Talk:Amphetamine/Archive 8

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Archive 7

Archive 8

Evidence vs. usage

In my view, the most problematic part of the Amphetamine article is that it overemphasizes "amphetamine is used for" and underemphasizes "there is evidence of efficacy and safety of amphetamine for treatment of." Both evidence and usage ought to be described (of course, this is an encyclopedia, after all), but there should be balance. Some readers may infer from the language in the first sentence of the lede that it is reasonable to treat obesity with amphetamine, however I expect that most experts would consider the harms of using amphetamines for obesity to outweigh the benefits. The lede could cite a recent large, well-done study of prevalence of use. It's not a meta-analysis, but is the best quality evidence we are likely to get.

Here's a draft sentence to consider for the lede: A 2018 study estimated that approximately 16 million people in the United States take amphetamines.

Please note that the AACE/ACE guidelines for obesity treatment do not recommend amphetamine nor do they even recommend phentermine alone, and the guidelines caution prescribers about use of lorcaserin (which can be abused by using high doses). (The extended-release combo of phentermine/topiramate is on the AACE/ACE list of recommended drugs.) this reflects a consensus among experts about use of drugs with abuse potential for treatment of obesity.

Sbelknap (talk) 22:09, 19 July 2018 (UTC)

Your concern is actually very similar to the one I mentioned at WT:MED. This article really only covers the safety/efficacy of amphetamine for ADHD, but it should cover this for ADHD, obesity, and narcolepsy. Unfortunately, there really aren't any meta-analyses that cover the efficacy of amphetamine for obesity (see this search). I would like to create the subsections on narcolepsy and obesity sometime in the near future though.

As for the lead, it wouldn't be a good idea to cover the safety/efficacy of its uses there since this article needs to give comparable coverage to each major subtopic in a very small amount of space (the limit for the size of the lead is 4 paragraphs for very large articles, per MOS:LEADLENGTH). I understand your desire to cover these things in the lead since many people come to articles and read leads, but I don't think that's entirely true for drug articles; e.g., whenever I go to an article as a reader and not an editor, I often ignore the lead altogether and go to the section pertaining to the topic that I'm interested in (and sometimes end up searching pubmed for relevant articles and expanding that section if I found it lacking). I can't imagine someone interested in knowing about its medical uses or pharmacology would stop at the 4 introductory paragraphs that summarize an entire article (especially one that's as massive as this one).
So, in a nutshell, I think the best approach would be to create the sections on obesity and narcolepsy. First, we need to get sources on amphetamine's efficacy for those uses though (i.e., meta-analyses for narcolepsy and medical reviews for obesity). I'll probably have time to look for sources on efficacy tonight once I've finished fleshing out the medical uses section of bupropion with the meta-analyses that I cited on bupropion's talk page. Once we have those sources, we can write those sections of this article.

As for the study you provided, my main concerns with using it to indicate the prevalence of prescription amphetamine use is that it doesn't quantify the use of amphetamine alone (i.e., it includes other prescription stimulants, like methylphenidate - which isn't a substituted amphetamine - and methamphetamine) and articles should ideally provide a global perspective. The global prevalence of both the licit (i.e., prescription) and illicit use of amphetamine-type stimulants is actually included in this article at present though: see the 1st table under Amphetamine#History, society, and culture. Seppi333 (Insert 2¢) 01:54, 20 July 2018 (UTC)

If you're willing to help me look for sources on efficacy, I would really appreciate your help! Seppi333 (Insert 2¢) 01:58, 20 July 2018 (UTC)

Obesity

I ran this search for recent reviews/practice guidelines/meta-analyses/systematic reviews that include amphetamine (in the title/abstract or mesh terms), obesity (in the title/abstract), and efficacy (in the title/abstract); came up with 7 sources and all of them were irrelevant. After repeating that search without the efficacy term, I found ~40. The only one that actually covered the efficacy of amphetamine for weight loss examined really old trials: PMID 25194183 doi:10.1016/j.bpg.2014.07.015). I don't think we'd be able to cover the efficacy in the obesity section. The only things we probably can cover are: (1) amphetamine is intended to be used as an adjunct therapy for a period of several weeks (per the prescribing information) and (2) what non-Pubmed indexed practice guidelines say about it. I don't think it's worth covering the mechanism of action for this given the lack of evidence on efficacy. Seppi333 (Insert 2¢) 12:41, 20 July 2018 (UTC)

List of references relevant to this section:

• AACE/ACE guideline
• PMID 25194183 (doi:10.1016/j.bpg.2014.07.015)
• Evekeo Prescribing Information

Narcolepsy

I'm running into a similar problem with sources on efficacy for narcolepsy. There's a lot of reviews, but no pubmed indexed meta-analyses, practice guidelines, or systematic reviews that actually quantify its efficacy on the basis of some metric of symptom reduction. The main difference is that all of the reviews I've read in the past and skimmed through now all assert that it has treatment efficacy. I'll probably end up citing clinical practice guidelines for narcolepsy as well. These sources seem relevant: AASM guideline, AASM review, PMID 29759269, 26716917, 27549768, 28424564.

