Talk:Amphetamine

Shudde

@Shudde: PLEASE SEE WT:MED DISCUSSION. If you want to contribute to the discussion regarding the citation standards and language regarding the United States in this article, feel free to contribute to the conversation there. Seppi333 (Insert 2¢ | Maintained) 12:31, 27 May 2014 (UTC)

@Shudde: Continue your review here. Seppi333 (Insert 2¢ | Maintained) 06:55, 24 April 2014 (UTC)

PS: It shouldn't take you two full months to review this article. Seppi333 (Insert 2¢ | Maintained) 06:57, 24 April 2014 (UTC)

There are plenty of comments at the recent FAC that probably need to be fully addressed. My comments there should be taken as guidance and examples of what further work is required, rather than a point by point list of problems. I'm not going to repeat all those here as it's not necessary. I'll repeat a couple of my concerns though, and will wait until these have been adequately addressed before giving the article another read through.

• There is Wikipedia:Citation overkill in this article, I'm not sure why we need a citation every single sentence rather than following this guideline. I don't know of another article that insists on at least one inline citation every sentence. As the essay says as per WP:PAIC, citations should be placed at the end of the passage that they support. If one source alone supports consecutive sentences in the same paragraph, one citation of it at the end of the final sentence is sufficient. It is not necessary to include a citation for each individual consecutive sentence, as this is overkill.

I'm seeking consensus on WT:MED at the moment. You're welcome to participate. The citation style will only follow what what is supported there. Seppi333 (Insert 2¢ | Maintained) 12:31, 27 May 2014 (UTC)

• Try and fix overlinking (WP:OVERLINK). As Tony1 says in User:Tony1/Build your linking skills -- It is only over the past few years that we have begun to realise the potential for refining wikilinking—how sophisticated decision-making is required to achieve a high standard of linking: what to link, what not to link, how and when to research more focused links, and how to integrate links smoothly into the text. In this respect, linking deserves attention just as does the prose in our articles. I'd recommend at least reading Tony1's guide on this before deciding what to link or not link. We've also got a large number of duplicate links.

I've addressed this to a max of 2 WL's/term using AWB. Seppi333 (Insert 2¢ | Maintained) 12:31, 27 May 2014 (UTC)

• There is a lot of jargon and technical language that needs to be reduced in order to increase accessibility. At the moment the article reads like it is written for an MD rather than a general audience. There are plenty of high quality references for those that want technical details -- also notes can help with this, giving more information than the general reader would require. Wikipedia:Manual of Style/Medicine-related articles expresses my concerns well. I'll point to the section Technical terminology, and also to the section Signs of writing or editing for (other) healthcare professionals. In particular You use jargon when there are suitable plain English words (for example, consider using "kidney" rather than "renal"). and You use a writing style appropriate only for graduate-level courses, because that's what you see in peer-reviewed journal articles and professional reference works.. For this reason, once you've reduced the jargon and tried to make the language less technical, it may be worth getting several non-experts to read through the text and give feedback on accessibility.

I believe I've addressed this in pharmacodynamics. I've gotten feedback from WT:MED on side effects and OD symptoms. My unorthodox link to the less technical version on Adderall was also supported in a discussion on WT:MED. I await your thoughts. Seppi333 (Insert 2¢ | Maintained) 12:31, 27 May 2014 (UTC)

• Once everything else is done, the lead probably needs a careful read through. At the moment there are four notes, and a large number of references. This really should not be necessary if the lead is written well, and if it doesn't cover any material not covered in the main text of the article. I would leave addressing this until you're happy with everything else though.

I'm seeking consensus on WT:MED at the moment. You're welcome to participate. I do not agree with you on this, but this is up to the community and not me or the FAC review. Seppi333 (Insert 2¢ | Maintained) 12:31, 27 May 2014 (UTC)

• The article is very US-centric. I mentioned this several times during the FAC, giving a few examples. However it's a general problem that is prevalent throughout the article.

I'm seeking consensus on WT:MED at the moment. You're welcome to participate. I don't believe that it is US centric, but I'm not entirely sure that I know what your concern is either. I've asked WT:MED to take a look and make a determination on this. Hence, the removal of any language regarding the US will be up to the consensus developed there. Seppi333 (Insert 2¢ | Maintained) 12:31, 27 May 2014 (UTC)

• Some concerns at the previous FAC, and the talk page archives have not been addressed and kept popping up. For example a number of Aa77zz's concerns are still present, and maybe some in the talk-page archives as well (lead verbosity for example). I suppose my point is that if people keep raising very similar concerns, there is probably something in it, even if you disagree, and may be worth the effort to make extra sure that it's been addressed adequately.

