User:Box73/sandbox

The restaurant was closed by January 2000.

3212 La Crescenta Ave, Glendale, CA 91208

Schenley Tunnel working refs
Ready for work: The last rail placed on the Junction Railroad

Wanted — 20 brickmasons

Work on the Junction Tunnel

Capital and labor notes

Death takes noted capitalist

The great short cut: Finishing touches to the Junction Road

Jaunt on the Junction: The connecting link of two great roads informally opened

The Marginal Scheme: Full text of the new bill

The Marginal Road: An afternoon spent at making ammendments

Local lawmakers: The Union Railway ordinance passed finally

Some prospect of fun: A lively contest likely to-day in select council: Over the Junction Railroad Bill—An indignation meeting—The Mayor's veto in full

The Marginal Scheme: How the projectors were fooled on Thursday: Indignation among the Baltimore, Pittsburgh and Chicago railroad people

Rebuked: The Marginal Scheme gets a black eye in select council: The ordinance rejected on first reading: But one vote needed for the utter defeat of the scheme

Still searching: Fourth session of the councilmanix investigating committee: Peter McGee testifies to offers of marginal stoc and money but declines to name the briber

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frisch's

copyedit of Frisch's early history
In 1905, Samuel Frisch opened the Frisch Cafe in Cincinnati, Ohio. Five years later he closed the café and moved to the Norwood suburb of Cincinnati eventually opening another small café there. In 1915 he built and opened Frisch's Stag Lunch. By the early 1920s, the successful restaurant moved to a larger structure and his sons, David, Reuben and Irving joined the business. When Sameul Frisch died in 1923, twenty year-old David assumed the leadership role.

In 1932 Dave Frisch sold his interest in Stag Lunch and opened his own Frisch's Café in Norwood. The café was a success, and in 1938 Frisch opened a second location. —the effects of the Great Depression led to bankruptcy and both units closed in 1938. A local businessman, Fred Cornuelle, counselled Frisch and a new restaurant and in 1939 the Mainliner opened on Wooster Pike in Fairfax. Cincinnati's first year-round drive-in, it was named after a passenger airplane flying overhead into nearby Lunken Airport. By 1944 a second Frisch's restaurant opened, designed to resemble George Washington's Mount Vernon home.

Current Franchising Costs
Big Boy Restaurants International and Frisch's Big Boy Restaurants both continue to franchises in their exclusive territories, both using 20 year terms. As of 2014 Big Boy Restaurants International charges a $40,000 franchise fee, and an ongoing 4% royalty and up to 3% advertising fees based on weekly gross revenue. (In most of Michigan the franchisee pays a 2% advertising fee and must spend an additional 1% on local advertising. Franchisees in the upper peninsula of Michigan or outside of Michigan pays a 0.5% advertising fee and must spend 1.5% on local advertising.) As of 2015 Frisch's Big Boy charges a $30,000 franchise fee, and an ongoing 3.75% royalty and 2.5% advertising fees. The majority of Big Boy Restaurant International units are franchised while the majority of Frisch's units are currently company owned. Big Boy Restaurants International franchise agreements are not renewable but new agreements are required.

In most of Michigan the franchisee pays a 2% advertising fee and must spend an additional 1% on local advertising. Franchisees in the upper peninsula of Michigan or outside of Michigan pays a 0.5% advertising fee and must spend 1.5% on local advertising.
 * Schoenbaum Hall (Ohio State)
 * Schoenbaum Library (University of Charleston)
 * Schoenbaum Family Enrichment Center (Charleston, WV)
 * Schoenbaum Family Enrichment Center (Charleston, WV)

a  b     c    d    e     f

Chewing betel quid—a mixture of a mixture of betel nut (nuts from the Areca catechu palm) with calcium hydoxide, and betel (leaves from the Piper betle vine)—produces stimulant effects and euphoria. Several psychoactive substances may contribute to the euphoriant effect: arecoline (a parasympathetic stimulant), arecaidine and guvacine (GABA uptake inhibitors), from the betel nuts, and aromatic phenolic compounds from betel leaves (causing adrenal epinephrine and norepinephrine release).

betel pepper leaves and areca nut with calcium hydoxide—produces stimulant effects and euphoria. The suspected euphoriants are arecoline (a parasympathetic stimulant), arecaidine and guvacine (GABA uptake inhibitors), and aromatic phenolic compounds from betel leaves (causing catecholamine release).

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Areca Nut
Chewing areca nut (seeds from the Areca catechu palm) with slaked lime (calcium hydroxide) produces stimulant effects and euphoria. The major psychoactive ingredients – arecoline (a muscarinic receptor partial agonist) and arecaidine (a GABA reuptake inhibitor) – are responsible for the euphoric effect.

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Arecaidine (a GABA uptake inhibitor and receptor antagonist) is a stimulant and mild euphoriant.

muscarinic parasympathetic stimulant

Euphoria has also been noted to occur in a very small percentage of individuals who used pregabalin in controlled trials as a treatment for neuropathic pain associated with diabetic peripheral neuropathy.

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Pregabalin
''Notes: The drug monograph reports euphoria for neuropathic pain but also fibromyalgia, and other studies do for other (or no) conditions, so neuropathic pain isn't necessary to mention. Controlled studies seem superfluous to mention.''

Pregabalin induces dose dependent euphoria. Occuring in a small percentage of individuals at recommended doses, euphoria is increasingly frequent at supratherapeutic doses (or with insufflation or intravenuous administration). At doses five times the maximum recommended, intense euphoria is reported.

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"ponent processes. Individual differences in the NAc's responses to monetary reward expectation explained the variance of pain modulation by way of placebo-induced analgesia. Rewards that are olfactory, gustatory, auditory, visual, and sexual produced an analgesic effect that involves the ventral striatum. However, paiory in outlining interfacing sensory and emotional pain components so that pain may be directly learned as a rewarding stimulus. For instance, pain of physical punishment may be the only sign of attention. Some pain may be an integral component of many pleasurable activities, be it sexual intercourse or consumption of a sizzling and spicy food. Conditioned cue-induced effects can also evoke pain symptomatology through backward n usually eclipses its opponent effect, namely, euphoria that only becomes noticeable with the conclusion of the proponent painful condition."https://en.wikipedia.org/wiki/User:Box73/sandbox2

"The pain-pleasure continuum is a key theconditioning. That is, euphoria of pain termination, particularly when combined with euphoria produced by an opioid analgesic, constitutes an intense teaching signal reinforcing more pain and pain behavior. Conversely, after repeated pairing, pain-related stress and negative affective states can grow into a conditioned stimulus eliciting future painful episodes.--"test cite ""3,4- m ethylene d ioxy-N- m ethyl a mphetamine

asdf Opioids are substances that act on opioid receptors to produce morphine-like effects. Opioids include, an older term that refers to such drugs derived from , including morphine itself. Other opioids are semi-synthetic and synthetic drugs such as hydrocodone, oxycodone and fentanyl; antagonist drugs such as naloxone and endogenous peptides such as the endorphins. Opioid drugs are predominantly central nervous system agents, most often used medically to relieve pain.

