Talk:Amphetamine/Archive 5

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Archive 1 Archive 3 Archive 4 Archive 5 Archive 6 Archive 7

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)Reply[reply]


 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  | Maintained) 11:22, 7 May 2014 (UTC)Reply[reply]

Military pilots

The article includes use for alertness in WW II. However, I understand that it has had more recent use for military pilots. See the 2003 article; Air force rushes to defend amphetamine use (I am not suggesting that the external article is a RS for the Wiki). Snowman (talk) 18:02, 28 May 2014 (UTC)Reply[reply]

The history and culture section in this article is really just a summary of History and culture of amphetamines, which is far more comprehensive. That article discusses the use of amphetamines during the Persian Gulf war in the air force. Seppi333 (Insert  | Maintained) 18:25, 28 May 2014 (UTC)Reply[reply]
This article is really begging for a dedicated sub-section on military usage of amphetamines. That is probably the most "officially approved" usage, and thus it's equal or more notable than some of the other uses discussed. Badon (talk) 23:00, 16 October 2014 (UTC)Reply[reply]
If you know of a high quality and current source (preferably something published by a governmental/military entity) that covers its current military use, I'd be happy to add content on it to the performance-enhancing or history/society/culture section. I've found that sources on performance enhancement aren't easy to find. In any event, like I mentioned earlier, I moved most of the historical military use over to the history and culture of substituted amphetamines article. Seppi333 (Insert  | Maintained) 06:57, 17 October 2014 (UTC)Reply[reply]

Amfetamine / Amphetamine

I wonder whether this page should be switched to the INN, "Amfetamine". I know that it is rather vulgar, but given that it is the INN (for better or worse). I suggest changing the heading and most of the mentions of "amphetamine" to "amfetamine", giving 'amphetamine' as an alternative spelling. Alternatively, the INN could be mentioned as a synonym. Klbrain (talk) 18:03, 4 June 2014 (UTC)Reply[reply]

The INN is mentioned in note 1 (located at the beginning of the first sentence of the lead), which contains synonyms and alternate spellings. The INN of dextroamphetamine and levoamphetamine is mentioned in note 2 (also located in the lead). The article uses the USAN instead of the INN because it's both the common name and the trivial chemical name (since it follows from the contraction: alpha-methyl phenyl-ethyl-amine). On the dextroamphetamine page, the USAN was replaced with the INN at one point, but a large number of users/IPs began to change it back to the USAN throughout the article. Seppi333 (Insert  | Maintained) 18:48, 13 June 2014 (UTC)Reply[reply]

Just in the event anyone cares to read it...

I've uploaded the textbook page citation associated with the ref named "Malenka_2009", simply because it cites a controversial claim (from the performance enhancement section) which started an edit war a year ago. Face-smile.svg Seppi333 (Insert  | Maintained) 21:36, 5 September 2014 (UTC)Reply[reply]

Typo

The penultimate 1:0 in the last table at the very bottom of the article seems to be reversed (left enantiomer confused with right one). 129.132.210.109 (talk) 22:19, 27 September 2014 (UTC)Reply[reply]

I understand your confusion, IP address. Lisdexamfetamine dimesylate makes it sound like it should be the L-enantiomer; however, the "lis" part actually refers to lysine, one of the essential amino acids. If it was "lislev" instead of "lisdex", then the ratio would be 0:1. Lisdexamfetamine dimesylate is actually dextroamphetamine (the right enantiomer) coupled with the amino acid lysine. I hope that clears things up. :) AmericanLemming (talk) 00:38, 29 September 2014 (UTC)Reply[reply]

Half-life?

Why is the half-life listed as 11-14 hours and cited using a specific time release form of amphetamine? — Preceding unsigned comment added by 71.33.17.132 (talk) 17:51, 8 October 2014 (UTC)Reply[reply]

The half-life in that source is specifically listed for the enantiomers, not the resin-bound XR medication; those values are consistent with the IR medication guide and the other sources used to cite the extended range (ph-dependent half-lives) in the pharmacokinetics section. I've appended the reference to the IR medication guide just to avoid confusion in the future though. Seppi333 (Insert  | Maintained) 19:28, 8 October 2014 (UTC)Reply[reply]

ah! well thank you for answering my question then :-) — Preceding unsigned comment added by 208.45.117.29 (talk) 20:42, 11 October 2014 (UTC)Reply[reply]

Informal peer review

Even though the article has been archived for the third time, I'm still going to review it, most likely by making minor copy-edits and then posting any comments I have on the article talk page here. I also asked Ian Rose to clarify what his intentions were in archiving the nomination, and I've transcluded the talk page discussion here for full disclosure. Thus, I'll be opting for the "informal peer review" option detailed below. AmericanLemming (talk) 06:11, 3 August 2014 (UTC)Reply[reply]

I was checking my watchlist today when I saw that amphetamine had been archived once again. I understand why; sometimes you just need a fresh start, but your last sentence left me a little confused: "I hope that AmericanLemming does indeed go through the article but, given the time this has been active, it will need to be outside the FAC process." What about the instructions at Wikipedia:Featured article candidates that say "Nominators whose nominations are archived with no (or minimal) feedback will be given exemptions" to the two week cooling-off rule?