AA77zz's concerns about the lead are now entirely moot. I'm seeking a consensus, rendering his personal preference unimportant, unless he wishes to participate in the discussion. Seppi333 (Insert 2¢ | Maintained) 12:31, 27 May 2014 (UTC)

I'll leave you to use this feedback. If you try and address these comments, and think the article is ready for FA, I'd then open a peer review and ask for further feedback. Having a peer review is better than using the talk page because it keeps everything together and can easily be referred to in the future (like past FACs, GA reviews etc) rather than an annoying search back through talk page archives. I'm not sure exactly how to take your last comment, but an incomplete review at FAC should not run to > 100 kB. That's probably a sign that the article was far from ready before being nominated. There is still a lot to do before the article is ready, and it's not just a case of giving it a little bit of a polish. Because of this, I'm going to give you at least a few weeks before coming back, but if you're convinced it's ready before then do let me know. I hope all this helps, and also hope you remember that there is no deadline here, better to take the time getting it right rather than rushing back to FAC, which could just lead to frustration (for everyone). -- Shudde ^talk 07:30, 25 April 2014 (UTC)

Alright, I'll work on that. Thank you for explaining that - I didn't understand the "big picture" that you had in mind during the FAC review - this helps me a lot more than a sentence-by-sentence review. Seppi333 (Insert 2¢ | Maintained) 13:51, 26 April 2014 (UTC)

@Shudde:How should I approach accessibility in sections that are inherently technical, like pharmacology, synthesis, and detection in bodily fluids? Seppi333 (Insert 2¢ | Maintained) 14:08, 26 April 2014 (UTC)

One suggestion I have for the pharmacodynamics section is to start out with a less technical overview focusing initially on what amphetamine does rather how it does it. For example, the current third paragraph could begin the section. I think this paragraph would provide a more accessible introduction to the section. Boghog (talk) 17:05, 26 April 2014 (UTC)

Good idea - I'll tinker with that section sometime today or tomorrow.
Thanks for your help with reducing overlinking! Seppi333 (Insert 2¢ | Maintained) 19:58, 26 April 2014 (UTC)

I'm not sure there is an easy way to reduce jargon and increase accessibility. I wish there was some kind of step-by-step guide out there, but I've not seen one. The only advice I can give is have a look at User:Tony1/Writing exercise box and see if there is anything in there that may be of use. I'm not sure what else I can suggest, other than maybe trying to recruit some non-experts to help with the copy-edit, but that may be difficult. -- Shudde ^talk 00:24, 27 April 2014 (UTC)

@All: I've been procrastinating - I'll make the edits to pharmacology before Friday and repost here once I'm done simplifying what I can.

Medical uses - Summary of Millichap's review

@Shudde: I'm still sort of unsure about what your concerns were with the long-term evidence review, so I was wondering if you would be willing to read the cited section excerpt and give me your thoughts on how you'd phrase it:

Quoted from pages 122-123 of the Millichap text (Link inside tab).

Text link Long-Term Usage of Stimulants and Outcome of ADHD Studies of long-term, uninterrupted stimulant therapy for ADHD are infrequent. One recent report of a 15-month controlled trial of amphetamine in 62 children, aged 6–11 years, showed continued improvements in behavior and learning ability, with no serious side effects. A multicenter, placebo-controlled trial of amphetamine treatment for ADHD in Sweden found significant improvements in attention, hyper- activity, and disruptive behaviors and a mean change in IQ of +4.5 after more than 9 months of amphetamine sulfate. Side effects included decreased appetite in 56%, abdominal pain in 32%, tics in 29%, and visual hallucinations requiring dose reduc- tion or withdrawal in 5%. Abdominal pain and tics occurred with equal frequency in the placebo group, and only one of 4 children with tics at baseline had an increase in symptoms during amphetamine (15 mg/day) treatment (Gillberg et al., 1997). The children in the Swedish study had a high incidence of comorbid diag- noses (42%), including pervasive developmental disorders, mild retardation, and oppositional defiant disorder. Long-term trials of stimulants in ADHD with less comorbidity would be expected to show greater beneficial effects and a lower inci- dence of side effects. The unusually high incidence of tic disorders in both treated and untreated children was remarkable. The following wasn't mentioned in the article, but it's one of the two additional amphetamine studies covered in the supplemental review I've linked below this tab. From page 121 of this textbook: Adderall XR, an extended-release form, reaches a peak level at 7–8 h and the effect may last for 12 h. In a long-term 24-month, multicenter, open-label, placebo-controlled trial of Adderall XR in 568 children, aged 6–12 years, sig- nificant improvements (>30%) in a Conners Global Index Scale, Parents version, were maintained. Adverse events included anorexia (15%), headache (15%), and insomnia (11%); 15% withdrew from the study because of adverse events. Serious adverse events occurred in 3%, including convulsions in two patients, at doses 10 and 20 mg/day. Mean systolic blood pressure increased by 3.5 mmHg, diastolic by 2.6 mmHg, and pulse rate by 3.4 beats per min (McGough et al., 2005).

The author stated that the underlined study was both multicenter and placebo controlled, which makes it higher quality evidence than the other open placebo-controlled studies. I uploaded this newer review which indicated more or less the same continuation of benefits from 2 studies involving ~2 years of amphetamine use (Scroll down to table 2 or search for the term "amfetamine" to get there - the paper uses the amphetamine INN); these were open, placebo-controlled trials though. Millichap also pointed out the unusually exceptional benefits beyond just a continued therapeutic effect that were observed in that multicenter trial as well.

• A note about the studies: I don't know if this is obvious or not, but it's not really possible to "blind" the patients in a study involving amphetamine, so none of the referenced studies are double-blinded. Amphetamine has a rapid onset with an extremely noticeable psychoactive effect even in long-term daily users of the drug. Receiving the drug vs placebo is probably about as obvious as taking very high-dose niacin vs a placebo in niacin megadose-naive individuals (i.e., the presence/absence of the massive full-body niacin-flush would be telling).
  