The side effects of opioids may include pruritus, sedation, nausea, respiratory depression, constipation, and euphoria. Tolerance and dependence will develop with continuous use, requiring increasing doses and leading to a withdrawal syndrome with abrupt discontinuation. The profound euphoria attracts recreational use; frequent and escalating recreational use of opioids typically results in addiction. Accidental overdose or concurrent use with other depressant drugs commonly results in death from respiratory depression. Because of opioid drugs' reputation for addiction and fatal overdose, most are highly controlled substances.

Primarily used for pain relief, including anesthesia, opioids are also approved to suppress cough, suppress diarrhea, treat addiction, reverse opioid overdose, and suppress opioid induced constipation,. Extremely potent opioids are used to immobilize large mammals. Opioids act by binding to opioid receptors, which are found principally in the central and peripheral nervous system and the gastrointestinal tract. These receptors mediate both the psychoactive and the somatic effects of opioids. Opioid drugs include partial agonists and antagonists, which produce moderate or no effect (respectively) but displace other opioids from binding in those receptors.

Opioids are among the world's oldest known drugs. The medical use of the opium poppy predates recorded history; recreational and religious use likewise precedes the common era. In the 19th century morphine was isolated and marketed, and the hypodermic needle invented, introducing rapid, metered administration of the primary active compound. Synthetic opioids were invented, and biological mechanisms discovered in the 20th century. Illicit production, smuggling, and addiction to opioids, prompted treaties, laws and policing which have realized limited success. In 2013 between 28 and 38 million people used opioids recreationally (0.6% to 0.8% of the global population between the ages of 15 and 65). In 2011 an estimated 4 million people the United States used opioids recreationally or were dependent on them. Current recreational use and addiction are attributed to over-prescription of opioid medications and inexpensive illicit heroin. Conversely, fears about over-prescribing, exaggerated side effects and addiction from opioids are similarly blamed for under-treatment of pain.

The terms and  are sometimes encountered as synonyms for opioid. is properly limited to the natural alkaloids found in the resin of the (opium poppy) although some authorities include semi-synthetic derivatives. , derived from or, is now a legal term that refers to cocaine and opioids, and their source materials; it is also loosely applied to any illegal or controlled psychoactive drug. The term has pejorative connotations and its use is generally discouraged.

Although the term is often used as a synonym for, the term {{opiate is properly limited to the natural alkaloids found in the resin of the Papaver somniferum (opium poppy), while opioid refers to both natural and synthetic compounds with an opium-like'' effect (by being agonists at the opioid receptor). i.e. all opiates are opioids, but not all opioids are opiates. Semi-synthetic opioids such as heroin, hydrocodone and oxycodone are sometimes classified as opiates. Because morphine does not act on all types of opioid receptors and these receptors produce different effects, opioids are now primarily defined by binding to opioid receptors rather than by morphine-like effects.

Opioid drugs include antagonists, inactive opioids that prevent other opioids from binding, and partial agonists that produce a moderate effect while prevening other opioids from binding.

Opioids are substances that act on the nervous system in a similar way to opiates such as morphine and codeine. In a medical context the term usually indicates medications that are artificially made rather than extracted from opium. Common examples include oxycodone, hydrocodone, and hydromorphone. Opioids are primarily used in medicine for the treatment of pain.

Opioids are substances that act on opioid receptors to produce morphine-like effects. Opioids include opiates, an older term that refers to such drugs derived from opium, including morphine itself. Other opioids are semi-synthetic and synthetic drugs such as hydrocodone, oxycodone and fentanyl; antagonist drugs such as naloxone and endogenous substances such as endorphins. Opioid drugs are predominantly central nervous system agents, most often used medically to relieve pain.

The side effects of opioids may include pruritus, sedation, respiratory depression, constipation, and euphoria. Tolerance and dependence will develop with continuous use, requiring increasing doses and leading to a withdrawal syndrome with abrupt discontinuation. The profound euphoria invites recreational use; continuous and escalating recreational use of opioids typically results in addiction. Accidental overdose or concurrent use with other depressant drugs commonly results in death from respiratory depression. Because of opioid drugs' reputation for addiction and fatal overdose, most are highly controlled substances.

Morphine-like opioids are well known for their addictive properties, and for their ability to produce euphoria, motivating some to use opioids recreationally.

A number of substances occurring naturally in the body that can decrease the sensation of pain are also classified as opioids. Opioid like compounds found in natural opium latex are classified as opiates, but are also opioids.

Primarily used for pain relief, opioids are also approved to provide anesthesia, suppress cough, suppress diarrhea, treat addiction and reverse opioid overdose. Highly potent opioids are used to tranquilize large mammals. Most opioid drugs are controlled subtances. Opioids act by binding to opioid receptors, which are found principally in the central and peripheral nervous system and the gastrointestinal tract. These receptors mediate both the psychoactive and the somatic effects of opioids. Opioid drugs include antagonists, inactive opioids that prevent other opioids from binding, and partial agonists that produce a moderate effect while prevening other opioids from binding.

Opioids are among the world's oldest known drugs. The medical use of the opium poppy predates recorded history; recreational and religious use likewise precedes the common era. In the 19th century morphine was isolated and marketed, and the hypodermic needle invented.introducing rapid, controlled administration. Synthetic opioids were invented, and biological mechanisms discovered in the 20th century. Illicit production and addiction to opioids, prompted treaties, laws and police actions with limited success. In 2013 between 28 and 38 million people used opioids recreationally (0.6% to 0.8% of the global population between the ages of 15 and 65). In 2011 about 4 million people the United States used opioids recreationally or were dependent on them. Current recreational use and addiction are attributed to over prescription of opioid medications and falling prices for illicit heroin.

Although the term opiate is often used as a synonym for opioid, the term opiate is properly limited to the natural alkaloids found in the resin of the Papaver somniferum (opium poppy), while opioid refers to both natural and synthetic compounds with an opium-like effect (by being agonists at the opioid receptor). i.e. all opiates are opioids, but not all opioids are opiates. Semi-synthetic opioids such as heroin, hydrocodone and oxycodone are sometimes classified as opiates.

