Editing Amphetamine (section)

=====Narcolepsy=====
Narcolepsy is a chronic sleep-wake disorder that is associated with excessive daytime sleepiness, [[cataplexy]], and [[sleep paralysis]].<ref name="Autoimmune basis review">{{cite journal | vauthors = Mahlios J, De la Herrán-Arita AK, Mignot E | title = The autoimmune basis of narcolepsy | journal = Current Opinion in Neurobiology | volume = 23 | issue = 5 | pages = 767–773 | date = October 2013 | pmid = 23725858 | pmc = 3848424 | doi = 10.1016/j.conb.2013.04.013 }}</ref> Patients with narcolepsy are diagnosed as either type 1 or type 2, with only the former presenting cataplexy symptoms.<ref name="Barateau_2022">{{cite journal |vauthors=Barateau L, Pizza F, Plazzi G, Dauvilliers Y |date=August 2022 |title=Narcolepsy |journal=Journal of Sleep Research |volume=31 |issue=4 |pages=e13631 |doi=10.1111/jsr.13631 |pmid=35624073 |quote=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).&nbsp;... A low level of Hcrt-1 in the CSF is very sensitive and specific for the diagnosis of NT1.&nbsp;...<br /> 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).&nbsp;...<br /> 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.}}</ref> Type 1 narcolepsy results from the loss of approximately 70,000 [[orexin]]-releasing neurons in the [[lateral hypothalamus]], leading to significantly reduced [[Cerebrospinal fluid|cerebrospinal]] orexin levels;<ref name="Narcolepsy guide">{{cite journal |vauthors=Mignot EJ |date=October 2012 |title=A practical guide to the therapy of narcolepsy and hypersomnia syndromes |journal=Neurotherapeutics |volume=9 |issue=4 |pages=739–752 |doi=10.1007/s13311-012-0150-9 |pmc=3480574 |pmid=23065655 |quote=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.&nbsp;...<br /> 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.&nbsp;...<br /> 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.&nbsp;...<br /> Numerous studies have shown that increased dopamine release is the main property explaining wake-promotion, although norepinephrine effects also contribute.}}</ref><ref name="Malenka_2015b">{{Cite book |title=Molecular Neuropharmacology: A Foundation for Clinical Neuroscience |vauthors=Malenka RC, Nestler EJ, Hyman SE, Holtzman DM |publisher=McGraw-Hill Medical |year=2015 |isbn=9780071827706 |edition=3rd |location=New York |pages=456–457 |chapter=Chapter 10: Neural and Neuroendocrine Control of the Internal Milieu |quote=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).}}</ref> this reduction is a [[Biomarker (medicine)|diagnostic biomarker]] for type 1 narcolepsy.<ref name="Barateau_2022" /> Lateral hypothalamic orexin neurons innervate every component of the [[ascending reticular activating system]] (ARAS), which includes [[Norepinephrine|noradrenergic]], [[dopamine]]rgic, [[histamine]]rgic, and [[Serotonin|serotonergic]] nuclei that promote [[wakefulness]].<ref name="Malenka_2015b" /><ref name="Malenka_2015a">{{Cite book |title=Molecular Neuropharmacology: A Foundation for Clinical Neuroscience |vauthors=Malenka RC, Nestler EJ, Hyman SE, Holtzman DM |publisher=McGraw-Hill Medical |year=2015 |isbn=9780071827706 |edition=3rd |pages=521 |chapter=Chapter 13: Sleep and Arousal |quote=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.}}</ref>

Amphetamine’s therapeutic mode of action in narcolepsy primarily involves increasing [[Monoamine neurotransmitter|monoamine]] neurotransmitter activity in the ARAS.<ref name="Narcolepsy guide" /><ref name="Amphetamine ARAS textbook">{{cite book |url=https://books.google.com/books?id=kWxWEdqvue4C&pg=PA81 |title=Sleep medicine a guide to sleep and its disorders |vauthors=Shneerson JM |date=2009 |publisher=John Wiley & Sons |isbn=9781405178518 |edition=2nd |page=81 |quote=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.}}</ref><ref name="Narcolepsy - Amphetamine and the ARAS" /> This includes noradrenergic neurons in the [[locus coeruleus]], dopaminergic neurons in the [[ventral tegmental area]], histaminergic neurons in the [[tuberomammillary nucleus]], and serotonergic neurons in the [[dorsal raphe nucleus]].<ref name="Malenka_2015a" /><ref name="Narcolepsy - Amphetamine and the ARAS">{{cite journal |vauthors=Schwartz JR, Roth T |year=2008 |title=Neurophysiology of sleep and wakefulness: basic science and clinical implications |journal=Current Neuropharmacology |volume=6 |issue=4 |pages=367–378 |doi=10.2174/157015908787386050 |pmc=2701283 |pmid=19587857 |quote=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.&nbsp;...<br /> 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.&nbsp;...<br /> 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.&nbsp;...<br />Sympathomimetic drugs have long been used to treat narcolepsy}}</ref> Dextroamphetamine, the more dopaminergic enantiomer of amphetamine, is particularly effective at promoting wakefulness because dopamine release has the greatest influence on cortical activation and cognitive arousal, relative to other monoamines.<ref name="Narcolepsy guide" /> In contrast, levoamphetamine may have a greater effect on cataplexy, a symptom more sensitive to the effects of norepinephrine and serotonin.<ref name="Narcolepsy guide" /> Noradrenergic and serotonergic nuclei in the ARAS are involved in the regulation of the [[Rapid eye movement sleep|REM]] sleep cycle and function as "REM-off" cells, with amphetamine's effect on norepinephrine and serotonin contributing to the suppression of REM sleep and a possible reduction of cataplexy at high doses.<ref name="Narcolepsy guide" /><ref name="Barateau_2022" /><ref name="Malenka_2015a" />