Any thoughts/advice/suggestions on communicating this material? Seppi333 (Insert 2¢ | Maintained) 08:43, 30 April 2014 (UTC)

Pharmacodynamics

I followed Boghog's advice and put the simpler and more general pharmacodynamic information first. It currently summarizes the effect it has on catecholamines and the neural pathways in acts upon in the first paragraph. I don't think I can simplify the subsequent material more than using the graphic I made to illustrate the process though. It simply requires a technical background to understand.
In any event, I'm satisfied with this section now. If you could take a look at it and give me your thoughts, I'd appreciate it. Seppi333 (Insert 2¢ | Maintained) 03:19, 4 May 2014 (UTC)

Wikilinks

Per AWB, there's now at most 2 wikilinks for any given term in the article. Seppi333 (Insert 2¢ | Maintained) 03:39, 4 May 2014 (UTC)

Discussion

@Shudde: Can you give me some feedback on the recent changes please? Seppi333 (Insert 2¢ | Maintained) 03:45, 4 May 2014 (UTC)

I'll have a brief look, but I've got a few other projects on the go at the moment, so can't promise too much time during the next two weeks. Sorry I forgot to answer the Millichap comment, but my problem was never with the use of them as a source, rather (as per my FAC comments) how the material was presented. There is a more detailed critique at the FAC. -- Shudde ^talk 04:05, 4 May 2014 (UTC)

Is there any specific area where you want feedback? Like I said I can't devote much time, so if you have a particular area you want me to look at then that would be good. -- Shudde ^talk 04:09, 4 May 2014 (UTC)

Just two things: help with phrasing the Millichap cited prose and your thoughts on the general layout of pharmacodynamics in terms of accessibility. Seppi333 (Insert 2¢ | Maintained) 04:18, 4 May 2014 (UTC)

Regarding the layout of that section, I'm not sure it makes life much easier regarding accessibility. Even the first sentence, indeed the first paragraph, reads much more like a technical review than an encyclopaedia article. Regarding the Millichap paragraph, it's very dry, which is one of the problems. It again reads as technical, is it important the children were Swedish? Do we need to know it was a 4.5 increase in IQ (rather than just an increase, or small increase, or moderate increase? Are these details important to non-technical readers? Technical readers should have access to the review and the primary literature, so if they want these details they are available; we shouldn't be including a lot of info on the methodology unless we absolutely have to. This is part of the problem with the article, it gives excessive technical detail, which hinders readability, does not increase accessibility, and seems unlikely to appeal to many non-lay readers. Try and cut that where you can, and if you really, really want to keep some of it, then retain it as a note rather than in the main body of text. That way someone that wants the technical details without accessing the sources (I would hope these would not be professionals or researchers) can do so, but it doesn't weigh down the text, or make the prose suffer. -- Shudde ^talk 04:46, 4 May 2014 (UTC)

I'll see what I can do what I can about the detail. I didn't make any changes to the Millichap sentence - I linked it above because I wanted your take on how to phrase it. I'm not entirely sure what your concern is so I don't think I can fix the problem myself. I was hoping you could take a look at it and give me your version. Seppi333 (Insert 2¢ | Maintained) 04:56, 4 May 2014 (UTC)

There are a number of problems in addition to those listed above, but really I wonder why it couldn't be simplified -- The safety and effectiveness of long-term amphetamine use in treating ADHD is well established. A nine month randomized controlled trial of amphetamine treatment for ADHD in children found that the children experienced improvements in attention, disruptive behaviors, and hyperactivity, and also found a small [or whatever, moderate?] increase in IQ. Of course, another problem with this paragraph (regardless of the prose) is that you've only used one review, and one nine month trial when elaborating on long-term safety and efficacy. It does come across as a bit flimsy, but if you're going to give examples supporting a statement (even though you don't need to have further evidence if they statement is well supported by RS) then this does seem like a strange one. Of course, for the lay reader you've helped a little because you've said what long-term means in this case (nine months). As well, all the terms used "attention, disruptive behaviors, and hyperactivity, and a small increase in IQ" would not be unfamiliar to an English speaking adult, so you don't have to stress about jargon. This is just a suggestion, but hopefully illustrates the kind of thing I've been thinking. -- Shudde ^talk 09:22, 5 May 2014 (UTC)

• Before

  Reviews of clinical stimulant research have established the safety and effectiveness of long-term amphetamine use for ADHD. An evidence review noted the findings of a randomized controlled trial of amphetamine treatment for ADHD in Swedish children following 9 months of amphetamine use. During treatment, the children experienced improvements in attention, disruptive behaviors, and hyperactivity, and an average change of +4.5 in IQ. It noted that the population in the study had a high rate of comorbid disorders associated with ADHD and suggested that other long-term amphetamine trials in people with less associated disorders could find greater functional improvements.

• After

  Reviews of clinical stimulant research have established the safety and effectiveness of long-term amphetamine use for ADHD. Controlled trials spanning two years have demonstrated continuous treatment effectiveness and safety. One review highlighted a 9 month randomized controlled trial in children that found an average increase of 4.5 in the IQ and continued improvements in attention, disruptive behaviors, and hyperactivity.