Opioids are substances that act on opioid receptors to produce morphine-like effects. Opioids include opiates, an older term that refers to such drugs derived from opium, including morphine itself. Other opioids are semi-synthetic and synthetic drugs such as hydrocodone, oxycodone and fentanyl; antagonist drugs such as naloxone and endogenous susbtances such as endorphins. Opioid drugs are predominantly central nervous system agents, most often used medically to relieve pain.

The lead paragraph definition of opioid should be replaced. It does not reflect the predominant definition which includes all such substances, including opiates. The second sentence isn't true and the third is really just defining non-opiates. Codeine likewise is mentioned to reinforce this opiate distinction. Relegating the predominant modern definition isn't appropriate.

I propose the following lead paragraph:

{{blockquote|text=Opioids are all drugs and endogenous substances that act on opioid receptors to produce morphine-like effects. It includes opiates, an older term that refers to such drugs derived from opium, including morphine itself. Opioid drugs are predominantly central nervous system agents, most often used medically to relieve pain.}}

1. Central could be cut to include peripheral actions but the article, literature and uses all deal overwhelmingly with CNS actions. 2. The first sentence could be expanded to "to produce or prevent morphine-like effects," to accommodate opioid antagonists which are technically opioids; 3. "drugs and endogenous substances" could be cut to "substances".

Because this lead issue has been so contentious, I cite the following:

{{blockquote|text=Opiate is the older term classically used in pharmacology to mean a drug derived from opium. Opioid, a more modern term, is used to designate all substances, both natural and synthetic, that bind to opioid receptors (including antagonists). (p 253) — Pharmacology and Physiology for Anesthesia: Foundations and Clinical Application }}

{{blockquote|text=In the strict sense, opiates are drugs derived from opium and include the natural products morphine, codeine, thebaine and many semi-synthetic congeners derived from them. In the wider sense, opiates are morphine-like drugs with non peptidic structures. The older term opiates is now more and more replaced by the term opioids which applies to any substance, whether endogenous or synthetic, peptidic or non-peptidic, that produces morphine-like effects through action on opioid receptors. (p 903) — Encyclopedia of Molecular Pharmacology }}

Opiate is a specific term that is used to describe drugs (natural and semi-synthetic) derived from the juice of the opium poppy. For example morphine is an opiate but methadone (a completely synthetic drug) is not.

Opioid is a general term that includes naturally occurring, semi-synthetic, and synthetic drugs, which produce their effects by combining with opioid receptors and are competively antagonized by nalaxone. In this context the term opioid refers to opioid agonists, opioid antagonist, opioid peptides, and opioid receptors. (p. 85) — Opioids in Medicine: A Comprehensive Review on the Mode of Action and the Use of Analgesics in Different Clinical Pain States

{{blockquote|text=An opiate, strictly defined, is a drug extracted from the exudate of the poppy. Therefore the term is restricted to two drugs found in the exudates: morphine and codeine. An opioid is any exogenous drug (natural, semisynthetic, or synthetic) that binds to an opiate receptor and produces agonistic, or morphinelike, effects. (p. 322) [This quote from the 12th edition (2011) of the book is an evolution from the 5th edition (1988) where "opiate refers to any natural or synthetic drug that exerts actions on the body in a way similar to those induced by morphine...". (p. 121)] — A Primer of Drug Action }}

{{blockquote|text=Opiates are drugs derived from opium, the extract of the seeds of the opium poppy, and include morphine, codeine, and heroin. The term opioid is more comprehensive and includes all agonists and antagonists with morphine-like activity, including natural opiates, semisynthetic drugs such as hydrocodone and hydromorphone, and synthetic drugs, such as oxycodone, methadone, buprenorphine, and fentanyl. — The ASAM Essentials of Addiction Medicine }}

{{blockquote|text=In this paper, the term, "opioid," is used in the sense originally proposed by Dr. George H. Acheson (personal communication) to refer to any chemical compound with morphine-like properties.(footnote, p. 55) — "Factors Regulating Oral Consumption of an Opioid (Etonitazene) by Morphine-Addicted Rats" in Psychopharmacologia }}

{{blockquote|text=The term opioid refers to all compounds that bind to opiate receptors. Conventionally, the term opiate can be used to describe those opioids that are alkaloids, derived from the opium poppy; these include morphine and codeine. Opioids include semi-synthetic opiates, i.e., drugs that are synthesized from naturally occurring opiates (such as heroin from morphine and oxycodone from thebaine), as well as synthetic opioids such as methadone, fentanyl, and propoxyphene. — "Opioids and the Treatment of Chronic Pain: Controversies, Current Status, and Future Directions" in Experimental and clinical psychopharmacology }}

About the existing citations:

The lead sentence says, "Opioids are substances that act on the nervous system in a similar way to opiates such as morphine and codeine." The cited source says, "Opiates are drugs derived from opium and include morphine, codeine, and the semi-synthetic derived from them and thebaine." but continues, "The term opioid applies to all agonists and antagonists with morphine like activity, and also naturally occurring and synthetic opioid peptides." Opiates are agonists, therefore opioids includes opiates.

The cited D'Arcy's chapter "4. Opioid Medications for Cancer Pain" defines opiates and opioids as mutually exclusive. Otherwise she never uses the term opiate, but refers to morphine as an opioid: "Some of the opioids are used in their natural form such as morphine and heroin," (p. 56) and "...there are many more formulations of opioids to use for analgesia than morphine." (p. 55)

Taber's Dictionary distinguishes opiate/opioid exclusively but also lists (includes only) "opiate receptors" while Wikipedia, including this article's lead, uses the modern term "opioid receptor". Taber's was certainly cited in good faith, but in this case the source seems dated.

Forgive my loquacity. — Box73 (talk) 14:27, 9 February 2016 (UTC)

{{reflist|closed=1}}

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Opioids are drugs and endogenous substances that produce effects like morphine, principally in the central nervous system, by acting on opioid receptors. In a medical context the term usually indicates medications that are artificially made rather than extracted from opium.{{sup|[2]}}Common examples include oxycodone, hydrocodone, and hydromorphone.{{sup|[3]}} Opioids are primarily used in medicine for the treatment of pain.

Opioids are all drugs and endogenous substances that act on opioid receptors to produce morphine-like effects. It is replacing an older term opiates, which refers to refers to natural (and some sources say semisynthetic) derivatives of opium, such as morphine. Opioids principally act on the central nervous system; Opioid drugs are are primarily used medically for the relief of pain, and recreationally, at significant risk of addiction and overdose.