Anyway, if I understand you correctly, Seppi333 can't renominate right away? I think that means you're suggesting that I peer-review the article, which I'm fine with. As far as getting the article promoted, a support from someone who peer-reviewed the article is worth as much as someone who supports promotion after reviewing the article at FAC, right? Just want to make sure I understand exactly what your recommendations are in this case. AmericanLemming (talk) 17:39, 2 August 2014 (UTC)

Yeah, this is what I meant. It's true that nominators whose articles received little feedback during FAC can be given exceptions to the two-week rule but ideally (!) extensive commentary on an article should take place prior to FAC. Several of our most successful FAC editors such as Brianboulton, Wehwalt, and Schrocat go through PR before FAC, and their PR commentators follow the article to FAC and support based on their knowledge of the article from PR. This is perfectly legit so long as the article hasn't undergone significant change since the PR. Mil​Hist people (like me) use the Mil​Hist A-Class Review process in a similar manner. In this case, the article doesn't necessarily need another PR for you to make comprehensive pre-FAC comments; that can be on the talk page and when it next comes to FAC you're free to say you support based on your informal peer review. That might be the kick it needs to attract some further comments and, hopefully, support to get it over the line. Cheers, Ian Rose (talk) 23:36, 2 August 2014 (UTC)
Face-smile.svg Thank you Seppi333 (Insert  | Maintained) 09:02, 3 August 2014 (UTC)Reply[reply]
Likewise, looking forward to your copyedits and comments. Cheers. Boghog (talk) 09:30, 3 August 2014 (UTC)Reply[reply]

Lead

Just finished reading through this part. It looks well-written, well-organized, and well-sourced. The first paragraph is a bit on the long side, as is the lead as a whole, but I'm not really sure you can cut anything out without losing something important. My four comments/questions are as follows:

  • “At therapeutic doses, this causes emotional and cognitive effects such as euphoria, change in libido, increased arousal, and improved cognitive control. It induces physical effects such as decreased reaction time, fatigue resistance, and increased muscle strength.” This wording implies to me that there aren’t any side effects at therapeutic doses, which probably isn’t the case.
  • After rereading it, I think I agree about the sentence on physical effects. The statement on psychological effects seems more or less neutral, since increased arousal can lead to insomnia or increased wakefulness. Similarly, changes in libido can be desirable or undesirable depending on the individual. I'll tweak the the physical effects clause over the next day or so to address this. Seppi333 (Insert  | Maintained)
  • Now that I look at it again, just leave the sentence alone. Sometimes less is more, and I think making it any wordier would decrease the intelligibility to the general reader. Besides, it is correct as it stands.
Good point; I'm okay with that. Seppi333 (Insert  | Maintained) 08:59, 10 August 2014 (UTC)Reply[reply]
  • “Very high doses can result in a psychosis (e.g., delusions and paranoia) which rarely occurs at therapeutic doses even during long-term use.” First, “a psychosis” sounds awkward to me. If it’s consistent with medical terminology, then by all means keep it, but otherwise I would drop the “a”. Second, so it’s pretty difficult to die of an overdose of amphetamine? That’s the impression I’m getting here.
  • There's different types of psychoses, though I agree it sounds weird so I'd be ok with removing it. As for overdoses, it's pretty rare to die from an overdose when medical treatment is sought. The doses that recreational users take are roughly 10-100 times higher than the maximum dose when its used medically. Seppi333 (Insert  | Maintained)
  • I've gone and removed the "a".
  • “Unlike methamphetamine, amphetamine's salts lack sufficient volatility to be smoked.” So if you can inhale amphetamine (see infobox), why can’t you smoke it? Or am I confusing smoking cigarettes and smoking other drugs?
  • The salts can't be smoked, but they can be snorted (insufflated) as a powder. That's really only a recreational route though. The medical route involves inhaling small amounts of the freebase via an inhaler (e.g., File:Benzedrine_inhaler_for_wiki_article.jpg). Unlike the salts, the freebase is a liquid at room temperature and CAN be smoked. Illicit amphetamine is almost never trafficked/sold as the freebase, which I'm assuming is due to its volatility. Seppi333 (Insert  | Maintained)
  • “Amphetamine is also chemically related to the naturally occurring trace amine neurotransmitters, specifically phenethylamine and N-methylphenethylamine” Two questions here: 1. Does phenethylamine = trace amine neurotransmitters? 2. Is it that amphetamine is chemically related to trace amine neurotransmitters but is most closely related to phenethylamine and N-methylphenethylamine? That’s what it sounds like to me. AmericanLemming (talk) 06:26, 4 August 2014 (UTC)Reply[reply]
  • Both phenethylamine and N-methylphenethylamine are trace amines; N-methylphenethylamine is the most closely chemically-related trace amine to amphetamine since it's an amphetamine isomer. If you can think of a better way to word it, feel free to change it! Seppi333 (Insert  | Maintained) 19:06, 5 August 2014 (UTC)Reply[reply]
  • I've taken a shot at that; please do double-check to make sure it's accurate.
Looks good. Seppi333 (Insert  | Maintained) 08:59, 10 August 2014 (UTC)Reply[reply]

I've made two edits to the lead, and I think that will do. The lead is meant to be the most accessible part of the article, and it really isn't the place to be explaining nuances and technicalities.