References

The main changes were the removal and addition of a review, summary of both reviews, and merging two sentences. Minor copyedits too. How's it look now? Seppi333 (Insert 2¢ | Maintained) 10:44, 5 May 2014 (UTC)

• The last sentence seems like a violation of WP:CRYSTAL (it may be better, but we don't know, so why mention it?) and you've still left details such as "+4.5 in IQ" (I mentioned this earlier). How have the reviews established anything? The research established it and I the experts have reached a consensus (I assume -- if not, lets make that clear). It's definitely better, but we still have things like "inconsequential adverse effects" when we could just say "safe". The addition of a two year trial does help though -- especially as this further helps define what is meant by long-term. But like I said, big improvement over what was there originally. -- Shudde ^talk 11:13, 5 May 2014 (UTC)

Eh, 4.5 points is roughly 5% of the average person's IQ. Seems sizeable to me, but I'll cut it if it's that much of an issue for you. I've made changes per your suggestion - the new section is reflected in the blockquote above. A minor detail, though the reviews cover 4 trials with durations of 9, 15, 24, and 24 months. Seppi333 (Insert 2¢ | Maintained) 12:49, 5 May 2014 (UTC)

@Shudde: Hey Shudde, how do you feel about what I've done with Amphetamine#Pharmacodynamics and Adderall#Mechanism of action to address accessibility? (See the hatnotes)Seppi333 (Insert 2¢ | Maintained) 03:22, 25 May 2014 (UTC)

I have seen the discussion at WT:MED -- and after reading your comments there, I've decided not to give further feedback -- it's just not worth my time. I've stated my objections to giving this article the star, and I'll leave it to you and others to try and address those. The article still lacks accessibility and has a number of other weaknesses (see the many hundreds (thousands?) or words I've written on this article). At the moment it's just not written for the general reader. It fails criteria 1a "its prose is engaging, even brilliant, and of a professional standard" -- there is no way the prose is engaging, and it's definitely not brilliant. And of course there is the WP:MOSMED problems I've stated before, (see the section Signs of writing or editing for (other) healthcare professionals). I've got limited time to edit at the moment, and I get the feeling you see producing an FA as jumping through a number of hoops, addressing a few comments, brow-beating over others, then eventually getting a nice star. I see it as producing an article of a certain quality (whether called "FA" or not). Because of this difference of view, and my limited time, I'd rather focus on WP:PR and other editing than comment further here. I hope you can find someone to help with the accessibility problem. -- Shudde ^talk 09:47, 28 May 2014 (UTC)

Adding a table of affinities

I believe that a good addition to this article would be adding a table that that includes Amphetamine's EC₅₀, IC₅₀, and dissociation constant (K_i) values. I think this table should include binding to the monoamine transporters (including VMAT), and receptor affinities (since amphetamine does have very minor, but notable) at some of the adrenergic receptors and dopamine receptors. Personally, I think that would pretty much complete this article.

What does everyone else think?

SwampFox556 (talk) 02:29, 27 April 2014 (UTC)

Double check the species in the database you're looking at. If it's not homo sapiens sapiens/homo sapiens, it's not relevant data for us. Wouldn't satisfy WP:MEDRS (WP:MEDANIMAL) anyway. I'm not aware of any postsynaptic receptor targets for amph in humans (I know of 5-ht and adrenergic receptor affinities in certain rodent species; IDK what species has DA affinities though). That said, if you've got a database or literature ref for human receptors, please let me know! Seppi333 (Insert 2¢ | Maintained) 08:49, 27 April 2014 (UTC)

Absolutely. I'll look right now in fact. If you also want to look (and if I remember correctly) it's DA affinity was something like 200ish Ki for D1 and 770ish Ki for D5. It's adrenergic affinity was something that surprised me (and that's why I remember), it had a Ki of 76 for Alpha-1 receptors, no affinity for alpha-2, and slight... I think it was...Beta-2? Anyways, the Ki was listed as 1000+.

Anyways, I'll check through my plethora of bookmarked studies and go from there ;). Good hunting!

SwampFox556 (talk) 01:09, 29 April 2014 (UTC)

Small nomenclature error in synthetic route 5

@Boghog: The imine intermediate in method 5 is incorrectly named (2-nitroprop-1-en-1-yl)benzene. I'm guessing that was accidentally carried over from method 4?

Since it's a primary imine, I'm pretty sure you'd just call it 1-phenylpropan-2-imine. BlackstarX (talk) 07:35, 1 May 2014 (UTC)

 Fixed. Thanks for catching the error. It now should be correct. Cheers. Boghog (talk) 13:46, 1 May 2014 (UTC)

Pharmacodynamics & Dopamine

Hello, I just wanted to suggest deleting the bold portion of the following sentence: "In certain brain regions, amphetamine increases the concentrations of dopamine in the synaptic cleft, heightening the response of the post-synaptic neuron." My concern with this excerpt is that it is both vague and misleading. To start, I'm not sure what is meant by the "response" of the post-synaptic neuron (and the cited article doesn't mention anything about such post-synaptic effects). I would naturally think that the "response" would refer to the initiation of an action potential at the postsynaptic neuron, in response to a stimulus-induced phasic dopamine signal via an action potential at the presynaptic neuron. However, amphetamines do not heighten, but instead reduce the likelihood of such postsynaptic responding (e.g. http://www.ncbi.nlm.nih.gov/pubmed/17907872). As mentioned in the wiki article, amphetamines inhibit reuptake of dopamine from the synapse into the presynaptic neuron following phasic signaling, which (among other mechanisms) weakens the postsynaptic effects of presynaptic dopamine release. — Preceding unsigned comment added by 104.33.82.254 (talk) 10:06, 7 May 2014 (UTC)

 Done - After rereading it, I tend to agree. That sentence was originally cited by another paper which appears to be referring to DA receptor binding instead of action potentials. I imagine that's what the original author had in mind when he/she wrote that.