The citation to D'Arcy's chapter "Opioid Medications for Cancer Pain" distinguishes between opiates and opioids as mutually exclusive, after which she discards "opiate" repeatedly refers to morphine as an "opioid". Even the chapter title uses the umbrella term.

The lead definition of opioid should be replaced. It does not reflect the predominant definition which includes all such substances, including opiates. which is an umbrella term that includes drugs classified as opiates. The current lead definition belongs in the discussion of various definitions, replaced by the modern definition.

I am revising it to:

Opioids are all drugs and endogenous substances that act on opioid receptors to produce morphine-like effects. It includes opiates, an older term that refers to such drugs derived from opium, including morphine itself. Opioid drugs are predominantly central nervous system agents, most often used medically to relieve pain.

The lead sentence says, "Opioids are substances that act on the nervous system in a similar way to opiates such as morphine and codeine." The cited source says, "Opiates are drugs derived from opium and include morphine, codeine, and the semi-synthetic derived from them and thebaine." but continues, "The term opioid applies to all agonists and antagonists with morphine like activity, and also naturally occurring and synthetic opioid peptides." Opiates are agonists, therefore opioids includes opiates.

The citation to D'Arcy's chapter "4. Opioid Medications for Cancer Pain" defines opiates and opioids as mutually exclusive. She never uses the term opiate again but refers to morphine as an opioid: "Some of the opioids are used in their natural form such as morphine and heroin," (p. 56)) and "...there are many more formulations of opioids to use for analgesia than morphine." (p. 55)

Taber's Dictionary distinguishes the two but also lists (includes only) "opiate receptors" while Wikipedia, including the lead, uses the modern term "opioid receptor".

I cite the following:

{{blockquote|text=Opiate is the older term classically used in pharmacology to mean a drug derived from opium. Opioid, a more modern term, is used to designate all substances, both natural and synthetic, that bind to opioid receptors (including antagonists). (p 253) — Pharmacology and Physiology for Anesthesia: Foundations and Clinical Application }}

{{blockquote|text=In the strict sense, opiates are drugs derived from opium and include the natural products morphine, codeine, thebaine and many semi-synthetic congeners derived from them. In the wider sense, opiates are morphine-like drugs with non peptidic structures. The older term opiates is now more and more replaced by the term opioids which applies to any substance, whether endogenous or synthetic, peptidic or non-peptidic, that produces morphine-like effects through action on opioid receptors. (p 903) — Encyclopedia of Molecular Pharmacology }}

...Opiate is a specific term that is used to describe drugs (natural and semi-synthetic) derived from the juice of the opium poppy. For example morphine is an opiate but methadone (a completely synthetic drug) is not.

Opioid is a general term that includes naturally occurring, semi-synthetic, and synthetic drugs, which produce their effects by combining with opioid receptors and are competively antagonized by nalaxone. In this context the term opioid refers to opioid agonists, opioid antagonist, opioid peptides, and opioid receptors. (p. 85)  — Opioids in Medicine: A Comprehensive Review on the Mode of Action and the Use of Analgesics in Different Clinical Pain States

{{blockquote|text=An opiate, strictly defined, is a drug extracted from the exudate of the poppy. Therefore the term is restricted to two drugs found in the exudates: morphine and codeine. An opioid is any exogenous drug (natural, semisynthetic, or synthetic) that binds to an opiate receptor and produces agonistic, or morphinelike, effects. (p. 322) — Primer of Drug Action }}

{{blockquote|text=Opiates are drugs derived from opium, the extract of the seeds of the opium poppy, and include morphine, codeine, and heroin. The term opioid is more comprehensive and includes all agonists and antagonists with morphine-like activity, including natural opiates, semisynthetic drugs such as hydrocodone and hydromorphone, and synthetic drugs, such as oxycodone, methadone, buprenorphine, and fentanyl. — The ASAM Essentials of Addiction Medicine }}

Dopamine reuptake via DAT provides the primary mechanism which clears dopamine from synapses in subcortical structures. However, because DAT is spare in the prefrontal cortex, dopamine clearance occurs by extrasynaptic diffusion and ultimately uptake by norepinephrine transporters as well as uptake2 by plasma membrane monoamine transporter and degradation by catechol-O-methyltransferase.

Dopamine reuptake via DAT provides the primary mechanism which clears dopamine from synapses in subcortical structures. However, DAT is spare in the prefrontal cortex so dopamine clearance there occurs by extrasynaptic diffusion and ultimately uptake by the norepinephrine transporter as well as uptake2 with degradation by catechol-O-methyltransferase.

from which other transporters sequester DA and NE into vesicles for later storage and release or

Dopamine reuptake via DAT provides the primary mechanism which clears dopamine from synapses in subcortical structures. However, DAT expression is spare in the prefrontal cortex so dopamine clearance there occurs by other mechanisms (i.e.,extrasynaptic diffusion and ultimately uptake by the norepinephrine transporter as well as uptake2 with degradation by catechol-O-methyltransferase).

note: There is evidence that dopamine captured by NET may be stored and later released. Other evidence suggests dopamine may be produced as a co-transmitter within cortical norandrenergic projections.

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Once in the synapse, dopamine binds to and activates dopamine receptors. These can be the D2Lh type, located on the postsynaptic target cells or the D2Sh autoreceptor type located on the membrane of the presynaptic cell.[8] After an action potential, the dopamine molecules quickly become unbound from their receptors. In subcortical regions they are then absorbed back into the presynaptic cell, via reuptake mediated either by the dopamine transporter or by the plasma membrane monoamine transporter.[20] Once back in the cytosol, dopamine can either be broken down by a monoamine oxidase or repackaged into vesicles by VMAT2, making it available for future release.[18]

However few dopamine transporters exist in the prefrontal cortex allowing the unbound dopamine to diffuse beyond the original synapse. It may be taken up by norepinephrine transporters in adjacent norandrenergic terminals (and likewise broken down by monoamine oxidase) or is catabolized by catechol-O-methyltransferase

However few dopamine transporters exist in the prefrontal cortex allowing the unbound dopamine to diffuse beyond the synapse, where it is free to act until it is either degraded by catechol-O-methyltransferase or is taken up by a norepinephrine transporter in a norandrenergic terminal

It may be taken up by norepinephrine transporters in adjacent norandrenergic terminals (and likewise broken down by monoamine oxidase) or is catabolized by catechol-O-methyltransferase

However few dopamine transporters exist in the prefrontal cortex, allowing the unbound dopamine to diffuse outside the synapse until either removed by norepinephrine transporters in norandrenergic terminals or degraded by extracellular catechol-O-methyltransferase. Some evidence suggests that norandrenergic neurons projecting into the prefrontal cortex may release dopamine as well as norepinephrine.

https://books.google.com/books?id=cWbYxSfKN3cC&pg=PA545&lpg=PA545#v=onepage&q&f=false

p 544-6

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2430672/

http://bmcneurosci.biomedcentral.com/articles/10.1186/1471-2202-6-31

Dopamine also activates α1, β1 and β2 adrenergic receptors. At these sites dopamine acts as a cardiac stimulant and vasopressor. α2 At β1 receptors dopamine increases heart rate and force while at α

benzedrine

Because that would overwhelm the field, and those brands aren't significant. Alternatively, consider amitriptyline and doxepin. Elavil and Sinequin (respectively) are listed but both brands are discontinued.