Medical

  • Question about this section in general: when we’re talking about medical uses of amphetamine, we’re almost always talking about Adderall, right?
  • Adderall (no generic name - i.e., a USAN/INN - even though it's almost always sold as a generic), dextroamphetamine (tons of brand names/generic forms), and lisdexamfetamine (brand:Vyvanse, still patented) are the currently available amphetamine-based pharmaceuticals; it covers this group of drugs. Seppi333 (Insert  | Maintained)
  • “Magnetic resonance imaging studies suggest that long-term treatment with amphetamine decreases abnormalities in brain structure and function found in subjects with ADHD, and improves function of the right caudate nucleus.” So it decreases abnormalities in brain structure and function in general and improves function of the right caudate nucleus in particular? If that’s so, I would suggest changing the second half to “ADHD; in particular, it improves the function of the right caudate nucleus.”
  • The caudate nucleus was one example that was highlighted in one of the reviews; there's improvement in function in more than one brain structure along the dopamine pathways that it acts upon. Seppi333 (Insert  | Maintained)
  • “but high doses of dextroamphetamine in such people should be avoided.” Because of the side effects? Long-term damage to some part of the body?
  • It exacerbates motor tics in people with Tourette's, which is a harmless but undesirable/annoying side-effect. Seppi333 (Insert  | Maintained)
  • “task saliency” this may warrant a quick note to define saliency; the Wikipedia article on the subject isn’t terribly helpful.
  • Good point; I'll go through later today and add this based upon the definition used in the textbook that cited that passage. Seppi333 (Insert  | Maintained)
plus Added - Diff Seppi333 (Insert  | Maintained)
  • “but this is prohibited at events regulated by the World Anti-Doping Agency.” From what I can gather, the World Anti-Doping Agency regulates just about every international and professional sporting event. I think this warrants another note/quick explanation in text, perhaps.
  • Better and worse. On one hand, I think adding the "regulated by collegiate, national, and international anti-doping agencies" does a much better job of explaining that amphetamine is widely prohibited in sporting events; on the other hand, expanding the tidbit about the World Anti-Doping Agency (WADA) turned the sentence into a run-on. I've trimmed the part on WADA to fix the sentence, and I think you could cut it out entirely if you wanted to. Your fix (adding "regulated by collegiate, national, and international anti-doping agencies") was a lot better than the one I suggested, and we don't need both. AmericanLemming (talk) 06:30, 11 August 2014 (UTC)Reply[reply]
minus Removed the WADA mention - Shudde insisted I add it during the FAC review that he didn't finish. I didn't really want it to include it anyway - seemed like trivia. Seppi333 (Insert  | Maintained) 16:00, 11 August 2014 (UTC)Reply[reply]
  • “In healthy people at oral therapeutic doses, amphetamine has been shown to increase physical strength, etc.” It may be worthwhile mentioning that there are some minor side-effects, even in healthy people at oral therapeutic doses. Otherwise, why aren’t we all on amphetamine? :)
Back to the issue: I tried to keep this section disjoint from the side effects section to avoid redundancy and maintain neutrality when covering it. I think it'd be alright to mention that there are additional physical side effects in that paragraph; however, I'm not sure it's a good idea to re-list the physical side effects alongside these, since it's both redundant with the side effects section and isn't relevant to the performance enhancing effect. This list of physical enhancement effects isn't included in the side effects section for the same reason. That said, I'll go ahead and add a clause mentioning the presence of additional side effects if that's what you had in mind. Seppi333 (Insert  | Maintained)
I would suggest adding something along the lines of "At these doses, the side effects are minimal." That's enough to help the reader keep the existence of side effects in mind without the unnecessary repetition of listing them all in two places. AmericanLemming (talk) 06:47, 11 August 2014 (UTC)Reply[reply]
plus AddedSeppi333 (Insert  | Maintained)
  • Also, with that same sentence, it does seem that this is one place where WP:OVERKILL might apply. I understand that the article’s on a fairly technical subject, but do you really need four inline citations of the exact same two sources for four words in a row? I suggest you put all three sources at the end of the sentence, like you do elsewhere. AmericanLemming (talk) 09:03, 6 August 2014 (UTC)Reply[reply]
  • I'd be okay with grouping them at the end of the sentence, though the main reason I did this is because the performance enhancing use of these drugs has generated much controversy, and until recently there hasn't been much high quality research/review supporting these effects in humans. I imagine that some people reading this article might come into it with a bias, which is why I cited them by effect. I'll go ahead and group the citations if you think it improves readability - let me know. Seppi333 (Insert  | Maintained)
  • I recommend doing that. Besides, you quote directly from the source in the inline citation, so if someone doubts whether the sentence is true they can just mouse over the citation and read it for themselves. And as it currently stands it's just hard to read. AmericanLemming (talk) 06:53, 11 August 2014 (UTC)Reply[reply]
 DoneSeppi333 (Insert  | Maintained)

Sorry for the late follow-up; I've been pretty busy this past week. I'll address these points momentarily! Regards, Seppi333 (Insert  | Maintained) 16:16, 9 August 2014 (UTC)Reply[reply]

Contraindications

  • I don’t think there’s anything in the manual of style against a one-paragraph section, but it does look somewhat odd. What do you think about combining the “Contraindications” section with the “Interactions” section? The “Interactions” section does a nice job of explaining why people with certain conditions or on certain drugs (MAOIs, for instance) shouldn’t take amphetamine.
I actually agree that it would make sense to combine these, since serious drug interactions give rise to contraindications; however, the current layout of level-2 headers is indicated in MOS:MED, so I can't really deviate from the present state. Barring unusual or unique circumstances, there isn't much wiggle room in the section ordering. Seppi333 (Insert  | Maintained) 14:19, 11 August 2014 (UTC)Reply[reply]
After further thought, I think it may be better to keep these sections separate; most of the drug databases we link to in the drugbox don't provide this information together. The FDA uses distinct sections for the information as well. Seppi333 (Insert  | Maintained) 18:17, 12 August 2014 (UTC)Reply[reply]
I agree with you; you really can't go against the MOS, especially when you want to get the article to FA status. As the next best alternative, I've added explanatory hatnotes to each section that tell the reader what the section is about and that direct them to the other section if that's not what they were looking for. AmericanLemming (talk) 06:39, 13 August 2014 (UTC)Reply[reply]
I think it might be best to use {{see also}} templates here, since some of the contraindications aren't substance-related. It seemed a bit difficult for me to summarize the relationship in a hatnote without it being really long. The first sentence of each section (I think) more or less implies how they're related though. Seppi333 (Insert  | Maintained) 09:31, 13 August 2014 (UTC)Reply[reply]
  • “Due to the potential for stunted growth, the USFDA advises monitoring the height and weight of children and adolescents prescribed amphetamines.” This contradicts the statement in the first paragraph of the “Medical uses” section that “humans experience normal development and nerve growth”. Do humans experience normal development when using amphetamine or not? AmericanLemming (talk) 07:20, 11 August 2014 (UTC)Reply[reply]
It's technically a transient effect due to a rebound growth spurt associated with a temporary cessation of treatment. IIRC, all dopaminergic stimulants suppress growth hormone release in adolescents (see page 4, paragraph 2 in this ref), so it's not unique to amphetamine. See section 5.3 of this ref for more detail. Seppi333 (Insert  | Maintained) 14:19, 11 August 2014 (UTC)Reply[reply]
Follow-up: After rereading the sentence I wrote in medical uses, I noticed there isn't actually a contradiction here. The full statement in medical uses is:

Long-term amphetamine exposure in some species is known to produce abnormal dopamine system development or nerve damage,[35][36] but humans experience normal development and nerve growth.

The "normal development" is in reference to the development of neural systems (not just dopaminergic systems) and the brain, as opposed to the body and physical development. All the citations included in that sentence are confined to this context as well.
I've clarified the point in the contraindications section. diff These are the references cited: see P125-127, see page 2-4, see P546. Seppi333 (Insert  | Maintained) 18:17, 12 August 2014 (UTC)Reply[reply]
I've changed "normal development" to "normal brain development" and similarly tweaked the note added in the "Contraindications" section. AmericanLemming (talk) 06:54, 13 August 2014 (UTC)Reply[reply]

Side effects

  • “Amphetamine may reduce gastrointestinal motility (i.e., intestinal peristalsis) if intestinal activity is high, or increase motility if the smooth muscle of the tract is relaxed.” I have no idea what this sentence means. You do a really nice job explaining what “contraction of the urinary bladder sphincter” means in plain English earlier in this paragraph; I would use that as a model here. AmericanLemming (talk) 07:20, 11 August 2014 (UTC)Reply[reply]
plus Added clarification earlier - I forgot to reply here after I did this. Please let me know if the current section is understandable! The current version:

If intestinal activity is high, amphetamine may reduce gastrointestinal motility, i.e., the rate at which content moves through the digestive system; however, amphetamine may increase motility when the smooth muscle of the tract is relaxed.

Seppi333 (Insert  | Maintained) 18:19, 12 August 2014 (UTC)Reply[reply]
Much better. I've put the definition in parentheses. Personally, I'm curious to know what causes the smooth muscle of the gastrointestinal tract to relax, but I'm not sure if the average reader shares my interest. :) AmericanLemming (talk) 07:02, 13 August 2014 (UTC)Reply[reply]
I'm not entirely sure to be honest. The enteric nervous system isn't well understood at the moment. Seppi333 (Insert  | Maintained) 20:47, 15 August 2014 (UTC)Reply[reply]

Overdose

Pasted from Wikipedia:Featured article candidates/Amphetamine/archive4

Update: I've finished going through the prose of the Overdose section, though I do plan to go through it again, as it's hard to catch everything the first time around. One general note: I have some issues with the organization of the section, particularly with the beginning and ending and with the subheadings. See the suggestions below. I would like to log in every day and keep an eye on developments here, but in reality we're probably looking at middle to end of next week or possible next weekend; I'm kind of busy through Wednesday. AmericanLemming (talk) 09:09, 14 September 2014 (UTC)Reply[reply]

1. This section is technical enough that I think a introduction paragraph is warranted. Give the general reader the bottom line about the most effective treatments, give a simplified description of the bimolecular mechanism of addiction, ditto with psychosis, toxicity, and withdrawal. Don't make them go digging for what they're looking for, especially when some of the content is highly technical.
2. Also, I don't think the "Psychosis" and "Toxicity" sections are long enough to warrant their own level 3 headings when "Dependence and addiction" is a level 3 heading with five paragraphs and those two are half-paragraphs. I suggest either significant expansion, consolidation of the two into one level 3 heading subsection, or addition to the top of the section with the rest of the overdose symptoms.
3. Put the Overdose symptoms into a chart as we talked about above and then move the giant annotated image further down so we're not sandwiching text between images.
4. I have some more ideas for rearranging and adding/moving subsection headers, but I'll wait on those until we've decided what to do with the above three proposals. AmericanLemming (talk) 09:09, 14 September 2014 (UTC)Reply[reply]

Most of that section is arranged according to MOS:MED#Drugs, medications and devices and a current proposal on MOS:MED's talkpage. Addiction is in that section because the phenomenon only develops with chronic high-dose use; it literally requires a pathological overactivation of the mesolimbic DA pathway (either directly through DA receptors or indirectly through a possibly complex mechanism, e.g., alcohol). Toxicity is an indicated subsection of overdose, so it kind of needs to be there. I could merge toxicity and psychosis into one section if you'd prefer. Seppi333 (Insert  | Maintained) 03:37, 11 October 2014 (UTC)Reply[reply]

And now for the prose comments for the rest of the section:

  • “Cognitive behavioral therapy” Could we give a brief definition in-text?
I'm not sure this would be easy for me to define succinctly... e.g., see Cognitive behavioral therapy#Description. I could probably define it in a note, I'd be more or less be restating parts of that section. Seppi333 (Insert  | Maintained)
  • “Cognitive behavioral therapy is currently the most effective clinical treatment for psychostimulant addiction” So even though it’s the most effective clinical treatment, isn’t that based on extremely limited evidence? Or does the Cochrane Collaboration review from the “Pharmacological treatments” subsection only refer to drugs?
Cochrane's review was just pharmacological therapy.Seppi333 (Insert  | Maintained)
  • The last sentence in the “Behavioral treatments” paragraph is pretty much unintelligible to the general reader. While I think the whole sentence is in need of some improvement, the very last part is the worst offender: I’ll start from the beginning of the sentence and take it by parts:
    1. “aerobic exercise decreases psychostimulant self-administration” I added a definition of self-administration in the above paragraph, so this is good.
    2. “attenuates sensitization to the rewarding effects of psychostimulants” So basically you don’t feel as good when you take the drug?
I'm just deleting that clause because its explanation is a lot longer than the clause itself. I'm not sure it affects reward perception necessarily; psychostimulant sensitization involves an increased of dopamine response in the nucleus accumbens from psychostimulant use, which increases the likelihood of developing an addiction.
  • 3. “reduces the reinstatement of drug-seeking behavior” So you’re less likely to relapse?
Yep, I've noted this. Seppi333 (Insert  | Maintained)
  • 4. induces opposite effects on striatal dopamine receptor D2 signaling to those induced by pathological stimulant use.” What are the “opposite effects” on striatal dopamine receptor D2 signaling caused be aerobic exercise, and what are the effects caused by pathological stimulant use?
I think I've addressed this. Let me know. Seppi333 (Insert  | Maintained)
  • “Current models of addiction from chronic drug use involve alterations in gene expression in certain parts of the brain.” Based on what I read later, I take it that “certain parts of the brain” really means the nucleus accumbens. How about “in certain parts of the brain, especially the nucleus accumbens”?
 Done Seppi333 (Insert  | Maintained)
  • “The most important transcription factors” I would suggest adding a note explaining the role of transcription factors in gene expression.
clock In progress I need to find a MEDRS-quality source first, but I intend to do this. Seppi333 (Insert  | Maintained)
 Done Added this as a note next to the first use of the "transcription factor" phrase. Seppi333 (Insert  | Maintained)
  • “since its overexpression in the nucleus accumbens is necessary and sufficient for many of the neural adaptations seen in drug addiction” I assume you’re referencing necessary and sufficient cause here, but the fact that you neither mention the word “cause” nor link to Necessary and sufficient causes is cause for confusion. Also, why is ΔFosB considered a “necessary and sufficient cause” of these neural changes? And what are these neural adaptations, anyway? If the neural adaptations are talked about in the caption to the giant annotated image, you should add “(see caption below image to the right)” so people can read up on that if they want to.
I meant to link to necessary and sufficient; I did it in other articles, but oddly enough, I missed it here. Essentially it means that the plasticity of addiction and ΔFosB overexpression always occur together, never alone. It's necessary and sufficient because it's been observed to produce this plasticity with viral overexpression (using viral vector gene transfer) and their occurrence doesn't occur with a viral block of ΔFosB expression (i.e., viral overexpression of ΔJunD opposes ΔFosB and hence this plasticity with concurrent drug use). This is rather technical - the reference that quotes that sentence explains it more. As for the plasticity, some of it is indicated in the psychostimulant column of the table below, which I've transcluded to several articles from FOSB. Seppi333 (Insert  | Maintained)
Summary of addiction-related plasticity
Form of neuroplasticity
or behavioral plasticity
Type of reinforcer Sources
Opiates Psychostimulants High fat or sugar food Sexual intercourse Physical exercise
(aerobic)
Environmental
enrichment
ΔFosB expression in
nucleus accumbens D1-type MSNs
[1]
Behavioral plasticity
Escalation of intake Yes Yes Yes [1]
Psychostimulant
cross-sensitization
Yes Not applicable Yes Yes Attenuated Attenuated [1]
Psychostimulant
self-administration
[1]
Psychostimulant
conditioned place preference
[1]
Reinstatement of drug-seeking behavior [1]
Neurochemical plasticity
CREB phosphorylation
in the nucleus accumbens
[1]
Sensitized dopamine response
in the nucleus accumbens
No Yes No Yes [1]
Altered striatal dopamine signaling DRD2, ↑DRD3 DRD1, ↓DRD2, ↑DRD3 DRD1, ↓DRD2, ↑DRD3 DRD2 DRD2 [1]
Altered striatal opioid signaling No change or
μ-opioid receptors
μ-opioid receptors
κ-opioid receptors
μ-opioid receptors μ-opioid receptors No change No change [1]
Changes in striatal opioid peptides dynorphin
No change: enkephalin
dynorphin enkephalin dynorphin dynorphin [1]
Mesocorticolimbic synaptic plasticity
Number of dendrites in the nucleus accumbens [1]
Dendritic spine density in
the nucleus accumbens
[1]
  • “Since natural rewards induce ΔFosB just like drugs of abuse do” What does it mean that they “induce” ΔFosB? They cause the body to make more of it?
It means it increases gene expression of ΔFosB. I've clarified this and linked to inducible gene with a pipe as "Since natural rewards induce expression of ΔFosB..." Seppi333 (Insert  | Maintained)
  • “and amphetamine-induced sex addictions.” Do these amphetamine-induced sex addictions occur frequently at therapeutic and/or recreational doses? How does amphetamine cause sex addictions? Does an amphetamine-induced sex addiction mean that you’re addicted to both amphetamine and sex? I’m not harping on this just because it mentions sex; I feel that the sentence as is introduces a condition/disease without really explaining it.
I clarified the text a little and added the appropriate quote to the reference ("In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some patients taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex"). It's simply compulsive sexual behavior as a result of amphetamine use. There is a notable interaction between reward perception with sexual behavior and amphetamine use, and an overactivation of DA networks involved in reward perception and reinforcement mediate that phenomenon. I actually rewrote sex addiction recently to try to explain that concept better (and because I got into an edit war with another editor...). Let me know if you think it needs more work in the article. Seppi333 (Insert  | Maintained)
  • “Psychosis” subsection: I feel that the current length of this section doesn’t do the topic justice. We don’t need four full paragraphs about it, but how about 8-10 sentences instead of the current four?
I'll look through the Cochrane review soon and see if I can add more material. Most of the content in the amphetamine psychosis section either isn't particularly relevant (e.g., first paragraph) or isn't cited by a MEDRS-quality source. Seppi333 (Insert  | Maintained) 03:47, 11 October 2014 (UTC)Reply[reply]
  • “Toxicity” subsection: Same concern as with the Psychosis subsection. Again, I’d feel much more comfortable with the article’s comprehensiveness with 8-10 sentences here instead of three.
There really isn't much to say about amphetamine toxicity in humans. Direct toxicity simply does not occur. I could probably write a whole paper on direct DA toxicity in rats, but including that in the article would be sort of POV because it's misleading. The mechanics of indirect toxicity are mediated entirely through oxidative events related to excessive dopamine release. I could probably add a sentence or two on its mechanics, but these are necessarily going to be fairly technical descriptions compared to the text currently in that section. Seppi333 (Insert  | Maintained) 03:47, 11 October 2014 (UTC)Reply[reply]
  • Actually, as I come to think about it, how about we expand the above two subsections slightly, delete the subsection headings, and then move them to the topic of the section where the other overdose side-effects are found?
Due to the the MOS indications that I mentioned in a #previous bullet, and the points I raised in the above two bullets, it may be best to simply combine the two sections if you'd prefer to have fewer subsections under the Overdose heading. Seppi333 (Insert  | Maintained)
  • “Manufacturer prescribing information does not indicate the presence” Which manufacturer? Or are we talking about US FDA prescribing regulations? I’m confused. AmericanLemming (talk) 09:09, 14 September 2014 (UTC)Reply[reply]
This actually refers to the prescribing information from all manufacturers of amphetamine pharmaceuticals. The prescribing information is under copyright, and they vary in format, but they're pretty much standardized in the information in they provide (I can link you to a few examples for amphetamine pharmaceuticals on pubchem if you'd like to see what I mean), even though it is copyrighted. Seppi333 (Insert  | Maintained)
@AmericanLemming: I've pasted this from the review so that I can address/reply the points by issue here. I've added the table for the symptoms - let me know what you think. There was a small addition of content in the behavioral treatments section since you last checked it as well. Seppi333 (Insert  | Maintained) 01:25, 11 October 2014 (UTC)Reply[reply]