That section from a year ago. Seppi333 (Insert 2¢ | Maintained) 11:22, 7 May 2014 (UTC)

Shudde

@Shudde: PLEASE SEE WT:MED DISCUSSION. If you want to contribute to the discussion regarding the citation standards and language regarding the United States in this article, feel free to contribute to the conversation there. Seppi333 (Insert 2¢ | Maintained) 12:31, 27 May 2014 (UTC)

@Shudde: Continue your review here. Seppi333 (Insert 2¢ | Maintained) 06:55, 24 April 2014 (UTC)

PS: It shouldn't take you two full months to review this article. Seppi333 (Insert 2¢ | Maintained) 06:57, 24 April 2014 (UTC)

There are plenty of comments at the recent FAC that probably need to be fully addressed. My comments there should be taken as guidance and examples of what further work is required, rather than a point by point list of problems. I'm not going to repeat all those here as it's not necessary. I'll repeat a couple of my concerns though, and will wait until these have been adequately addressed before giving the article another read through.

• There is Wikipedia:Citation overkill in this article, I'm not sure why we need a citation every single sentence rather than following this guideline. I don't know of another article that insists on at least one inline citation every sentence. As the essay says as per WP:PAIC, citations should be placed at the end of the passage that they support. If one source alone supports consecutive sentences in the same paragraph, one citation of it at the end of the final sentence is sufficient. It is not necessary to include a citation for each individual consecutive sentence, as this is overkill.

I'm seeking consensus on WT:MED at the moment. You're welcome to participate. The citation style will only follow what what is supported there. Seppi333 (Insert 2¢ | Maintained) 12:31, 27 May 2014 (UTC)

• Try and fix overlinking (WP:OVERLINK). As Tony1 says in User:Tony1/Build your linking skills -- It is only over the past few years that we have begun to realise the potential for refining wikilinking—how sophisticated decision-making is required to achieve a high standard of linking: what to link, what not to link, how and when to research more focused links, and how to integrate links smoothly into the text. In this respect, linking deserves attention just as does the prose in our articles. I'd recommend at least reading Tony1's guide on this before deciding what to link or not link. We've also got a large number of duplicate links.

I've addressed this to a max of 2 WL's/term using AWB. Seppi333 (Insert 2¢ | Maintained) 12:31, 27 May 2014 (UTC)

• There is a lot of jargon and technical language that needs to be reduced in order to increase accessibility. At the moment the article reads like it is written for an MD rather than a general audience. There are plenty of high quality references for those that want technical details -- also notes can help with this, giving more information than the general reader would require. Wikipedia:Manual of Style/Medicine-related articles expresses my concerns well. I'll point to the section Technical terminology, and also to the section Signs of writing or editing for (other) healthcare professionals. In particular You use jargon when there are suitable plain English words (for example, consider using "kidney" rather than "renal"). and You use a writing style appropriate only for graduate-level courses, because that's what you see in peer-reviewed journal articles and professional reference works.. For this reason, once you've reduced the jargon and tried to make the language less technical, it may be worth getting several non-experts to read through the text and give feedback on accessibility.

I believe I've addressed this in pharmacodynamics. I've gotten feedback from WT:MED on side effects and OD symptoms. My unorthodox link to the less technical version on Adderall was also supported in a discussion on WT:MED. I await your thoughts. Seppi333 (Insert 2¢ | Maintained) 12:31, 27 May 2014 (UTC)

• Once everything else is done, the lead probably needs a careful read through. At the moment there are four notes, and a large number of references. This really should not be necessary if the lead is written well, and if it doesn't cover any material not covered in the main text of the article. I would leave addressing this until you're happy with everything else though.

I'm seeking consensus on WT:MED at the moment. You're welcome to participate. I do not agree with you on this, but this is up to the community and not me or the FAC review. Seppi333 (Insert 2¢ | Maintained) 12:31, 27 May 2014 (UTC)

• The article is very US-centric. I mentioned this several times during the FAC, giving a few examples. However it's a general problem that is prevalent throughout the article.

I'm seeking consensus on WT:MED at the moment. You're welcome to participate. I don't believe that it is US centric, but I'm not entirely sure that I know what your concern is either. I've asked WT:MED to take a look and make a determination on this. Hence, the removal of any language regarding the US will be up to the consensus developed there. Seppi333 (Insert 2¢ | Maintained) 12:31, 27 May 2014 (UTC)

• Some concerns at the previous FAC, and the talk page archives have not been addressed and kept popping up. For example a number of Aa77zz's concerns are still present, and maybe some in the talk-page archives as well (lead verbosity for example). I suppose my point is that if people keep raising very similar concerns, there is probably something in it, even if you disagree, and may be worth the effort to make extra sure that it's been addressed adequately.

AA77zz's concerns about the lead are now entirely moot. I'm seeking a consensus, rendering his personal preference unimportant, unless he wishes to participate in the discussion. Seppi333 (Insert 2¢ | Maintained) 12:31, 27 May 2014 (UTC)

I'll leave you to use this feedback. If you try and address these comments, and think the article is ready for FA, I'd then open a peer review and ask for further feedback. Having a peer review is better than using the talk page because it keeps everything together and can easily be referred to in the future (like past FACs, GA reviews etc) rather than an annoying search back through talk page archives. I'm not sure exactly how to take your last comment, but an incomplete review at FAC should not run to > 100 kB. That's probably a sign that the article was far from ready before being nominated. There is still a lot to do before the article is ready, and it's not just a case of giving it a little bit of a polish. Because of this, I'm going to give you at least a few weeks before coming back, but if you're convinced it's ready before then do let me know. I hope all this helps, and also hope you remember that there is no deadline here, better to take the time getting it right rather than rushing back to FAC, which could just lead to frustration (for everyone). -- Shudde ^talk 07:30, 25 April 2014 (UTC)