• The AASM narcolepsy review states the following about the efficacy/use of amphetamine:

Selected excerpts from the AASM narcolepsy review

The traditional stimulants are considered mainstays for treatment of sleepiness associated with narcolepsy.21 The previous practice parameters published in 2001 by the AASM identified three level 2 studies and four level 5 studies that support the efficacy of traditional stimulants for treatment of sleepiness in narcolepsy.21 Our updated search from 1999 through October, 2006 identified no new studies of traditional stimulants for this indication that met inclusion criteria. Our search identified one small case series with level 4 evidence involving five adolescents with Kleine-Levin syndrome treated with lithium carbonate.57 Although all patients experienced relapses while receiving lithium carbonate, the duration of hypersomnia episodes was shorter and there were no behavioral symptoms during episodes in which subjects were treated with lithium carbonate. Several small case reports indicate varying degrees of improvement or lack of improvement associated with treatment with a variety of medications including stimulants, anti-epileptic medications, antidepressants, and neuroleptics. A systematic review of Kleine-Levin syndrome patients by Arnulf, et al.58 reports that sleepiness decreased in 40% of 75 treated patients, using stimulants (primarily amphetamines). We identified no controlled studies that report results of treatment of recurrent hypersomnia with medications. The AASM issued a statement in August, 2006 that addressed the “black box” warning (www.aasmnet.org). The statement reviewed that amphetamine preparations are effective agents for the treatment of sleepiness associated with narcolepsy, and should not be withheld from appropriate patients. They are generally used in patients with more severe sleepiness and when other medications have proven ineffective. The statement also indicated that physicians who prescribe amphetamines should be knowledgeable about the drugs and should carefully assess the risk-benefit ratio for each patient.

• The AASM narcolepsy guideline states the following about amphetamine:

Selected excerpts from the AASM narcolepsy guideline

c. Amphetamine, methamphetamine, dextroamphetamine, and methylphenidate are effective for treatment of daytime sleepiness due to narcolepsy [4.1.1.1] (Guideline). This recommendation is unchanged from the previous recommendation. These medications have a long history of effective use in clinical practice but have limited information available on benefit-to-risk ratio.4 This lack of information may reflect the limited sources of research funding for medications available in generic form rather than clinical utility of these medications 7. The following medications may be effective for treatment of daytime sleepiness in idiopathic hypersomnia (with and without long sleep time), recurrent hypersomnia, and hypersomnia due to a medical condition: amphetamine, methamphetamine, dextroamphetamine, methylphenidate, and modafinil [4.7, 4.8, 4.9] (Option) The literature supporting the efficacy of these medications for other specific disorders such as narcolepsy have been reviewed. Where published evidence meeting search criteria is available for the use of any of these medications in the conditions listed, this has been provided in sections 4 and 5. This recommendation applies to those medications and conditions combinations for which published literature meeting search criteria is not available. Although there is no reason to suspect they will not improve alertness, individualized therapy and close follow-up to ensure efficacy and monitor for side effects is needed. The recommendations for these disorders are based on committee consensus. iv. Of the stimulants used to treat hypersomnia of central origin, amphetamines, especially at high doses, are the most likely to result in the development of tolerance 1. Comparisons of traditional stimulants to newer somnolytic agents for hypersomnia due to narcolepsy. Several large randomized, placebo-controlled studies indicate that modafinil and sodium oxybate are effective for treatment of hypersomnia associated with narcolepsy. The traditional stimulants (amphetamine, methamphetamine, dextroamphetamine, and methylphenidate) which are available in generic form and are less expensive, have a long history of use in clinical practice, but have limited high-level evidence from published studies. There is a need for randomized trials that compare the newer agents to the traditional stimulants to establish relative efficacy and safety of these agents to guide the clinician in choosing between them for individual patients.

• PMID 29759269 (doi:10.1016/j.jsmc.2018.02.009) mentions:

Excerpts from PMID 29759269

Treatment of excessive daytime sleepiness Stimulants still are the mainstay of the treatment of EDS.10,11 They enhance release and inhibit the reuptake of catecholamines and, to a lesser extent, serotonin in the central nervous system and the periphery. They are also weak inhibitors of monoamine oxidase. These include dextroamphetamine (5–60 mg/d; usually in 1–3 doses per day), ... Long-acting agents (modafinil, armodafinil, dexamphetamine, methylphenidate, controlled release) are generally better tolerated than the short-acting ones. The quick and short-acting agents can be used to good effect when targeted at social events or difficult periods during the day. For this reason, combinations of stimulants may be tailored to the circumstances. Unfortunately, there are no studies assessing the advantages or disadvantages of combinations of stimulants.

Random aside: this review also asserted something I thought was interesting: the alerting effect of 6 cups of strong coffee is comparable with that of 5 mg of dexamphetamine.

• PMID 26716917 (doi:10.1056/NEJMra1500587) mentions: Methylphenidate, as well as dextroamphetamine and similar amphetamines, can be more potent than modafinil, but side effects are more common with these drugs. It doesn't really go that much into treatment efficacy. Figure 2A is a pretty good diagram of the ascending reticular activating system though.
• PMID 27549768 – still need to read through this review.
• PMID 28424564 – still need to read through this review.

I need to read through the last 2 reviews and check for additional practice guidelines for narcolepsy. I don't have any more time to do this right now, so I'll continue this later. Seppi333 (Insert 2¢) 00:11, 21 July 2018 (UTC)

Section reflist

References

References tweaked

I removed pointers/links to sci-hub, as links to that site are blacklisted on en.wp and the WP:TLD keeps changing anyway, instead leaving DOI links. Obviously if you want to use sci-hub, that is enough info to find the articles there. DMacks (talk) 12:24, 17 October 2018 (UTC)

Updates

Monoaminergic/glutamatergic mechanisms

Things to add once I come across a second review covering all of these together - needs to provide context (citations for each are in the collapse tab below):

• Cover RhoA+ROCK-mediated DAT internalization - add to Amphetamine#Dopamine
• Cover RhoA-mediated EAAT3 internalization in mesolimbic dopamine neurons - add to Amphetamine#Other neurotransmitters, peptides, and hormones after the current sentence on EAAT3.
• Mention that VGlut2 (SLC17A6) is expressed in mesolimbic dopamine neurons and that both dopamine and glutamate are released from mesolimbic dopamine neurons - add to Amphetamine#Other neurotransmitters, peptides, and hormones immediately following the content on amphetamine-induced EAAT3 internalization.