I get your reasoning and desire to keep this focused. Benzedrine belongs because it is established in our vocabulary. It is listed in Oxford and Merriam-Webster Dictionaries. The 2012 Atlantic article, The Lost World of Benzedrine. This isn't true of Alentol, Psychoton or Simpamina. This makes it a special case belonging there. Is there a way to distinguish it in the list without causing clutter or undue attention? — ~

onset

response re benzyl methyl carbinamine

{{blockquote|text=(we don't include the majority of amphetamine synonyms ( http://www.commonchemistry.org/ChemicalDetail.aspx?ref=300-62-9 ). I've removed the term and redirected Benzyl methyl carbinamine here since it doesn't seem to be widely used or notable)}}

I appreciate that there is a difference of opinion.

α-methylphenethylamine is the best synonym largely because it was the source of the term amphetamine There are many other synonyms of amphetamine, more than could or should be listed, yet my addition was not capricious. Benzyl methyl carbinamine was the original synonym used in the 1930s. It is notable that Alles derived "Benzedrien" by combining "BENZyl methyl carbinamine" with "ephEDRINE". For the first several years benzyl methyl carbinamine was widely used to identify the drug, typically parenthetically following Benzedrine. In fact, "amphetamine" was little used originally.

The American Chemical Society database at Common Chemistry is a reliable source but not the gatekeeper of acceptable synonyms. Benzyl methyl carbinamine is listed elsewhere. Wide usage exists in early medical literature—secondary sources concerning the name. Benzyl methyl carbinamine is not trivial. The term was used by the process inventor (Alles), manufacturer (SK&F), and notable physicians such as Bradley reporting his discovery treating attentional disorders. (β-phenylisopropylamine was another early term encountered. )

Wikipedia editors are encouraged to develop drug infoboxes and the field "synonym s " currently lists but a single term. Benzyl methyl carbinamine is historically notable and widely used, and is reasonable to include. Pending any remaining objections, the deletion should be reverted with improved citations (1 or 2). — Box73 (talk) 03:06, 13 January 2016 (UTC)

I appreciate that there is a difference of opinion. Here is my reasoning: Forgetting all the brand names, and street names, there are way too many amphetamine chemical synonyms to reasonably list. There has to be restraint and discrimination. But the template's plural "synonyms" provides for a reasonable few. I believe benzyl methyl carbinamine is a reasoned choice, not simply a spaceholder. It is the original conventional chemical name of amphetamine, something I didn't know a month ago. (There should be no necessity of a third term but three seems a reasonable limit.)
 * 1) c. 1932-1946 the common trivial name was benzedrine not amphetamine. (note lower case "b".) Just like amphetamine, benzedrine is a contraction of a systemic name plus the known congener: benzedrine = benzyl methyl carbinamine + ephedrine = benz+edrine) ("amphetamine" was convened by a party of the AMA; "benzedrine" was by Gordon Alles.)
 * 2) c. 1932-1946 The name "benzyl methyl carbinamine" enjoyed wide-spread use alone or following benzedrine in journal articles and pharmaceutical advertisements.       inclusion in a list of amphetamine synonyms. historical SKF documents including blueprint of factory producing benzyl methyl carbinamine
 * 3) The amphetamine article encompasses not just scientific but also historic perspectives. This synonym is historically notable.
 * 4) It is common for drugs to include several synonyms. For example methamphetamine has 3, aspirin has 4.
 * 5) One way to improve articles is to add information to infoboxes in drug articles.
 * 6) The American Chemical Society database in "Common Chemistry" is certainly a reliable source but it is neither absolutely comprehensive nor the final judge of valid synonyms.
 * 7) Let's be fair. Substituted amphetamines doesn't seem to be widely used per Wikipedia's definition.

Now, if only benzyl methyl carbinamine would fit on a single line!

While enantiopure dextromethamphetamine is a more potent drug than racemic methamphetamine, the racemic form is sometimes produced and sold instead of dextromethamphetamine due to the relative ease of its synthesis by certain methods and the limited availability of associated chemical precursors.

benzyl methyl carbinamine

N- meth yl- a lpha- m ethyl ph en et hyl amine

New citation test


 * 1) Severe overdose / CNS, add generalized tonic-clonic seizures.    Seizures are uncommon with mild to moderate overdose but occur with large, severe overdose. The first two citations should be sufficient; the third is a good secondary source.
 * 2) Seppi may be interested in this related item: The Nucleus Accumbens: A Comprehensive Review.

These represent the current brands in the United States, except Adderall which is discontinued but available generically. Dexedrine was available in 1937 as an instant release tablet, which is discontinued but available as Zenzedi and generically; Dexedrine listed here represents the extended release "Spansule" capsule which was approved in 1976. Amphetamine sulfate tablets, now sold as Evekeo (brand), were originally sold as Benzedrine (brand) sulfate in 1935 and discontinued sometime after 1976. Vyvanse and Dyanavel are only available as brand pharmaceuticals, due to the patented mechanisms used to release the active amphetamine ingredient.

Severe overdose / CNS, add generalized tonic-clonic seizures. Seizures are uncommon with mild to moderate overdose but occur with large, severe overdose.

Amphetamine

Consider changing hyperpyrexia to hyperthermia which is the

All contain dextroamphetamine sulfate, which obviously is equal. Amphetamine sulfate and dextroamphetamine sulfate are considered equal in drug monographs. The other salts in Adderall have a higher molecular weight, which is noted in pharmaceutical literature, and this effects the amount of base and the potency. This is considered in pulished research, such as the base content comparison quoted in the research below.

Concerning equipotent daily doses with lisdexamfetamine.