Alright, I'll work on that. Thank you for explaining that - I didn't understand the "big picture" that you had in mind during the FAC review - this helps me a lot more than a sentence-by-sentence review. Seppi333 (Insert 2¢ | Maintained) 13:51, 26 April 2014 (UTC)

@Shudde:How should I approach accessibility in sections that are inherently technical, like pharmacology, synthesis, and detection in bodily fluids? Seppi333 (Insert 2¢ | Maintained) 14:08, 26 April 2014 (UTC)

One suggestion I have for the pharmacodynamics section is to start out with a less technical overview focusing initially on what amphetamine does rather how it does it. For example, the current third paragraph could begin the section. I think this paragraph would provide a more accessible introduction to the section. Boghog (talk) 17:05, 26 April 2014 (UTC)

Good idea - I'll tinker with that section sometime today or tomorrow.
Thanks for your help with reducing overlinking! Seppi333 (Insert 2¢ | Maintained) 19:58, 26 April 2014 (UTC)

I'm not sure there is an easy way to reduce jargon and increase accessibility. I wish there was some kind of step-by-step guide out there, but I've not seen one. The only advice I can give is have a look at User:Tony1/Writing exercise box and see if there is anything in there that may be of use. I'm not sure what else I can suggest, other than maybe trying to recruit some non-experts to help with the copy-edit, but that may be difficult. -- Shudde ^talk 00:24, 27 April 2014 (UTC)

@All: I've been procrastinating - I'll make the edits to pharmacology before Friday and repost here once I'm done simplifying what I can.

Medical uses - Summary of Millichap's review

@Shudde: I'm still sort of unsure about what your concerns were with the long-term evidence review, so I was wondering if you would be willing to read the cited section excerpt and give me your thoughts on how you'd phrase it:

Quoted from pages 122-123 of the Millichap text (Link inside tab).

Text link Long-Term Usage of Stimulants and Outcome of ADHD Studies of long-term, uninterrupted stimulant therapy for ADHD are infrequent. One recent report of a 15-month controlled trial of amphetamine in 62 children, aged 6–11 years, showed continued improvements in behavior and learning ability, with no serious side effects. A multicenter, placebo-controlled trial of amphetamine treatment for ADHD in Sweden found significant improvements in attention, hyper- activity, and disruptive behaviors and a mean change in IQ of +4.5 after more than 9 months of amphetamine sulfate. Side effects included decreased appetite in 56%, abdominal pain in 32%, tics in 29%, and visual hallucinations requiring dose reduc- tion or withdrawal in 5%. Abdominal pain and tics occurred with equal frequency in the placebo group, and only one of 4 children with tics at baseline had an increase in symptoms during amphetamine (15 mg/day) treatment (Gillberg et al., 1997). The children in the Swedish study had a high incidence of comorbid diag- noses (42%), including pervasive developmental disorders, mild retardation, and oppositional defiant disorder. Long-term trials of stimulants in ADHD with less comorbidity would be expected to show greater beneficial effects and a lower inci- dence of side effects. The unusually high incidence of tic disorders in both treated and untreated children was remarkable. The following wasn't mentioned in the article, but it's one of the two additional amphetamine studies covered in the supplemental review I've linked below this tab. From page 121 of this textbook: Adderall XR, an extended-release form, reaches a peak level at 7–8 h and the effect may last for 12 h. In a long-term 24-month, multicenter, open-label, placebo-controlled trial of Adderall XR in 568 children, aged 6–12 years, sig- nificant improvements (>30%) in a Conners Global Index Scale, Parents version, were maintained. Adverse events included anorexia (15%), headache (15%), and insomnia (11%); 15% withdrew from the study because of adverse events. Serious adverse events occurred in 3%, including convulsions in two patients, at doses 10 and 20 mg/day. Mean systolic blood pressure increased by 3.5 mmHg, diastolic by 2.6 mmHg, and pulse rate by 3.4 beats per min (McGough et al., 2005).

The author stated that the underlined study was both multicenter and placebo controlled, which makes it higher quality evidence than the other open placebo-controlled studies. I uploaded this newer review which indicated more or less the same continuation of benefits from 2 studies involving ~2 years of amphetamine use (Scroll down to table 2 or search for the term "amfetamine" to get there - the paper uses the amphetamine INN); these were open, placebo-controlled trials though. Millichap also pointed out the unusually exceptional benefits beyond just a continued therapeutic effect that were observed in that multicenter trial as well.

• A note about the studies: I don't know if this is obvious or not, but it's not really possible to "blind" the patients in a study involving amphetamine, so none of the referenced studies are double-blinded. Amphetamine has a rapid onset with an extremely noticeable psychoactive effect even in long-term daily users of the drug. Receiving the drug vs placebo is probably about as obvious as taking very high-dose niacin vs a placebo in niacin megadose-naive individuals (i.e., the presence/absence of the massive full-body niacin-flush would be telling).
  