Seppi333 (Insert 2¢) 21:11, 6 December 2016 (UTC)

Pharmacodynamics diagram updates + new pharmacodynamics table

PMID 27092049 - covers partial PKB signaling cascade: New TAAR1-DA neuron signaling diagram CAMKII signaling Check for newer research involving: PMID 26162812 – could participate in CAMKIIα phosphorylation mentioned in in the section on CAMKII PMID 24854234 – same as above with MDMA and SERT Seppi333 (Insert 2¢) 02:00, 31 March 2016 (UTC) Updated 02:05, 27 April 2016 (UTC) RhoA/ROCK signaling + DAT/EAAT3 internalization Review - covers effects of amph on RhoA signaling and RhoA-mediated EAAT3 internalization Primary - covers amph's cytosolic targets, effects of amph on RhoA signaling, ROCK activation, and ROCK-mediated DAT internalization (Note: this ref indicates that VGlut2 - the vesicular transport protein for glutamate which is located on glutamatergic synaptic vesicles - is expressed in mesolimbic TH-positive [i.e., dopamine] neurons; this implies that glutamatergic synaptic vesicles are present in mesolimbic DA neurons, which is a DA projection from midbrain nuclei [VTA+SNc] where EAAT3 is highly expressed according to PMID 25033183.) Quote from ref on VGlut2 Here we focused on the actions of AMPH on RhoA-dependent internalization of the DAT and explored how these effects on DAT trafficking might contribute to the acute behavioral response to the drug. However, recently we also demonstrated that a neuronal glutamate transporter, EAAT3, can be internalized in response to AMPH through a process that also appears to require Rho activation (17). This EAAT3 internalization in response to AMPH leads to a potentiation of glutamatergic synaptic responses in dopamine neurons and reveals a previously undescribed action of AMPH on glutamatergic signaling. A recent study has shown striking compartmentalization of glutamatergic and dopaminergic release sites within the processes of TH-positive neurons, where the two vesicular transporter types, VMAT2 and VGluT2, are segregated within distinct subcompartments (31). Intriguingly, we observe Rho activation broadly distributed within the processes of dopamine neurons. Taken together, these findings suggest a complex integration of dopaminergic and glutamatergic transmission within the mesoaccumbens pathway. Primary - covers amph's RhoA-mediated signaling cascade to DAT: transporter internalization via ROCKs (note to self: this ref covers PKC-mediated EAAT2 internalization; this is very likely the protein kinase that mediates TAAR1-mediated EAAT2 internalization by methamphetamine in astroglia - still have no clue why amphetamine doesn't do this) Primary already cited in the article - first paper to describe amphetamine-induced, RhoA-mediated internalization of EAAT3 in midbrain DA neurons Seppi333 (Insert 2¢) 22:02, 6 November 2016 (UTC); Updated 17:53, 14 November 2016 (UTC) Wikitable to add when updating pharmacodynamics diagram Will probably definitely need to add something analogous to the following sentence in a note in order to explain how the columns in the table below are related: Amphetamine interacts with its receptor protein target(s) (i.e., TAAR1 and a currently unidentified biomolecular target which initiates its CAMKIIα cascade), which triggers the activation of protein kinases. The activated kinases then phosphorylate their respective transporter(s), which in turn causes a conformational change in transporter protein, thereby altering its function and affecting dopaminergic/glutamatergic neurotransmission at dopaminergic synapses. Effects of amphetamine on membrane transport proteins in dopamine neurons Biological target of amphetamine Secondary effector protein kinase Phosphorylated transporter Effect on transporter function Effect on neurotransmission Sources Unidentified CAMKIIαTooltip Calcium/calmodulin-dependent protein kinase II alpha DATTooltip Dopamine transporter Reverse transport of dopamine Dopamine efflux into synaptic cleft TAAR1Tooltip Trace amine-associated receptor 1 ROCKTooltip Rho-associated protein kinase† DAT Transporter internalization Dopamine reuptake inhibition TAAR1 ROCK† EAAT3Tooltip Excitatory amino acid transporter 3 Transporter internalization Glutamate reuptake inhibition TAAR1 PKATooltip Protein kinase A DAT Transporter internalization Dopamine reuptake inhibition TAAR1 PKCTooltip Protein kinase C DAT Reverse transport of dopamine Transporter internalization Dopamine efflux into synaptic cleft Dopamine reuptake inhibition †Note: ROCK-mediated transporter internalization is transient due to the inactivation of RhoA (which activates ROCK) by PKA. The phosphorylation / inactivation of RhoA by PKA occurs roughly 10–15 minutes following neuronal exposure to amphetamine and more or less plateaus by 20–30 minutes post-exposure, based upon in vitro research. Seppi333 (Insert 2¢) 17:53, 14 November 2016 (UTC) Amphetamine-induced ERK1/2-mediated phosphorylation of DAT on the Thr53 residue, which induces DA efflux, also appears to occur; ERK1/2 is likely activated by the PKCβ isoform of PKC. Updated to reflect Fig 6, but listing ROCK (2nd effector) instead of RhoA (2nd messenger) based upon this ref.. Seppi333 (Insert 2¢) 21:51, 22 October 2019 (UTC) Section reflist Tentative changes to diagram Pharmacodynamics of amphetamine in a dopamine neuron via AADC Amphetamine enters the presynaptic neuron across the neuronal membrane or through DAT. Once inside, it binds to TAAR1 or enters synaptic vesicles through VMAT2. When amphetamine enters synaptic vesicles through VMAT2, it collapses the vesicular pH gradient, which in turn causes dopamine to be released into the cytosol (light tan-colored area) through VMAT2. When amphetamine binds to TAAR1, it reduces the firing rate of the dopamine neuron via G protein-coupled inwardly rectifying potassium channels (GIRKs) and activates protein kinase A (PKA) and protein kinase C (PKC), which subsequently phosphorylate DAT. PKA phosphorylation causes DAT to withdraw into the presynaptic neuron (internalize) and cease transport. PKC-phosphorylated DAT may either operate in reverse or, like PKA-phosphorylated DAT, internalize and cease transport. Amphetamine is also known to increase intracellular calcium, an effect which is associated with DAT phosphorylation through a CAMKIIα-dependent pathway, in turn producing dopamine efflux. Things to add to or change in the {{Amphetamine pharmacodynamics}} diagram: add some sort of geometric figure w/ "Unidentified intracellular target(s)" written in the center as text Just going to wait for the CAMKII-alpha cascade to be fully elucidated, but I have a gut feeling it's also TAAR1-activated. add glutamatergic synaptic vesicles w/ VGlut2 add some glutamate molecules to the figure add EAAT3 on the plasma membrane draw pathway from amphetamine through TAAR1, through RhoA, then through ROCK, then to both DAT and EAAT3 - indicate transporter internalization occurs† draw pathway from amphetamine through "Unidentified intracellular target(s)", through CAMKIIα, then to DAT, indicate DA efflux occurs‡ change "DAT internalization" to "PKA- or ROCK-mediated DAT internalization" change "Dopamine release" to "PKC- or CAMKIIα- mediated dopamine efflux" consider removing phenethylamine + trace amine signaling from the figure if it becomes too complicated as a result of these changes † need to wait for a ref to be published which explicitly states that DAT and EAAT3 are phosphorylated by a ROCK or a different RhoA-activated protein kinase ‡ need to find a ref to verify that CAMKII signaling is triggered by amphetamine interacting with an intracellular target before doing this - stated in this review: "Importantly, AMPH treatment of DAT transfected cells produced a rise in intracellular Ca2+ that could be blocked by thapsigargin or cocaine, supporting a model whereby AMPH is first transported into cells where it can then produce release of endoplasmic reticulum Ca2+ stores. Subsequently, AMPH was shown to activate CaMKII in DAT transfected cells (Wei et al., 2007)." Seppi333 (Insert 2¢) 17:53, 14 November 2016 (UTC) Diagram reflist