References

  1. ^ a b c d e f g h i j k l m Cite error: The named reference Natural and drug addictions was invoked but never defined (see the help page).

"Smoking crystal."

I'd just like to point out an inaccuracy in the article. Towards the end of the initial overview (last paragraph, second sentence) it is said that: "Unlike methamphetamine, amphetamine's salts lack sufficient volatility to be smoked." While the aforementioned statement is correct in saying that amphetamine is far less volatile than methamphetamine, it is incorrect since methamphetamine is generally vaporized, not smoked. Smoking methamphetamine would necessitate combustion, which would then in turn decompose the methamphetamine and render it useless as a recreational drug.

See "Mode of use" - http://www.emcdda.europa.eu/publications/drug-profiles/amphetamine Seppi333 (Insert  | Maintained) 21:05, 18 November 2014 (UTC)Reply[reply]

Racemic free base?

I dispute the claim that amphetamine only "properly" refers to the racemic free base. The Drug Bank source supports the idea that amphetamine refers to the racemic compound (implied) but not the idea that salts aren't proper amphetamine. It calls Adderall a mix of amphetamine and dextroamphetamine despite it being all salts. The NLM source classifies racemic and levoamphetamine in the page but lists dextroamphetamine as a subcategory. Sorry for being so disorganized but is there any evidence in either of the sources that proper amphetamine has to be both equally racemic and free base to be proper? Clr324 06:29, 25 November 2014 (UTC)

I think a reasonable definition of amphetamine is the racemic free base as it follows general naming conventions used both in organic chemistry and pharmacology. When the name "amphetamine" stands alone, it implicit that it refers to the free base. For example, the International Nonproprietary Name for amphetamine is amfetamine. According to the World Health Organization's "Guidance on INN". An INN is usually designated for the active part of the molecule only, to avoid the multiplication of entries in cases where several salts, esters, etc. are actually used. In such cases, the user of the INN has to create a modified INN (INNM) himself ; mepyramine maleate (a salt of mepyramine with maleic acid) is an example of an INNM.. Hence the INNM for the hydrochloride salt of "amfetamine" would be "amfetamine hydrochloride". In other words, "amfetamine" refers to the freebase whereas "amfetamine hydrochloride" refers to a specific salt of "amfetamine". Furthermore Adderall is not a mixture of amphetamine and dextroamphetamine free bases. Rather it is a very specific mixture of aspartate, sulfate, saccharate salts of amphetamine and dextroamphetamine. Finally Drug Bank and the NLM are not definitive nomenclature authorities. They have grouped several stereoisomers and salts of amphetamine together not to define the term, but rather for indexing purposes. Boghog (talk) 20:44, 25 November 2014 (UTC)Reply[reply]
I just used Drug Bank and NLM as source because that is what the article used those sources are citations and they weren't in those citations. Clr324 03:10, 26 November 2014 (UTC)
It was inferred from those citations, moreso NLM than DrugBank. It's not an assertion that can be cited directly since there isn't really a database/repository for exact chemical references. Boghog's explained the rationale for the statement pretty well though. Edit: the inference from these citations follows from the fact that "Amphetamine" and salts of amphetamine have different chemical identifiers. NLM also makes the statement that amphetamine is "a specific chemical". Seppi333 (Insert  | Maintained) 03:40, 26 November 2014 (UTC)Reply[reply]
So should we use the WHO guide as a citation? Clr324 03:48, 27 November 2014 (UTC) — Preceding unsigned comment added by Clr324 (talkcontribs)
That would probably be best, yes; the WHO citation at the very least implies the assertion in the lead. It still isn't directly supported by the source, however, it is the lead, so WP:V (that is to say, a citation with an assertion which directly supports the sentence) isn't strictly necessary for the statement. In any event, I'll append the citation per your suggestion. Thanks for pointing it out. Face-smile.svg Seppi333 (Insert  | Maintained) 19:31, 1 December 2014 (UTC)Reply[reply]
Nevermind. The lack of direct support by the cited refs was annoying me. I added 2 new refs (a different WHO webpage/document and a textbook on amphetamine + substituted amphetamines) which directly supports the proper term reference; excerpts are included in the refs. Seppi333 (Insert  | Maintained) 20:57, 1 December 2014 (UTC)Reply[reply]