Any thoughts/advice/suggestions on communicating this material? Seppi333 (Insert 2¢ | Maintained) 08:43, 30 April 2014 (UTC)

Pharmacodynamics

I followed Boghog's advice and put the simpler and more general pharmacodynamic information first. It currently summarizes the effect it has on catecholamines and the neural pathways in acts upon in the first paragraph. I don't think I can simplify the subsequent material more than using the graphic I made to illustrate the process though. It simply requires a technical background to understand.
In any event, I'm satisfied with this section now. If you could take a look at it and give me your thoughts, I'd appreciate it. Seppi333 (Insert 2¢ | Maintained) 03:19, 4 May 2014 (UTC)

Wikilinks

Per AWB, there's now at most 2 wikilinks for any given term in the article. Seppi333 (Insert 2¢ | Maintained) 03:39, 4 May 2014 (UTC)

Discussion

@Shudde: Can you give me some feedback on the recent changes please? Seppi333 (Insert 2¢ | Maintained) 03:45, 4 May 2014 (UTC)

I'll have a brief look, but I've got a few other projects on the go at the moment, so can't promise too much time during the next two weeks. Sorry I forgot to answer the Millichap comment, but my problem was never with the use of them as a source, rather (as per my FAC comments) how the material was presented. There is a more detailed critique at the FAC. -- Shudde ^talk 04:05, 4 May 2014 (UTC)

Is there any specific area where you want feedback? Like I said I can't devote much time, so if you have a particular area you want me to look at then that would be good. -- Shudde ^talk 04:09, 4 May 2014 (UTC)

Just two things: help with phrasing the Millichap cited prose and your thoughts on the general layout of pharmacodynamics in terms of accessibility. Seppi333 (Insert 2¢ | Maintained) 04:18, 4 May 2014 (UTC)

Regarding the layout of that section, I'm not sure it makes life much easier regarding accessibility. Even the first sentence, indeed the first paragraph, reads much more like a technical review than an encyclopaedia article. Regarding the Millichap paragraph, it's very dry, which is one of the problems. It again reads as technical, is it important the children were Swedish? Do we need to know it was a 4.5 increase in IQ (rather than just an increase, or small increase, or moderate increase? Are these details important to non-technical readers? Technical readers should have access to the review and the primary literature, so if they want these details they are available; we shouldn't be including a lot of info on the methodology unless we absolutely have to. This is part of the problem with the article, it gives excessive technical detail, which hinders readability, does not increase accessibility, and seems unlikely to appeal to many non-lay readers. Try and cut that where you can, and if you really, really want to keep some of it, then retain it as a note rather than in the main body of text. That way someone that wants the technical details without accessing the sources (I would hope these would not be professionals or researchers) can do so, but it doesn't weigh down the text, or make the prose suffer. -- Shudde ^talk 04:46, 4 May 2014 (UTC)

I'll see what I can do what I can about the detail. I didn't make any changes to the Millichap sentence - I linked it above because I wanted your take on how to phrase it. I'm not entirely sure what your concern is so I don't think I can fix the problem myself. I was hoping you could take a look at it and give me your version. Seppi333 (Insert 2¢ | Maintained) 04:56, 4 May 2014 (UTC)

There are a number of problems in addition to those listed above, but really I wonder why it couldn't be simplified -- The safety and effectiveness of long-term amphetamine use in treating ADHD is well established. A nine month randomized controlled trial of amphetamine treatment for ADHD in children found that the children experienced improvements in attention, disruptive behaviors, and hyperactivity, and also found a small [or whatever, moderate?] increase in IQ. Of course, another problem with this paragraph (regardless of the prose) is that you've only used one review, and one nine month trial when elaborating on long-term safety and efficacy. It does come across as a bit flimsy, but if you're going to give examples supporting a statement (even though you don't need to have further evidence if they statement is well supported by RS) then this does seem like a strange one. Of course, for the lay reader you've helped a little because you've said what long-term means in this case (nine months). As well, all the terms used "attention, disruptive behaviors, and hyperactivity, and a small increase in IQ" would not be unfamiliar to an English speaking adult, so you don't have to stress about jargon. This is just a suggestion, but hopefully illustrates the kind of thing I've been thinking. -- Shudde ^talk 09:22, 5 May 2014 (UTC)

• Before

  Reviews of clinical stimulant research have established the safety and effectiveness of long-term amphetamine use for ADHD. An evidence review noted the findings of a randomized controlled trial of amphetamine treatment for ADHD in Swedish children following 9 months of amphetamine use. During treatment, the children experienced improvements in attention, disruptive behaviors, and hyperactivity, and an average change of +4.5 in IQ. It noted that the population in the study had a high rate of comorbid disorders associated with ADHD and suggested that other long-term amphetamine trials in people with less associated disorders could find greater functional improvements.

• After

  Reviews of clinical stimulant research have established the safety and effectiveness of long-term amphetamine use for ADHD. Controlled trials spanning two years have demonstrated continuous treatment effectiveness and safety. One review highlighted a 9 month randomized controlled trial in children that found an average increase of 4.5 in the IQ and continued improvements in attention, disruptive behaviors, and hyperactivity.