Addiction

• Really interesting papers based upon the abstracts; probably useful information worth adding to relevant articles: PMID 31749652, 29511807, 31071288, 31698743, 31680830
• Need to indicate that the current evidence base for physical exercise as a treatment for amph/meth addiction supports its use even as a monotherapy sans behavioral therapy and is more effective than CBT in certain outcome domains. Also a stronger evidence base for exercise as an addiction prophylactic PMID 31344831, 29266758, 29430384, 29338767
• PMID 31695630 - interesting cognitive control-based strategy (maximal utilization of working memory) to interfere with craving/incentive salience for drug use
• May 2017 meta-analysis

References

Menstrual cycle

• Seppi333 (Insert 2¢) 03:13, 29 September 2016 (UTC)

Need more evidence on this before covering sex-dependent differences in drug response. Seppi333 (Insert 2¢) 17:39, 25 December 2019 (UTC)

References

Effects

• - may be worth covering some content from this chapter:
  1. acute effect on glucocorticoids via HPA axis  Done
  2. amphetamine increases orgasm pleasure, libido increases more in women than in men, high/supratherapeutic doses significantly promote libido  Pending
     • Also covered in PMID 26147855
     • Sexual arousal examined in this RCT: PMID 29511807

Seppi333 (Insert 2¢) 08:28, 4 December 2015 (UTC)

Updated 06:54, 9 October 2016 (UTC)

Updated 17:39, 25 December 2019 (UTC)

References

• Sooo, it's literally just synthetic adrenaline? lol 67.193.213.188 (talk) —Preceding undated comment added 16:58, 24 June 2020 (UTC)

Completed updates

Resolved threads

Older addiction content

• Review: human studies involving environmental enrichment and physical exercise

   Partly done - need to cover research on human environmental enrichment-based addiction treatments in Amphetamine#Behavioral treatments and summarize the added material in the 2nd paragraph under Amphetamine#Overdose. Seppi333 (Insert 2¢) 21:30, 16 November 2016 (UTC)

References

Pharmaceuticals + related article text

Resolved

• - also need to update table entry  Done

Seppi333 (Insert 2¢) 17:33, 16 November 2015 (UTC)

References

Abuse contraindication

Resolved

• Add note on abuse history and prescriptions  Done

Seppi333 (Insert 2¢) 21:21, 9 December 2015 (UTC)

References

another ergogenic effect

Resolved

• greater power output without any change in perceived exertion  Added
• neurophysiological mechanism is mediated by CNS dopamine, which allows the body to increase power output without affecting perceived exertion, presumably by raising the core temperature limit.  Added

Seppi333 (Insert 2¢) 08:18, 9 March 2016 (UTC)

References

Ntox

Resolved

• Review - covers relationship between amphetamine-induced hyperthermia and neurotoxicity  Added

Seppi333 (Insert 2¢) 22:02, 6 November 2016 (UTC)

