = 7 | pages = 539–554 |date=July 2011 | pmid = 21699268 | doi = 10.2165/11589380-000000000-00000 | s2cid = 3449435 | quote = Several other studies,<sup>[97-101]</sup> including a meta-analytic review<sup>[98]</sup> and a retrospective study,<sup>[97]</sup> suggested that stimulant therapy in childhood is associated with a reduced risk of subsequent substance use, cigarette smoking and alcohol use disorders.&nbsp;... Recent studies have demonstrated that stimulants, along with the non-stimulants atomoxetine and extended-release guanfacine, are continuously effective for more than 2-year treatment periods with few and tolerable adverse effects. The effectiveness of long-term therapy includes not only the core symptoms of ADHD, but also improved [[quality of life]] and academic achievements. The most concerning short-term adverse effects of stimulants, such as elevated blood pressure and heart rate, waned in long-term follow-up studies.&nbsp;... 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&nbsp;years), lifetime stimulant treatment for ADHD was effective and protective against the development of adverse psychiatric disorders.}}</ref><ref name="Millichap" /><ref name="Long-term 2015">{{cite journal | vauthors = Arnold LE, Hodgkins P, Caci H, Kahle J, Young S | title = Effect of treatment modality on long-term outcomes in attention-deficit/hyperactivity disorder: a systematic review | journal =PLOS ONE| volume = 10 | issue = 2 | pages = e0116407 | date = February 2015 | pmid = 25714373 | pmc = 4340791 | doi = 10.1371/journal.pone.0116407 | quote = The highest proportion of improved outcomes was reported with combination treatment (83% of outcomes). Among significantly improved outcomes, the largest effect sizes were found for combination treatment. The greatest improvements were associated with academic, self-esteem, or social function outcomes.| bibcode = <!-- No --> | doi-access = free | title-link = doi }}<br />[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4340791/figure/pone.0116407.g003/ Figure 3: Treatment benefit by treatment type and outcome group]</ref> [[Randomized controlled trial]]s of continuous stimulant therapy for the treatment of ADHD spanning 2&nbsp;years have demonstrated treatment effectiveness and safety.<ref name="Long-Term Outcomes Medications" /><ref name="Millichap" /> Two reviews have indicated that long-term continuous stimulant therapy for ADHD is effective for reducing the core symptoms of ADHD (i.e., hyperactivity, inattention, and impulsivity), enhancing [[quality of life]] and academic achievement, and producing improvements in a large number of functional outcomes{{#tag:ref|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).<ref name="Long-term 2015" /><br /><br />The largest [[effect size]]s 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).<ref name="Long-term 2015" /><br /><br />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.<ref name="Long-term 2015" /> 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.<ref>{{cite journal | vauthors = Sibley MH, Flores S, Murphy M, Basu H, Stein MA, Evans SW, Zhao X, Manzano M, van Dreel S | title = Research Review: Pharmacological and non-pharmacological treatments for adolescents with attention deficit/hyperactivity disorder - a systematic review of the literature | journal = Journal of Child Psychology and Psychiatry, and Allied Disciplines | volume = 66 | issue = 1 | pages = 132–149 | date = January 2025 | pmid = 39370392 | doi = 10.1111/jcpp.14056 | quote = 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&nbsp;...<br />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). }}</ref>|group="note"}} across 9&nbsp;categories of outcomes related to academics, [[Anti-social behaviour|antisocial behavior]], driving, non-medicinal drug use, obesity, occupation, [[self-esteem]], service use (i.e., academic, occupational, health, financial, and legal services), and social function.<ref name="Long-Term Outcomes Medications" /><ref name="Long-term 2015" /> Additionally, a 2024 [[Meta-analysis|meta-analytic]] [[systematic review]] reported moderate improvements in quality of life when amphetamine treatment is used for ADHD.