After administration of a single LDX [lisdexamfetamine] dose of 70 mg under three dose conditions (fasting and with capsule only; fasting and with solution containing capsule contents; and intact capsule after a high-fat meal), systemic exposure of d-amphetamine was bioequivalent, as measured by drug plasma concentration-time plots and maximum drug concentration. The 70-mg dose is expected to be therapeutically equivalent to the amphetamine base content of 30-mg MAS-XR (20.8 mg vs. 18.8 mg, respectively), which is known to be therapeutically active in children with ADHD.

This agrees with the template, excepting that the study used the nearest manufactured dose unit for practical purposes. They make this clear noting the base content is 20.8mg vs, 18.8mg (lisdexamfetamine vs. Adderall). (MAS is Mixed Amphetamine Salts; used because Adderall is a brand-name; However Adderall is used in Wikipedia.}.The template uses exactly equal base amounts, resulting in 35mg Adderall XR = 74mg lisdexamfetamine..(The range for Adderall, amphetamine sulfate and amphetamine base suspension addressed a concern by one editor that pure stimulant effects of dextroamphetamine are 4 times stronger than levoamphetamine. In treatment for ADHD the two enantiomers are considered equally potent, as is evident in the cited source above.) By keeping the base content exactly equal allowed all of the form to coexist in the template.

A concern was raised about food effecting the pharmacokinetics of lisdexamfetamine. No significant effect was found.

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Covering a number of issues

Routes of administration: Since Benzedrine inhalers are long gone, nasal inhalation should be eliminated from Medical, or somehow qualified.

Metabolism. I'm confused between "amphetamine only" and "other". Does "other" mean active metabolites?

Onset of action: This gets into medical vs recreational distinctions as well as site of action (central vs nasal). Duration of action presents the same issues as onset. I believe the current IR values listed are for oral amphetamine, either Adderall or pure racemic forms. (That is another reason the onset value for IR should be oral.) I am skeptical that these values are for non oral administration (and decongestant effect) which might have different durations and possibly slightly different half-lives (for example, the decongestant is local vs systemic).
 * 1) We need to divide IR into oral and intranasal/intravenous. Perhaps IR (oral) and IR (intranasal/intravenous). However since XR refers to oral, and IR tends to be used for oral, keep XR and IR for oral, and isolate intranasal/intravenous. Perhaps IR, XR, IN/IV?
 * 2) Despite IR standing for immediate release, oral IR effects certainly are not immediate. Immediate only means it isn't a time release / sustained release / extended release formulation. The time to be ingested, absorbed, cross the BBB, accumulate concentrations to cause clinical effect exist.
 * 3) IR and XR (oral) should both have the same onset since a part of the (larger) XR dose is in IR form.
 * 4) The reported value for IR oral is 30-60 minutes. (I don't have the references at hand, but they vary by source.)
 * 5) Although IN or IV is almost immediate, I suggest "rapid" over "immediate". (Also relieves confusion with immediate release.)

Medical. "Amphetamine ... is sometimes prescribed for its past medical indications ... such as ... nasal congestion."

Amphetamine is no longer prescribed for nasal congestion. Currently, psychiatrists sometimes prescribe amphetamine for depression and rheumatologists occasionally for chronic fatigue syndrome. However, the Benzedrine inhalers are long gone and no competent provider would prescribe oral amphetamine (or d-amphetamine) for congestion.

As mentioned, chronic fatigue syndrome might be a potential candidate for notable off-label use. I'm collecting sources and will follow up.

Amphetamine derivatives. The definition of Amphetamine derivatives is right on. As my friend Seppi would guess, my two issues deal with substituted amphetamines: (note: I recognize that this issue is wider than the amphetamine article itself and certainly belongs to the substituted amphetamines article.) "Amphetamines" is a common term and commonly includes amphetamine (and its enantiomers) as well as derivatives. (The extent of the derivatives varies.) "Substituted amphetamines" is not a common term but a somewhat esoteric term and frequently excludes amphetamine and its enantiomers. Its esoteric nature makes it difficult to collect many definitions. (If we search Lithuanian literature, we would find Lithuanian terms to be common, but outside of Lithuanian literature, the Lithuanian terms would be rare. They are esoteric. Should we use Lithuanian literature to demonstrate that the terms are common (i.e., popular) generally? (except in Lithuania.)
 * It is equating "amphetamines" with "substituted amphetamines".
 * It is saying both are common terms.
 * It (referring to substituted amphetamines here as derivatives) is meant to recognize/satisfy criticisms (I've raised) while continuing to use it inclusively elsewhere.

At the risk of beating a dead horse, here are my overdue sources dealing with substituted amphetamines:

Amphetamine is clearly excluded in these quotes from different versions of a classic psychiatry reference:"The classic substituted amphetamines include MDMA, MDEA, 2,5-dimethoxy-4-methylamphetamine (DOM, STP), dimethyltryptamine (DMT), MMDA, and trimethoxyamphetamine (TMA), which are also commonly classified with amphetamines. — Kaplan and Sadock's Pocket Handbook of Clinical Psychiatry""With a few notable exceptions, animals in experimental situations self-administer most of the drugs that humans tend to use and abuse. Included among the drugs are μ- and δ-opioid agonists, cocaine, amphetamine and amphetamine-like agents, substituted amphetamines, such as MDMA, alcohol, barbiturates, many benzodiazepines, a number of volatile gases and vapors (e.g., nitrous oxide and ether), PCP, and nicotine. — Kaplan & Sadock's Comprehensive Textbook of Psychiatry"In the first quote above note that he said, "also commonly classified with amphetamines" not "also commonly classified as amphetamines"

This literally distinguishes amphetamine from substituted amphetamines: "Amphetamine and substituted amphetamines, including methamphetamine, methylphenidate (Ritalin), methylenedioxymethamphetamine (ecstasy), and the herbs khat and ephedra, encompass the only widely administered class of drugs that predominantly release neurotransmitter, in this case principally catecholamines, by a non-exocytic mechanism. — 'Mechanisms of neurotransmitter release by amphetamines: a review' in Progress in Neurobiology"The following text likewise excludes amphetamine from substituted amphetamines. In fact it would exclude not only amphetamine but close congeners such as ephedrine and methamphetamine; this may explain the distinction between "amphetamine-like agents" (or "amphetamine-type stimulants") and "substituted amphetamines" (or Ecstasy) as used in Kaplan."MDMA is one of a number of closely related substances known as substituted amphetamines.... The substituted amphetamines are entirely synthetic ... in most western countries substituted amphetamines are illegal... Some ecstasy tablets many not contain any substituted amphetamines at all, they may contain methamphetamnine, LSD, ketamine or inert substances. — Drink, Drugs and Dependence: From Science to Clinical Practice"These chapter end questions is Fundamentals of Pharmacology allude to the distinction of amphetamines from MDMA, which is commonly referred to a substituted amphetamine. "3. What is the chemical name for ecstasy? To which class of drugs is it closely related? ... 5 Compare and contrast the effects of ecstasy with those of amphetamines. — Fundamentals of Pharmacology"A Penn State Dept. of Chemistry PowerPoint presentation includes a slide graphic showing amphetamine as the source but excluding it from the class. Note yellow color of title and substituted amphetamines structural diagrams vs red for amphetamine.