References

Carbonic anhydrases

Resolved

Brain carbonic anhydrase activation

Human carbonic anhydrase activation potency Enzyme KA (nMTooltip nanomolar) Sources hCA4 94 hCA5A 810 hCA5B 2560 hCA7 910 hCA12 640 hCA13 24100 hCA14 9150 @Boghog: Can you help me create CA5A/carbonic anhydrase 5A and CA13/carbonic anhydrase 13? Those are the only carbonic anhydrase genes/proteins that WP is missing articles on (according to list of human protein-coding genes 1). Seppi333 (Insert 2¢) 22:19, 31 December 2019 (UTC) Given that the following passage very closely paraphrases (w/ entire clauses repeated verbatem; they even cite my molecular neuropharmacology textbook... lol) a late-2017 amphetamine revision, I don't really care about the length of the quote in the citation to the 1st paper. I.e., this entire paragraph: Amines 5–9 are strong central nervous system (CNS) stimulants and were originally used as drugs, for the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, obesity, nasal congestion, and depression35–37. They interfere with the catecholamine neurotransmitters norepinephrine and dopamine metabolism, by the activation of a trace amine receptor31, which leads to an increase of monoamine and excitatory neurotransmitter activity in the brain, leading to emotional and cognitive effects such as euphoria, change in desire for sex, increased wakefulness, accompanied by improved cognitive control38–40. However, drug addiction is a serious risk with the recreational use of these substances, with high doses leading to psychosis, such as delusions and paranoia, as well as many other serious side effects41. Need to create a wikitable to add activation data to the article in the very near future. Other refs on CA activation: IUPHAR/BPS entry and a primary source covering amph-induced activation of 2 hCA isoforms Regarding glaucoma-implicated CA isoenzymes (CA2, CA4, and CA12): References

Re

@Doc James and Casliber: Would like your feedback on Amphetamine#Pharmacomicrobiomics; pinging you two since you recently took an interest in this article. Only the second paragraph is technically "on topic" and within the article's scope, but the 2nd paragraph almost seems like trivia without a contextual understanding, which is what the first paragraph provides: it states the types of clinically significant drug-microbiota interactions. Really just looking for general feedback, but also wondering whether you think this particular statement from the 1st paragraph is worth keeping or cutting: The nascent and active field of research on drug-microbe interactions – known as pharmacomicrobiomics – lies at the intersection of systems microbiology, genomics, systems pharmacology, and personalized medicine.

@AmericanLemming: If you could proofread/copyedit this section like you did with the other technical ones during the FAC review, I'd greatly appreciate it. I did my best to make it accessible, but I think you might be a better judge of what is/isn't understandable to a layperson than me for this topic. Seppi333 (Insert 2¢) 16:37, 5 August 2019 (UTC)

I agree that the first paragraph is too off-topic to include. I'd remove it. Cas Liber (talk · contribs) 20:34, 5 August 2019 (UTC)

I also agree with removing that paragraph due to it being off topic. Doc James (talk · contribs · email) 04:04, 7 August 2019 (UTC)

Initial comments

1. I agree with CasLiber that the first paragraph is a bit off-topic; the information there probably fits better in the main pharmacomicrobiomics article.

2. Also, it would be helpful to briefly explain the significance/implications of this study; for example, do the authors think that differences in the microbiome between individuals might explain some of the differences in how they respond to amphetamine?

3. I noticed that the link for tyramine oxidase redirects to the article on monoamine oxidase; is this bacterial enzyme analogous to human monoamine oxidase?

That's all for today. AmericanLemming (talk) 01:05, 7 August 2019 (UTC)

Re 1&2: Excluding the statements in the note and the first sentence about microbial and human genomes, everything in the first paragraph is mentioned in that study; the clinical significance of the finding is also mentioned in the paper, but I figured that since it's a primary source, I probably shouldn't be using it to cite a clinical claim. In a nutshell, the clinical significance is that E. coli can affect amphetamine's pharmacokinetics (its oral bioavailability and its metabolism) and variations in gastrointestinal E. coli colonization/concentration between individuals explains some of the inter-individual variation in amphetamine's clinical response (very high prevalence of E. coli in the gut → reduced clinical efficacy relative to people with normal [low] amounts of E. coli in the gut). It goes on to discuss the use of the findings in redesigning the drug (see the quote below or read the end of the paper here: sci-hub.tw/10.1002/jcb.28396); however, I don't think the authors knew that amphetamine's prodrug (lisdexamfetamine) isn't converted into dextroamphetamine until it's absorbed into human blood plasma, which is (normally) sterile. I don't think it's likely that lisdexamfetamine would be metabolized by E. coli's tyramine oxidase due to the sizable difference in the chemical structure, but I may be wrong. @Doc James: do you think I should just cite the paper for the clinical statements?

Re 3: the tyramine oxidase they're referring to is the tyramine oxidase encoded by E. coli's tynA gene (this isn't mentioned in the paper, but they refer readers to expasy.org, which after navigating through the cross-links, one can find that tynA is listed as the encoding gene for E. coli's tyramine oxidase; also, the tyramine oxidase for one of the E. coli strains (i.e., MS 116‐1) that were mentioned in the paper (strains ATCC 8739, HS, MS 116‐1, MS 146‐1, MS 175‐1) on NCBI Protein is listed as being encoded by tynA). The correct article on this would be primary amine oxidase (per the NCBI Protein link, [1], and the UniProt entry for tynA in E. coli) since that's the name of the protein that tynA encodes and the fact that we normally use protein names as article titles.