The [[American Academy of Sleep Medicine]] (AASM) 2021 [[clinical practice guideline]] conditionally recommends dextroamphetamine for the treatment of both type 1 and type 2 narcolepsy.<ref name="narcolepsy efficacy">{{cite journal | vauthors = Maski K, Trotti LM, Kotagal S, Robert Auger R, Rowley JA, Hashmi SD, Watson NF | title = Treatment of central disorders of hypersomnolence: an American Academy of Sleep Medicine clinical practice guideline | journal = Journal of Clinical Sleep Medicine | volume = 17 | issue = 9 | pages = 1881–1893 | date = September 2021 | pmid = 34743789 | pmc = 8636351 | doi = 10.5664/jcsm.9328 | quote = The TF identified 1 double-blind RCT, 1 single-blind RCT, and 1 retrospective observational long-term self-reported case series assessing the efficacy of dextroamphetamine in patients with narcolepsy type 1 and narcolepsy type 2. These studies demonstrated clinically significant improvements in excessive daytime sleepiness and cataplexy. }}</ref> Treatment with pharmaceutical amphetamines is generally less preferred relative to other stimulants (e.g., [[modafinil]]) and is considered a [[Therapy#Lines of therapy|third-line treatment]] option.<ref name="narcolepsy addiction">{{cite journal |vauthors=Barateau L, Lopez R, Dauvilliers Y |date=October 2016 |title=Management of Narcolepsy |journal=Current Treatment Options in Neurology |volume=18 |issue=10 |pages=43 |doi=10.1007/s11940-016-0429-y |pmid=27549768 |quote=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.&nbsp;...<br /> Despite the potential for drug abuse or tolerance using stimulants, patients with narcolepsy rarely exhibit addiction to their medication.&nbsp;...<br /> Some stimulants, such as mazindol, amphetamines, and pitolisant, may also have some anticataplectic effects.}}</ref><ref>{{cite journal | vauthors = Dauvilliers Y, Barateau L | title = Narcolepsy and Other Central Hypersomnias | journal = Continuum | volume = 23 | issue = 4, Sleep Neurology | pages = 989–1004 | date = August 2017 | pmid = 28777172 | doi = 10.1212/CON.0000000000000492 | quote = 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. }}</ref><ref>{{cite journal | vauthors = Thorpy MJ, Bogan RK | title = Update on the pharmacologic management of narcolepsy: mechanisms of action and clinical implications | journal = Sleep Medicine | volume = 68 | pages = 97–109 | date = April 2020 | pmid = 32032921 | doi = 10.1016/j.sleep.2019.09.001 | quote = 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) }}</ref> Medical reviews indicate that amphetamine is safe and effective for the treatment of narcolepsy.<ref name="Narcolepsy guide" /><ref name="narcolepsy addiction" /><ref name="narcolepsy efficacy" /> Amphetamine appears to be most effective at improving symptoms associated with [[Excessive daytime sleepiness|hypersomnolence]], with three reviews finding clinically significant reductions in [[Somnolence|daytime sleepiness]] in patients with narcolepsy.<ref name="Narcolepsy guide" /><ref name="narcolepsy addiction" /><ref name="narcolepsy efficacy" /> Additionally, these reviews suggest that amphetamine may dose-dependently improve cataplexy symptoms.<ref name="Narcolepsy guide" /><ref name="narcolepsy addiction" /><ref name="narcolepsy efficacy" /> However, the quality of evidence for these findings is low and is consequently reflected in the AASM's conditional recommendation for dextroamphetamine as a treatment option for narcolepsy.<ref name="narcolepsy efficacy" />
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<!-- ====Obesity====
Topics to cover:

Amphetamine's MoA in the periphery:
* cover amphetamine-triggered induction of lipolysis via peripheral (nor-)adrenergic signaling in adipose fat cells which induces the release of triglycerides into blood plasma
* cover amphetamine-induced TAAR1 signaling in peripheral organs (i.e., cover "File:TAAR1 organ-specific expression and function.jpg" in the context of amphetamine's MoA for treating obesity), provided that I can find a review mentioning amphetamine+TAAR1+obesity at some point

Amphetamine's MoA in the CNS:
* indicate that every monoamine neurotransmitter is involved in energy homeostasis, specify how, and mention which DA/NE-ergic projections are involved [cite PMID 22547886 and the refs I added to the "energy homeostasis" article]
** cover the systems neurobiology of monoaminergic regulation of feeding behavior
* amphetamine-induced hypothalamic CART induction probably plays some role in the mechanism of action, but would need to find a source once its GPCR has been IDed
**quotes on CART's physiological/cognitive effects: "CART promotes physical activity and wakefulness" [PMID 22547886] and markedly inhibits hunger [pubchem amphetamine entry] (pubchem quote: "this anorectic peptide inhibits both normal and starvation-induced feeding and completely blocks the feeding response induced by neuropeptide Y and regulated by leptin in the hypothalamus")
:Note: PMID 22547886 contains material relevant to both narcolepsy and obesity as well as covers CART; doesn't mention amphetamine though

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