<ref name="2024 QOL meta-analysis">{{Cite journal |vauthors=Bellato A, Perrott NJ, Marzulli L, Parlatini V, Coghill D, Cortese S |date=30 May 2024 |title=Systematic Review and Meta-Analysis: Effects of Pharmacological Treatment for Attention-Deficit/Hyperactivity Disorder on Quality of Life |journal=Journal of the American Academy of Child and Adolescent Psychiatry |pages=S0890–8567(24)00304–6 |doi=10.1016/j.jaac.2024.05.023 |pmid=38823477 |quote=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.&nbsp;...<br /> 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. |doi-access=free | title-link = doi |volume=64 |issue=3 |hdl=11586/524122 |hdl-access=free }}</ref> One review highlighted a nine-month randomized controlled trial of amphetamine treatment for ADHD in children that found an average increase of 4.5&nbsp;[[intelligence quotient|IQ]] points, continued increases in attention, and continued decreases in disruptive behaviors and hyperactivity.<ref name="Millichap">{{cite book | vauthors = Millichap JG | veditors = Millichap JG | title = Attention Deficit Hyperactivity Disorder Handbook: A Physician's Guide to ADHD | year = 2010 | publisher = Springer | location = New York, US | isbn = 9781441913968 | pages = 121–123, 125–127 | edition = 2nd | chapter = Chapter 9: Medications for ADHD | quote = 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.}}</ref> Another review indicated that, based upon the longest [[Prospective cohort study|follow-up studies]] conducted to date, lifetime stimulant therapy that begins during childhood is continuously effective for controlling ADHD symptoms and reduces the risk of developing a [[substance use disorder]] as an adult.<ref name="Long-Term Outcomes Medications" /> 

Models of ADHD suggest that it is associated with functional impairments in some of the brain's [[neurotransmitter systems]];<ref name="Malenka_2009_03" /> these functional impairments involve impaired [[dopamine]] neurotransmission in the [[mesocorticolimbic projection]] and [[norepinephrine]] neurotransmission in the noradrenergic projections from the [[locus coeruleus]] to the [[prefrontal cortex]].<ref name="Malenka_2009_03" /> Stimulants like [[methylphenidate]] and amphetamine are effective in treating ADHD because they increase neurotransmitter activity in these systems.<ref name="Malenka_2009" /><ref name="Malenka_2009_03">{{cite book |vauthors=Malenka RC, Nestler EJ, Hyman SE |veditors=Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York, US | isbn = 9780071481274 | pages = 154–157 | edition = 2nd | chapter = Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin }}</ref><ref name="cognition enhancers">{{cite journal |vauthors=Bidwell LC, McClernon FJ, Kollins SH | title = Cognitive enhancers for the treatment of ADHD | journal =Pharmacology Biochemistry and Behavior| volume = 99 | issue = 2 | pages = 262–274 |date=August 2011 | pmid = 21596055 | pmc = 3353150 | doi = 10.1016/j.pbb.2011.05.002 }}</ref> Approximately 80% of those who use these stimulants see improvements in ADHD symptoms.<ref name="Long-term 36">{{cite journal | vauthors = Parker J, Wales G, Chalhoub N, Harpin V | title = The long-term outcomes of interventions for the management of attention-deficit hyperactivity disorder in children and adolescents: a systematic review of randomized controlled trials | journal =Psychology Research and Behavior Management| volume = 6 | pages = 87–99 | date = September 2013 | pmid = 24082796 | pmc = 3785407 | doi = 10.2147/PRBM.S49114 | quote = Only one paper<sup>53</sup> examining outcomes beyond 36 months met the review criteria.&nbsp;... There is high level evidence suggesting that pharmacological treatment can have a major beneficial effect on the core symptoms of ADHD (hyperactivity, inattention, and impulsivity) in approximately 80% of cases compared with placebo controls, in the short term. | doi-access = free | title-link = doi }}</ref> 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.