Tangential point: Based upon the reaction that tyramine oxidase catalyzes (i.e., RCH₂NH₂ + H₂O + O₂ $\rightleftharpoons$ RCHO + NH₃ + H₂O₂) and more specifically the fact that tynA metabolizes phenethylamine into phenylacetaldehyde and tyramine (4-hydroxyphenethylamine) into 4-hydroxyphenylacetaldehyde (I created this article today due to the number of red backlinks; the metabolic pathway I'm talking about here is now covered in that article), E. coli would seem to metabolize amphetamine into alpha-methylphenylacetaldehyde (which is probably further metabolized by E. coli's feaB enzyme into a methylated derivative of phenylacetate, based upon the metabolic fate of phenylacetaldehye and 4-hydroxyphenylacetaldehyde in E. coli - this pathway is covered in the UniProt link); that compound isn't naturally produced by any human enzymes. I obviously can't state any of this in the article since I can't (yet) cite a paper that explicitly covers it. Seppi333 (Insert 2¢) 11:31, 7 August 2019 (UTC)

Edit: I fixed the tyramine oxidase link in the article and mentioned tyramine oxidase/tynA in primary amine oxidase. The tyramine oxidase redirect is probably correctly targeted since I'm fairly certain that synonym maps either to the human MAOA gene or both human MAO genes. Seppi333 (Insert 2¢) 05:16, 8 August 2019 (UTC)

Is this clinically important. Doc James (talk · contribs · email) 13:55, 8 August 2019 (UTC)

Yes, and this information can be used clinically in any doctors' office that can test for microbial concentrations of specific strains of bacteria (which admittedly is very few at the moment, as it would require employing the same molecular biology techniques as required for diagnosing small intestinal bacterial overgrowth - i.e., gut fluid aspiration and a microbiological culture). Seppi333 (Insert 2¢) 03:58, 10 August 2019 (UTC)

References

Follow-up comments

I’m pretty satisfied with the section as a whole; I just have some suggestions for replacing some technical language with simpler language that conveys largely the same meaning.

4. In the first paragraph, it says “Homo sapiens cells”; I would just call them “human cells”.

5. Also, I think it would still be a good idea to give a brief definition of what “pharmacomicrobiomics” means and link to the article on it. I suggest something like “there is considerable potential for interactions between drugs and an individual's microbiome. The study of these interactions is called pharmacomicrobiomics, which include drugs altering the composition of the human microbiome…”

6. As for the second paragraph, we should probably link promiscuous metabolism (needs to be piped) and include a brief definition in a footnote, since I don't feel that the introduction to the Enzyme promiscuity article is all that helpful for a non-expert like me.

7. Replacing human gastrointestinal microbiota with “gut bacteria” would probably be an oversimplification, but if bacteria are mainly responsible for drug metabolism by microbes, could we put say “primarily bacteria” in parentheses afterward?

8. Also, replacing “into blood plasma” with “into the blood” would sacrifice a little precision but would be a little simpler. AmericanLemming (talk) 03:03, 13 August 2019 (UTC)

@AmericanLemming: Sorry about the long delay in my reply; I'd meant to respond earlier but was tied up at the time and forgot about it in the meantime.

4.  Done

5.  Added at the end of the first paragraph: "The field that studies these interactions is known as pharmacomicrobiomics."

6. I think what the authors meant here was that amphetamine is likely a ligand for (i.e., likely metabolized by) many currently unidentified microbial enzymes, not that the enzymes themselves are promiscuous.

7.  Done

8.  Done - changed it to "into the blood stream"

Seppi333 (Insert 2¢) 12:07, 16 August 2019 (UTC)

@AmericanLemming: Thank you for reviewing that for me! Seppi333 (Insert 2¢) 06:34, 18 August 2019 (UTC)

I find this page to be biased in the emphasis on how safe amphetamines are and that when abused then there are problems. Many people end up with issues at prescribed doses such as withdrawal and dependence which can also be found in research. Mentions how younger kids are less likely to abuse drugs later on in life if they start on amphetamines at a young age. What is skipped is that starting at any other age increases the chance. Ignores acute tolerance which happens within hours of taking the medication and was used to base the design of various extended release products. Ignores many harmful aspects such as oxidative stress, downregulation of receptors and the production of neurotransmitters, neurotransmitter depletion, Instead it only mentions pathways to addiction. Dependence is related, but not mentioned when the brain no longer efficiently manages it's own neurotransmitters and has to rely on the medication to do it. Even at low doses people often feel the Adderall crash when it wears off. All be it mildly. Feels like every section has to say something about it's safe at prescribed doses or implies negative outcomes only for abusers. Seems more like damage control and people trying to sell me on the idea. Safety and what not should be in one section, not in every section as if trying to protect peoples perceptions. Not a single mention of the effects on the endocrine system. Skipped the issue on stunted growth all together. etc. Aside from that, very informative. — Preceding unsigned comment added by 69.248.160.198 (talk) 10:32, 9 April 2023 (UTC)

I don't 🤷 Strawkipedia (talk) 06:29, 8 July 2023 (UTC)