Synthesis section

The synthesis section was removed in this edit with the edit summary too technical to be of interest to 99% of our readers, and 2) see WP:NOTHOWTO. The appropriateness of synthesis sections in drug articles was previously discussed here. I have restored this section for the following reasons:

  1. Wikipedia is the sum of all human knowledge and that knowledge includes organic synthesis. Wikipedia also conforms to the Long tail. Even if this is of only interest to a small fraction of our readers, that fraction is not zero. Furthermore it is rather presumputous to decide what others might be interested in.
  2. The scope of this article is wider than WP:PHARMA. It also includes WP:CHEMS and WP:CHEMMOS suggests a section on preparation be included. (argument originally made by Seppi333).
  3. We are attempting to promote this article to FA status. One of the criteria for FA is comprehensiveness. It is incomprehensible that any complete encyclopedic article on amphetamine would not contain a synthesis section. This section is especially notable because of wide spread illicit synthesis of amphetamine.
  4. It was specifically requested to expand this section in a FA review.
  5. This section is not "how to". There is not enough detail in this section to repeat any of the syntheses. One would need to consult the primary literature.

Boghog (talk) 10:36, 1 January 2015 (UTC)Reply[reply]

I agree with Boghog about keeping this section. I'll admit that I felt uneasy about adding synthesis sections in articles on controlled substances in the past. I've since reconciled my concerns about including this section in any article which isn't a US/UN schedule 1 controlled substance and is a currently prescribed pharmaceutical. Such compounds will inevitably have detailed synthesis coverage in academic literature anyway, some of this literature might even be open-access (e.g., the comprehensive review cited in this article includes detailed primary literature references for the dozens of synthesis routes shown in the table/diagrams on pages 18, 19, 21, and 25). Even if a synthesis section is esoteric and incomprehensible to most people (this includes me), an article on a pharmaceutical would still need this for FA status simply because all pharmaceuticals are notable chemicals (thus requiring MOS:CHEM adherence to satisfy the FA criterion of comprehensive coverage). I only see an ethical cost with only a marginal and solely academic benefit from adding laboratory synthesis sections in articles on globally banned substances that have no medical use (e.g., MDMA, which I assume is what prompted this deletion based upon the synthesis discussion at Talk:MDMA).
With that in mind, it might be worth having a more general discussion with WT:CHEM + WT:PHARM on where to draw the line on laboratory synthesis coverage for the articles on banned or heavily controlled substances. Seppi333 (Insert  | Maintained) 04:01, 3 January 2015 (UTC)Reply[reply]
Amphetamine/Archive 5
Just to reiterate, there is not enough detail given in the synthesis section to actually carry out any of these syntheses. Wikipedia is not censored nor is it a "how-to" guide. Hence including this information on first principles should not be prohibited but at the same time this level of detail is not appropriate to include in an encyclopedia article. Furthermore as Seppi333 has pointed out, this information is widely available from other sources (see for example Google web search or Google image search). To me, the bigger issue with synthesis sections is notability. Here the regular rules apply. If a subject has been covered by reliable secondary sources, it is by definition notable. In the case of amphetamine synthesis, there are a number relevant reviews (see for example here, here, and [http://www.amazon.com/Amphetamine-Syntheses-Overview-Reference-Professionals/dp/0966312805 here]). Boghog (talk) 09:51, 3 January 2015 (UTC)Reply[reply]
My primary objection had nothing to do with illicit labs so much as that the information is unintelligible to 99% of our readers, and most of the other 1% will go to other, more specialized sources when looking for synthetic route details. If we're going to include the synthetic route, why not include an IR spectrum and maybe a proton NMR? Those will be just as useful to most of our readers as letting them know that the amino group is introduced by a sequence involving the Hell-Vollhard-Zelinsky reaction as the second step. Also, there are scores of ways to make almost any compound, and so we have the issue of why any particular route is more notable than others. Formerly 98 (talk) 10:37, 3 January 2015 (UTC)Reply[reply]
Why not include an IR spectrum and maybe a proton NMR? – Because this level of detail is simply not appropriate to include in an encyclopedia article. The question is where to draw the line. Spectral data will not normally be included in a review article either and a Wikipedia article should not be more detailed than the secondary sources that are used to support it. On the other hand, the synthetic routes mentioned in this article's synthesis section have been covered by at least one secondary source and therefore notable by definition. Finally the Leuckart reaction is independently notable because it is widely used for illicit synthesis. Boghog (talk) 11:33, 3 January 2015 (UTC)Reply[reply]
Sorry, that was a mildly sarcastic reference, but my point was that the IR spectrum and the information that the Leukhart reaction is used in the synthesis are likely to be equally un-interpretable technical details to most of our readers. But I can see you feel strongly about this, and I don't, so I will drop the matter. Formerly 98 (talk) 13:25, 3 January 2015 (UTC)Reply[reply]
I have no problem with sarcasm as my Aspergian tendencies (see figure to the right) endows me with a high level of ignorance to such references ;-). At the risk of beating a dead horse into the ground, most readers will read the lede and then focus on the sections they are interested in. The synthesis section is in the last 1/3 of the article. Most readers will skip right over this section. Given where it is placed, it is hardily distracting. On the other hand, a few readers may be keenly interested in this section, and that is reason enough to include it. Boghog (talk) 00:07, 4 January 2015 (UTC)Reply[reply]