Substituted amphetamines is a technical term used by chemists. Similarly substituted morphinans or simply morphinans is a technical term used by chemists which includes morphine and its many congeners. Neither are commonly used. We don't talk about the abuse of prescription (substituted) morphinans. We don't commonly call heroin a (substituted) morphinan. We don't say morphine derivatives are commonly called opioids and (substituted) morphinans. To do so is a promotion of the esoteric term to the level of the common term. Now I can find the term morphinans used by chemists and toxicologists but not in common usage. Chemists and toxicologists use "substituted amphetamines" to include amphetamine itself and all its derivatives. But the term, while a bit more common than morphinans is not common and when applied in medicine and pharmacology is typically not inclusive or not used. By contrast, the term amphetamines is common and always includes amphetamine itself, it almost always includes chemically related stimulants, and frequently MDMA type derivatives with psychedelic properties.

The problem here is, of course that amphetamine is a chemically derived name like barbiturate and benzodiazepine, yet we don't commonly add substituted to them. Looking at other psychoactive drugs, we have the modern term opioid which spans morpinans (which includes opiates) and non-morphinans (which are unrelated structures). (The mutually exclusive meaning of opiate and opioid is passing as opioid becomes the umbrella term.) So opioid has become a functional class. So too antipsychotic, anticonvulsant (or increasingly anti seizure/epilepsy medication), mood stabilizer (which is lithium and many anticonvulsants). Then there are tranquilizer, major tranquilizer, neuroleptic, anti-anxiety medication and so on which are either antiquated or vernacular. These are all functional classes.

The problem here is, of course that amphetamine is a chemically derived name like barbiturate and benzodiazepine, yet we don't commonly add substituted to them. Like amphetamine (unintended pun) we have phenethylamine.(aka phenylethylamine) and cathinone. Both are a substance and a chemical drug class. The substances are not generally encountered as often as amphetamine, in use or language, and the classes occur with and without "substituted". Here again, we see chemists and Wikipedia using substituted X, but commonly just X as the drug class. When substituted X is commonly used, it is exclusive of X: derivatives of X or X with substitutions. So here too the inclusive definition is pretty much common to chemists and Wikipedia. They present the same potential mistranslations as substituted amphetamines, but fewer real linguistic dangers because they aren't commonly encountered (or much less frequently).

Consider the related term substituted cathinone. A recent article Emerging drugs of abuse: current perspectives on substituted cathinones begins: Substituted cathinones are synthetic analogs of cathinone... Like substituted amphetamines, substituted cathiones is generally used to refer to derivatives: in this case so called "bath salts".

In all the medical literature I searched, I never found the term "substituted amphetamine psychosis", "substituted amphetamine dependence" or "substituted amphetamine withdraw", though all of these are true for (and likely more frequent with) methamphetamine, which technically is a substituted amphetamine, and various other amphetamine derivatives.

Inclusive use of "substituted amphetamines".

I have found that toxicologists are those tending to use substituted amphetamines and using it in the inclusive sense. For example James O'Callaghan "Neurotoxic effects of substituted amphetamines in rats and mice" a chapter in Handbook of Neurotoxicology, Vol II and another book titled Neurobiological Mechanisms of Drugs of Abuse: Cocaine, Ibogaine, and Substituted Amphetamines. Although the latter is a collection of papers presented at a seminar on drug abuse, substituted amphetamines is only used two articles, one being the chapter/paper co-written by O'Callaghan and the editor. Another toxicologist is George Ricaurte, a controversial anti-drug researcher best known for a retracted article in the journal Science where methamphetamine toxicity was attributed to MDMA. I got the impression that these fellows never met an amphetamine that wasn't toxic and the term "substituted amphetamines" was being used as a melting pot. O'Callaghan for example, concerned about therapeutic doses of amphetamine used in ADHD writes, "[I]t is not uncommon to see all substituted amphetamines labelled as potentially or outright neurotoxic." which he disavows but seems to arrive at anyway by discussing asymptomatic brain changes such as dopamine deficits prior to the presentation of Parkinson's. He and Miller seem rather loquacious, expansive in terms of toxicity, eager to apply rodent research to humans and fond of the term "substituted amphetamines". What I'm saying is "substituted amphetamines" is being used by those with a scientific prejudice or a political agenda, particularly Ricaurte. But all that aside, these toxicologists impress me as predominant published users of "substituted amphetamines" inclusive of amphetamine—Wikipedia and them.

The other issue is what I cannot cite. All of the books, papers and journal articles by credentialed professionals that never use the term substituted amphetamines. All of the physicians that had to take organic chemistry to get into med school who don't use substituted amphetamines or use it differently when they publish. All of the editorial boards who don't promote the term. The lack of letters to JAMA or various neuropsychiatry journals complaining about the ambiguity of the term amphetamines. The term isn't common.

Regarding the template Amphetamine base in marketed amphetamine medications, this was changed from transcluded to substituted on the grounds that two articles are not sufficient reason to transclude a template. After consultation, I can find no Wikipedia policy concerning a minimum number of articles being required for transclusion; this would not be a reason to substitute the template (given two or more articles access the template). Obviously transclusion is more efficient in improving the content. If transclusion is acceptable at Dextroamphetamine, Adderall and Lisdexamfetamine, I can see no reason why it needs to be substituted instead at Amphetamine. Concerns over content effect all articles the template is transcluded in, so transclusion, with discussion and editing at the template itself, would benefit all of these articles.

After reviewing the improvements of syntax and tweaking of references in the substituted copy, most have been incorporated into the base template, the exception being revisions to the syntax of the chemical formulas which would permit the formulas to break. Line breaks in the formulas is confusing and burdensome. Likewise I maintained the heavier dot, as the standard dot is difficult to perceive with some resolutions and for some people.

The substitution raises issues of ownership (WP:OWN) as this would maintain control over a certain article rather than resolving common issues. (How do the changes to the substituted template apply only to the amphetamine article?) Given the previous reasoning and to correct appearances of ownership, the transclusion of the Amphetamine base... template should be restored and improvements shared by all.