References

The main changes were the removal and addition of a review, summary of both reviews, and merging two sentences. Minor copyedits too. How's it look now? Seppi333 (Insert 2¢ | Maintained) 10:44, 5 May 2014 (UTC)

• The last sentence seems like a violation of WP:CRYSTAL (it may be better, but we don't know, so why mention it?) and you've still left details such as "+4.5 in IQ" (I mentioned this earlier). How have the reviews established anything? The research established it and I the experts have reached a consensus (I assume -- if not, lets make that clear). It's definitely better, but we still have things like "inconsequential adverse effects" when we could just say "safe". The addition of a two year trial does help though -- especially as this further helps define what is meant by long-term. But like I said, big improvement over what was there originally. -- Shudde ^talk 11:13, 5 May 2014 (UTC)

Eh, 4.5 points is roughly 5% of the average person's IQ. Seems sizeable to me, but I'll cut it if it's that much of an issue for you. I've made changes per your suggestion - the new section is reflected in the blockquote above. A minor detail, though the reviews cover 4 trials with durations of 9, 15, 24, and 24 months. Seppi333 (Insert 2¢ | Maintained) 12:49, 5 May 2014 (UTC)

@Shudde: Hey Shudde, how do you feel about what I've done with Amphetamine#Pharmacodynamics and Adderall#Mechanism of action to address accessibility? (See the hatnotes)Seppi333 (Insert 2¢ | Maintained) 03:22, 25 May 2014 (UTC)

I have seen the discussion at WT:MED -- and after reading your comments there, I've decided not to give further feedback -- it's just not worth my time. I've stated my objections to giving this article the star, and I'll leave it to you and others to try and address those. The article still lacks accessibility and has a number of other weaknesses (see the many hundreds (thousands?) or words I've written on this article). At the moment it's just not written for the general reader. It fails criteria 1a "its prose is engaging, even brilliant, and of a professional standard" -- there is no way the prose is engaging, and it's definitely not brilliant. And of course there is the WP:MOSMED problems I've stated before, (see the section Signs of writing or editing for (other) healthcare professionals). I've got limited time to edit at the moment, and I get the feeling you see producing an FA as jumping through a number of hoops, addressing a few comments, brow-beating over others, then eventually getting a nice star. I see it as producing an article of a certain quality (whether called "FA" or not). Because of this difference of view, and my limited time, I'd rather focus on WP:PR and other editing than comment further here. I hope you can find someone to help with the accessibility problem. -- Shudde ^talk 09:47, 28 May 2014 (UTC)

Adding a table of affinities

I believe that a good addition to this article would be adding a table that that includes Amphetamine's EC₅₀, IC₅₀, and dissociation constant (K_i) values. I think this table should include binding to the monoamine transporters (including VMAT), and receptor affinities (since amphetamine does have very minor, but notable) at some of the adrenergic receptors and dopamine receptors. Personally, I think that would pretty much complete this article.

What does everyone else think?

SwampFox556 (talk) 02:29, 27 April 2014 (UTC)

Double check the species in the database you're looking at. If it's not homo sapiens sapiens/homo sapiens, it's not relevant data for us. Wouldn't satisfy WP:MEDRS (WP:MEDANIMAL) anyway. I'm not aware of any postsynaptic receptor targets for amph in humans (I know of 5-ht and adrenergic receptor affinities in certain rodent species; IDK what species has DA affinities though). That said, if you've got a database or literature ref for human receptors, please let me know! Seppi333 (Insert 2¢ | Maintained) 08:49, 27 April 2014 (UTC)

Absolutely. I'll look right now in fact. If you also want to look (and if I remember correctly) it's DA affinity was something like 200ish Ki for D1 and 770ish Ki for D5. It's adrenergic affinity was something that surprised me (and that's why I remember), it had a Ki of 76 for Alpha-1 receptors, no affinity for alpha-2, and slight... I think it was...Beta-2? Anyways, the Ki was listed as 1000+.

Anyways, I'll check through my plethora of bookmarked studies and go from there ;). Good hunting!

SwampFox556 (talk) 01:09, 29 April 2014 (UTC)

Small nomenclature error in synthetic route 5

@Boghog: The imine intermediate in method 5 is incorrectly named (2-nitroprop-1-en-1-yl)benzene. I'm guessing that was accidentally carried over from method 4?

Since it's a primary imine, I'm pretty sure you'd just call it 1-phenylpropan-2-imine. BlackstarX (talk) 07:35, 1 May 2014 (UTC)

 Fixed. Thanks for catching the error. It now should be correct. Cheers. Boghog (talk) 13:46, 1 May 2014 (UTC)

Pharmacodynamics & Dopamine

Hello, I just wanted to suggest deleting the bold portion of the following sentence: "In certain brain regions, amphetamine increases the concentrations of dopamine in the synaptic cleft, heightening the response of the post-synaptic neuron." My concern with this excerpt is that it is both vague and misleading. To start, I'm not sure what is meant by the "response" of the post-synaptic neuron (and the cited article doesn't mention anything about such post-synaptic effects). I would naturally think that the "response" would refer to the initiation of an action potential at the postsynaptic neuron, in response to a stimulus-induced phasic dopamine signal via an action potential at the presynaptic neuron. However, amphetamines do not heighten, but instead reduce the likelihood of such postsynaptic responding (e.g. http://www.ncbi.nlm.nih.gov/pubmed/17907872). As mentioned in the wiki article, amphetamines inhibit reuptake of dopamine from the synapse into the presynaptic neuron following phasic signaling, which (among other mechanisms) weakens the postsynaptic effects of presynaptic dopamine release. — Preceding unsigned comment added by 104.33.82.254 (talk) 10:06, 7 May 2014 (UTC)

 Done - After rereading it, I tend to agree. That sentence was originally cited by another paper which appears to be referring to DA receptor binding instead of action potentials. I imagine that's what the original author had in mind when he/she wrote that.

That section from a year ago. Seppi333 (Insert 2¢ | Maintained) 11:22, 7 May 2014 (UTC)