• Mentions how younger kids are less likely to abuse drugs later on in life if they start on amphetamines at a young age. What is skipped is that starting at any other age increases the chance. That's news to me. Feel free to cite a reliable medical source, and I'd add that information myself.
• Many people end up with issues at prescribed doses such as withdrawal and dependence which can also be found in research. Yes, it's mild and lasts about a week, if it occurs at all. It's not mild for recreational users, but it still only persists for a few weeks even in the heaviest recreational users. Why does this deserve to be mentioned for people taking therapeutic doses when it's generally subclinical (i.e., doctors and psychiatrists discontinuing the medication don't gradually taper the dose), if it occurs at all, though? Moreover, wouldn't covering this reaffirm your belief that the article is biased in convincing you of safety?
• Ignores acute tolerance which happens within hours of taking the medication and was used to base the design of various extended release products. What?
• Ignores many harmful aspects such as oxidative stress, downregulation of receptors and the production of neurotransmitters, neurotransmitter depletion, Feel free to cite some medical sources discussing evidence found in humans, and I'll add it to the article.
• Skipped the issue on stunted growth all together. You clearly did not actually read the article. It's been covered in Amphetamine#Contraindications for at least the past 6 years.
• Generally speaking, for a drug that's used clinically and recreationally, why do you expect the article to conflate the effects of clinical low-dose use and recreational high-dose use? It either biases the reader into thinking recreational use is safer than it actually is, clinical use is less safe than it actually is, or both. I don't particularly care whether the inclusion of content makes people think the article is biased. I do care about the omission of content, though.

Seppi333 (Insert 2¢) 19:41, 25 July 2023 (UTC)

WP:FACR: 2c

@Headbomb: You updated 2 page ranges, added 2 pmcs, added 3 issues, and added a missing year in [2]; those were the useful revisions. Meanwhile, you changed some of the abbreviated journal titles to full titles, while leaving e.g., references 101, 102, 103, and 105 abbreviated. All of the journals were consistently formatted before you used a bot to bork the citation formatting (which is why those bots were denied from editing this page before you removed them from the template). You need to consistently format the journal titles in this article or I'm going to revert your edit. It's not my job to clean up after bot edits that inconsistently revise this page's citations. Seppi333 (Insert 2¢) 20:06, 24 December 2019 (UTC)

Should be fixed now. Citations were located in different templates. Headbomb {t · c · p · b} 20:17, 24 December 2019 (UTC)

6, 8, 11, 184, and 188 are all still "J. soandso." Seppi333 (Insert 2¢) 20:35, 24 December 2019 (UTC)

Same reason. Done. Headbomb {t · c · p · b} 20:55, 24 December 2019 (UTC)

@Headbomb: Thanks. With that fixed, your revisions were rather helpful overall. Seppi333 (Insert 2¢) 23:24, 24 December 2019 (UTC)

Abbreviations

Resolved

@Seppi333: It isn't clear if MOS:FIRSTABBR should apply to citations since they stand alone in their usage. For example, there is no problem with repeating the same link in many citations within an article MOS:REPEATLINK. Whywhenwhohow (talk) 06:22, 25 December 2019 (UTC)

@Whywhenwhohow: I'm familiar with the exception for links in citations; I simply dislike them. When I click something in a citation, I expect to navigate outside WP, not internally. Ignoring the guideline entirely, an abbreviation for a website or publisher entry is just extraneous markup; it doesn't serve any purpose like it does in the article text.

Anyway, can you restore the publisher parameters in the citations to the FDA website that you changed to DailyMed? It should be listed as the manufacturer; regardless of what website hosts the prescribing information, the publisher would still remain the same. I already restored a few, but there's others that need to be fixed. Seppi333 (Insert 2¢) 06:58, 25 December 2019 (UTC)

Yes, but why do you prefer the ones from the FDA website? They are PDF format and harder to navigate? The NIH DailyMed website is the official provider of FDA label information Whywhenwhohow (talk) 08:27, 25 December 2019 (UTC)

I don't have a fixed preference for DailyMed or the FDA's labels as a citation since both have an advantage over the other; the actual content is identical though. The PDFs have page numbers which makes verifiability easier when the prescribing information is rather long, but DailyMed is easier to navigate given its design. I'm just used to citing FDA labels since I've always used Drugs@FDA to search for drug information (e.g., the label itself, approval data, and information on current/actively marketed brands as well as discontinued drug products associated with the active ingredient I'm searching).

In any event, I just realized that I worded my earlier request about the publisher information very poorly; what I meant to say was to restore the publisher parameters from the FDA citations in the DailyMed citations. Databases like Drugs@FDA and DailyMed that host a drug label online should always just be listed in the website/work parameter of {{cite web}}, so you were doing that part correctly. The publishers are the entities that write/edit and produce a document, which in this case is the prescribing information − i.e., pharmaceutical companies like Shire Plc, Hoffmann-La Roche, Merck & Co, etc.. While the FDA approves prescribing information for drugs, the drug label for any given drug is the copyrighted intellectual property of the manufacturer/pharmaceutical company that produces the drug because they're the authors of the corresponding drug label; that's why they're listed as the publisher for drug labels. I've added the original citation templates below as an example. In any event, I'll go ahead and fix the DailyMed citations since you already spent time actioning my poorly worded request. Seppi333 (Insert 2¢) 09:59, 25 December 2019 (UTC)

They're all fixed now. If you want to change the 2 FDA drug label citations I added to DailyMed citations, feel free to do so. I don't really care which one we use. Seppi333 (Insert 2¢) 10:19, 25 December 2019 (UTC)