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In a different context, "W-section" is a term commonly used by engineers and architects but most people won't understand us unless we say "I-beam".

Finally substituted amphetamines like substituted morphinans sounds like it belongs in a graduate level paper.

I appreciate the schematic drawings used in amphetamine and several other pages. Indeed they make those in medical texts look basic. I am concerned that many can't appreciate them, but are intimidated. Many don't understand the basics of neurotransmission at the presynaptic terminal. They can't pick out the basic actions from the detailed mechanisms.

Now I am not discounting the existing drawings, not proposing replacing or eliminating them. Rather drawings with reduced schematic detail might coexist with them. These may be sufficient for some readers, the limits of comprehending for some, a stepping stone for some making the detailed easier to grasp. Of course some will be baffled by the basic diagrams while they will be unnecessary for others. Maybe its analogous to a map US states or European countries, and one showing capital and major cities, lakes and rivers, major highways, time zones, and area/country codes.

What is missed is that such graphics present information overload. Most people don't understand the basic events of neurotransmission in the presynaptic terminal. Along with the more detailed, technical diagram, a more basic, less daunting diagram should exist. For some it will be a stepping stone for others sufficient or they most they can handle.

I wouldn't mind this term being mentioned but it is an esoteric term being forced on us.

There are too many sources to list where substituted amphetamines is used referring to MDMA type amphetamine analogues without reason for the author to define substituted amphetamines as excluding amphetamine itself. There are even more sources where the term amphetamines is used to described amphetamine and/or its derivatives without use of the term substituted amphetamines.

Regarding the graphic Pharmacodynamics of amphetamine enantiomers in a dopamine neuron

I suggest: Pharmacodynamics of amphetamine enantiomers in a dopamine neuron. Enantiomers is unnecessary since amphetamine is amphetamine enantiomers.

Could the colors be revised so amphetamine and amphetamine trafficking are both red.

At the risk of making this more detailed... Doesn't amphetamine also (reversibly) inhibit monoamine oxidase, reducing dopamine metabolism, thus increasing dopamine levels. (Enantiomer preferences of MAOA vs MAOB are schematically superfluous since both subtypes metabolize dopamine.)

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Approximate equivalency: 30 mg dextroamphetamine ≈ 35 mg Adderall ≈ 75 mg lisdexamfetamine (Vyvanse). (Assuming levoamphetamine and dextroamphetamine are equipotent.) test -The following issues should be addressed. Comments please.

In the Lead section: In the Medical section:
 * 1) Revise: "...in the United States, where both racemic methamphetamine and dextromethamphetamine are classified as schedule II controlled substances. In contrast, enantiopure levomethamphetamine is an over-the-counter drug which is marketed as a nasal decongestant in the United States." Sounds like isolated levomethamphetamine is not a controlled substance in the U.S. Very wrong. "Under 21 C.F.R. § 1308.12(d), methamphetamine or its isomers is a Schedule II controlled substance unless specially excepted."  Two exceptions exist for nasal inhalers made by Vicks and Classic Pharmaceuticals (now Aphena, who packages the product for others such as CVS and RiteAid). Every other form or quantity of levomethamphetamine, even isolating it from the inactive ingredients in these inhalers makes it a Schedule II drug. Could be revised to: "...in the United States, where all forms of methamphetamine are classified as schedule II controlled substances. However, decongestant nasal inhalers containing limited quantities of levoamphetamine are permitted as over-the-counter products in the United States." but a more comprehensive revision would be better. There is really no need to mention nasal inhalers in the lead since it is addressed in the Medical section of the article.
 * 1) "Severe" should be deleted. "[M]ethamphetamine ... has been approved by the FDA for treating severe ADHD" Severe ADHD does not appear in the FDA monograph. Compared to other stimulants methamphetamine is rarely prescribed for many reasons: because of its profound illicit use and greater concerns of abuse, greater number/promotion of other stimulants/formulations, neurotoxic potential, high cost/exclusions from insurance formularies, extremely limited supply due to stingy/declining DEA issued Production Quotas, and lack of practitioner experience / lack of current therapeutic research / exclusion from medical reference guides. When used, methamphetamine is likely tried in persons with ADHD whose symptoms are not relieved by other ADHD medications. Some may be persons with severe ADHD but some might simply be persons with treatment resistant ADHD. Nonetheless the FDA indications do not specify severe ADHD. (Don't confuse American Society of Health-System Pharmacists' monographs with FDA monographs.)
 * 2) Wrong definition for exogenous obesity. "... and [for treating] exogenous obesity (obesity originating from factors outside the patient's control)" The phrase in parenthesis should be deleted (or corrected) because it is not the definition of exogenous obesity but is true for endogenous obesity. Exogenous obesity means consuming more calories than needed or used by the body (as compared to endogenous obesity which means obesity resulting from endocrine or metabolic dysfunction). For example, obesity may result from hypothyroidism and hypothyroidism is outside the patient's control but this would not be considered exogenous obesity.
 * 3) I challenge this statement: "It is rarely prescribed due to concerns over toxicity."  Accepting that A. methamphetamine is neurotoxic and B. methamphetamine is rarely prescribed does not prove the assertion. It is more likely that its recreational reputation (including violence and personal devastation) and the availability of other efficacious drugs (stimulants & non-stimulants) is the most prominent reason. Measures which were established to combat abuse/diversion such as the Controlled Substances Act, Prescription Monitoring Programs and state/DEA disciplinary actions against prescribers clearly are a major influence on methamphetamine prescribing. It would be a much better to say, "It is rarely prescribed due to concerns over abuse and toxicity." or similar. ("Recreational use" is the MOS preferred term to abuse.) Otherwise please provide support for the prescription-toxicity assertion, not just A and B above. (Granted it isn't easy to find specific quality evidence about this.)
 * 4) Change "sometimes" to "also". "... methamphetamine is sometimes prescribed off label for narcolepsy and idiopathic hypersomnia." "Also" would be more appropriate than "sometimes". "Sometimes" infers methamphetamine is a fringe therapy while the the drug has a long established history treating narcolepsy and the medical community considers narcolepsy a valid indication.
 * 5) The FDA black box warning should be deleted. The FDA requires a number of drugs to display black box warnings but I am aware of no others where it is copied verbatim into a Wikipedia article. It should be sufficient to mention the existence of the black box warning, cite the source and if needed, put the actual quoted warning in a footnote. The concerns raised in the warning should already exist elsewhere in the article.
 * 6) Consider neuroprotective effects. While the article repeatedly mentions neurotoxicity, editors might consider methamphetamine's neuroprotective effects at low doses in persons with stroke and CNS trauma.

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