<ref name="Millichap_3">{{cite book | vauthors = Millichap JG | veditors = Millichap JG | title = Attention Deficit Hyperactivity Disorder Handbook: A Physician's Guide to ADHD | year = 2010 | publisher = Springer | location = New York, US | isbn = 9781441913968 | pages = 111–113 | edition = 2nd | chapter = Chapter 9: Medications for ADHD}}</ref><ref name="ADHD">{{cite web | title=Stimulants for Attention Deficit Hyperactivity Disorder | url=http://www.webmd.com/add-adhd/childhood-adhd/stimulants-for-attention-deficit-hyperactivity-disorder | website = WebMD | publisher = Healthwise | date = 12 April 2010 | access-date=12 November 2013 }}</ref> The [[Cochrane (organisation)|Cochrane]] reviews{{#tag:ref|Cochrane reviews are high quality meta-analytic systematic reviews of randomized controlled trials.<ref name="pmid16052183">{{cite journal |vauthors=Scholten RJ, Clarke M, Hetherington J |title=The Cochrane Collaboration |journal=European Journal of Clinical Nutrition|volume=59 |issue=Suppl 1 |pages=S147–S149; discussion S195–S196 |date=August 2005 |pmid=16052183 |doi=10.1038/sj.ejcn.1602188|s2cid=29410060 |doi-access=free | title-link = doi }}</ref>| group = "note" }} on the treatment of ADHD in children, adolescents, and adults with pharmaceutical amphetamines stated that short-term studies have demonstrated that these drugs decrease the severity of symptoms, but they have higher discontinuation rates than non-stimulant medications due to their adverse [[side effect]]s.<ref name="Cochrane Amphetamines ADHD">{{cite journal | vauthors = Castells X, Blanco-Silvente L, Cunill R | title = Amphetamines for attention deficit hyperactivity disorder (ADHD) in adults | journal =Cochrane Database of Systematic Reviews| volume = 2018 | pages = CD007813 | date = August 2018 | issue = 8 | pmid = 30091808 | doi = 10.1002/14651858.CD007813.pub3 | pmc = 6513464 }}</ref><ref name="pmid26844979">{{cite journal | vauthors = Punja S, Shamseer L, Hartling L, Urichuk L, Vandermeer B, Nikles J, Vohra S | title = Amphetamines for attention deficit hyperactivity disorder (ADHD) in children and adolescents | journal =Cochrane Database of Systematic Reviews| volume = 2016 | pages = CD009996 | date = February 2016 | issue = 2 | pmid = 26844979 | doi = 10.1002/14651858.CD009996.pub2| pmc = 10329868 }}</ref> However, a 2025 meta-analytic systematic review of 113 randomized controlled trials found that stimulant medications were the only intervention with robust short-term efficacy, and were associated with lower all-cause treatment [[discontinuation]] rates than non-stimulant medications (e.g., [[atomoxetine]]).{{#tag:ref|In contrast to the Cochrane reviews that observed higher treatment discontinuation from adverse effects alone, this figure represents '''any cause''' of discontinuation (e.g., insufficient perceived treatment benefit).<ref name="2025_113_RCTs" /> |name="all-cause discontinuation"|group="note"}}<ref name="2025_113_RCTs">{{Cite journal |vauthors=Ostinelli EG, Schulze M, Zangani C, Farhat LC, Tomlinson A, Del Giovane C, Chamberlain SR, Philipsen A, Young S, Cowen PJ, Bilbow A, Cipriani A, Cortese S |year=2025 |title=Comparative efficacy and acceptability of pharmacological, psychological, and neurostimulatory interventions for ADHD in adults: a systematic review and component network meta-analysis |journal=The Lancet. Psychiatry |volume=12 |issue=1 |pages=32–43 |doi=10.1016/S2215-0366(24)00360-2 |pmid=39701638 |quote=Our findings were based on 113 RCTs, including 14 887 participants, and indicated that stimulants were the only intervention that was supported by evidence of efficacy in the short term (ie, at timepoints closest to 12 weeks) for core symptoms of ADHD in adults (both self-reported and clinician-reported) and was associated with good acceptability (all-cause discontinuation). |doi-access=free |title-link=doi}}</ref> A Cochrane review on the treatment of ADHD in children with [[tic disorder]]s such as [[Tourette syndrome]] indicated that stimulants in general do not make [[tic]]s worse, but high doses of dextroamphetamine could exacerbate tics in some individuals.<ref name="pmid29944175">{{cite journal | vauthors = Osland ST, Steeves TD, Pringsheim T | title = Pharmacological treatment for attention deficit hyperactivity disorder (ADHD) in children with comorbid tic disorders | journal =Cochrane Database of Systematic Reviews| volume = 2018 | pages = CD007990 | date = June 2018 | issue = 6 | pmid = 29944175 | pmc = 6513283 | doi = 10.1002/14651858.CD007990.pub3 }}</ref>
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