Drug label citation templates

{{cite web|title=Adderall IR Prescribing Information|url=www.accessdata.fda.gov/drugsatfda_docs/label/2015/011522s042lbl.pdf|publisher = Teva Pharmaceuticals USA, Inc.|work = United States Food and Drug Administration|date=October 2015|accessdate=18 May 2016|pages=1–6}} {{cite web|title = Adderall XR Prescribing Information|url = www.accessdata.fda.gov/drugsatfda_docs/label/2013/021303s026lbl.pdf|page = 11|publisher = Shire US Inc.|work = United States Food and Drug Administration|date=December 2013|accessdate = 30 December 2013}} {{cite web|title=Evekeo Prescribing Information|url=www.evekeo.com/assets/evekeo-pi.pdf|publisher=Arbor Pharmaceuticals LLC|accessdate=20 July 2018|pages=1–2|date=September 2016}} {{cite web|title=Dyanavel XR Prescribing Information|url=www.accessdata.fda.gov/drugsatfda_docs/label/2017/208147s003lbl.pdf|publisher= Tris Pharma, Inc.|work=United States Food and Drug Administration|accessdate=4 August 2017|pages=1–14|date=May 2017|quote=DYANAVEL XR contains d-amphetamine and l-amphetamine in a ratio of 3.2 to 1 ... The most common (≥2% in the DYANAVEL XR group and greater than placebo) adverse reactions reported in the Phase 3 controlled study conducted in 108 patients with ADHD (aged 6–12 years) were: epistaxis, allergic rhinitis and upper abdominal pain. ... <br />DOSAGE FORMS AND STRENGTHS<br />Extended-release oral suspension contains 2.5 mg amphetamine base per mL.}} {{cite web|title=Vyvanse Prescribing Information|url=www.accessdata.fda.gov/drugsatfda_docs/label/2017/021977s045,208510s001lbl.pdf|pages = 3–13, 17–21|website = United States Food and Drug Administration|publisher = Shire US Inc.|accessdate=10 July 2017|date = May 2017}} {{cite web|title=Mydayis Prescribing Information|url=www.accessdata.fda.gov/drugsatfda_docs/label/2017/022063s000lbl.pdf|website=United States Food and Drug Administration|publisher=Shire US Inc.|accessdate=8 August 2017|pages=1–21|date=June 2017}} {{cite web|title=Adzenys XR-ODT Prescribing Information|url=www.accessdata.fda.gov/drugsatfda_docs/label/2017/204326s002lbl.pdf|website = United States Food and Drug Administration|publisher=Neos Therapeutics, Inc.|accessdate=10 August 2017|page=16|date=January 2017|quote = ADZENYS XR-ODT (amphetamine extended-release orally disintegrating tablet) contains a 3 to 1 ratio of d- to l-amphetamine, a central nervous system stimulant.}}

Page size

At 241,890 bytes of wiki markup, this page is far too large. That's particularly troubling for a page listed as a featured article. How can it best be divided? For example, splitting off the entire 'Pharmacology' section would remove over a fifth of that (less if a summary is kept here). Andy Mabbett (Pigsonthewing); Talk to Andy; Andy's edits 11:19, 2 January 2020 (UTC) @Pigsonthewing:

Document statistics:

File size: 989 kB

Prose size (including all HTML code): 123 kB

References (including all HTML code): 25 kB

Wiki text: 236 kB

Prose size (text only): 49 kB (6811 words) "readable prose size"

References (text only): 2506 B

User_talk:Dr_pda/prosesize.js

To quote WP:TOOBIG: These rules of thumb apply only to readable prose and not to wiki markup size (as found on history lists or other means), and each kB can be equated to 1,000 characters.

I'm not even going to consider splitting this article right now given that it's not even that long by the actual guideline metric. Seppi333 (Insert 2¢) 11:43, 2 January 2020 (UTC)

Wow, four bigs, and and underline? -- Mikeblas (talk) 19:56, 12 July 2020 (UTC)

"I'm not even going to consider..." That's OK, you're not required to participate. But in declaring that you're not participating, please don't selectively quite only parts of a guideline, as you do - unnecessarily garishly - above. The guidleline also says, near the top of the page (and so before the subsection you quote): "There are three related measures of an article's size: Readable-prose size [...] Wiki markup size [and] Browser-page size". Andy Mabbett (Pigsonthewing); Talk to Andy; Andy's edits 12:05, 2 January 2020 (UTC)

Yes, and the guideline says absolutely nothing about hard-limits on markup size like it does with the prose size, which you clearly are trying to use as a justification for splitting pages based upon their on markup size. The thing is, this page might have a markup size in the 200+kB range, but both this script and xtools indicate that the prose size is 49-50kB. No one is going to buy what you are selling if you keep trying to argue that this page needs to be split based upon markup size. And even if that was an issue, which it clearly is not, I could simply move this entire page's source code to a template and transclude it in, causing this page's markup size to drop to <10kB while the readable prose size remains the same. Seppi333 (Insert 2¢) 12:14, 2 January 2020 (UTC)

Not so; for example the guideline says: "The text on a 32 kB page takes about five seconds to load for editing on a dial-up connection, with accompanying images taking additional time, so pages significantly larger than this are difficult for older browsers to display. Some large articles exist for topics that require depth and detail, but typically articles of such size are split into two or more smaller articles. ". Andy Mabbett (Pigsonthewing); Talk to Andy; Andy's edits 12:21, 2 January 2020 (UTC)

I don't see a hard/fixed limit anywhere in the text you quoted. It appears to assert the incredibly obvious fact that shittier connections load webpages more slowly, and we're talking about two-tenths of one megabyte. Seppi333 (Insert 2¢) 12:26, 2 January 2020 (UTC)

Wikipedia talk:Article size is available, should you wish to dispute the contents of the guideline. Andy Mabbett (Pigsonthewing); Talk to Andy; Andy's edits 12:50, 2 January 2020 (UTC)

@Pigsonthewing: Dispute the guideline? Why would I do that? It supports my assertion and contradicts yours. I'm actually happy with it the way it is. Also, thank you again for the nomination. You're doing me a favor here. Seppi333 (Insert 2¢) 13:15, 2 January 2020 (UTC)