Semi-protected edit request on 1 January 2015

Please edit. Text is triple 77.251.10.24 (talk) 23:26, 1 January 2015 (UTC)Reply[reply]

Rejected No intelligible request present.  B E C K Y S A Y L E 00:00, 2 January 2015 (UTC)Reply[reply]

Semi-protected edit request on 1 February 2015

A physical side effect is excessive sweating 166.137.118.88 (talk) 23:14, 1 February 2015 (UTC)Reply[reply]

"Profuse sweating" is currently listed as a potential side effect in that section. Seppi333 (Insert  | Maintained) 23:39, 1 February 2015 (UTC)Reply[reply]

Figure url

@Doc James: Hey James, can you give me the url link for the figure that supports the statement you added which was cited by this[1] ref? I can't seem to find it in the paper so I'm assuming it's in one of the figures... I'd like to add the url to the citation.

Thanks, Seppi333 (Insert  | Maintained) 23:26, 3 March 2015 (UTC)Reply[reply]

Page 132 in the pdf. Table 2. Doc James (talk · contribs · email) 23:27, 3 March 2015 (UTC)Reply[reply]
Ahh ok. I just noticed the 68 MB supplemental appendix has a ton of even more detailed information, so I'm going to link to that instead of the pdf in the url field. Seppi333 (Insert  | Maintained) 23:50, 3 March 2015 (UTC)Reply[reply]


Question about the lead

I went to go support this article's TFA request but I realized I had a question to ask about the lead first. The second paragraph says " At therapeutic doses, this causes emotional and cognitive effects such as euphoria, change in libido, increased wakefulness, and improved cognitive control." -- is euphoria an effect at therapeutic doses? Is it the first effect that should be mentioned - since Adderall at least lists euphoria as an adverse effect? I'm sure you guys thought carefully about the wording, but this order in the list stood out to me. Opabinia regalis (talk) 04:16, 10 March 2015 (UTC)Reply[reply]

@Opabinia regalis: Euphoria is an effect that is associated with rapid tolerance at any dose; this is the chief reason why recreational users that chase a euphoric-high end up abusing the drug at very high doses. At therapeutic doses, individuals who begin using amphetamine for the first time or restart use following a sufficient period of time off the drug will tend to experience euphoria for the first few days. Several refs cite euphoria as a side effect at therapeutic doses, but I'll just point to the FDA's drug label since it's readily accessible: see page 8 of this ref where it's listed as an "adverse" effect under the heading labeled "Central nervous system".
Also, while it isn't mentioned anywhere in the article, (this is based upon my personal experience – WP:OR) it noticeably potentiates exercise-induced euphoria (without noticeable tolerance) which is mediated by very similar mechanisms in the brain. Seppi333 (Insert  | Maintained) 04:37, 10 March 2015 (UTC)Reply[reply]
Thanks. Sure, I know euphoria is a known effect, but listing it first sort of reads like it's part of the therapeutic purpose, not a side/adverse effect. Opabinia regalis (talk) 06:28, 10 March 2015 (UTC)Reply[reply]

Issues

There are a number of issues with the medical uses section

Statement not supported by refs

This sentence "Reviews of clinical stimulant research have established the safety and effectiveness of long-term amphetamine use for ADHD" is not supported by the references provided.

  1. This ref says "Evidence has shown that stimulants, along with the non-stimulants atomoxetine and extended-release guanfacine, are continuously effective for 24-month treatment periods with few and tolerable adverse effects."
And per the authors, that's a long-term outcome. Seppi333 (Insert  | Maintained) 18:48, 15 March 2015 (UTC)Reply[reply]
Really were does it say that? Appear to be WP:OR Doc James (talk · contribs · email) 19:38, 15 March 2015 (UTC)Reply[reply]
Yes different papers come to different conclusions. The evidence of long term effects is of low quality. And there is a lack of high quality evidence of long term benefit. Doc James (talk · contribs · email) 19:43, 15 March 2015 (UTC)Reply[reply]
  1. This ref says "There is little evidence to suggest that the effects observed over the relatively short term are maintained throughout longer periods of impairment. Furthermore, much of the existing evidence examining effectiveness beyond 12 months does not include newer medications currently available" and "can be effective in managing the core ADHD symptoms and academic performance at 14 months. However, the effect size may decrease beyond this period." and "little is known regarding the long-term effectiveness."

This of course is because the longest RCT is 14 months. Additionally we have other refs that are less than supportive. Doc James (talk · contribs · email) 14:18, 15 March 2015 (UTC)Reply[reply]

The 2015 ref, PMID 25714373, covers long-term studies with a mean duration of over 7 years. It also cites the 2013 review and discusses the issue with the 14 month window. You're KNOWINGLY quoting material which I've already pointed out is NOT specific to stimulants, while once again ignoring the content that is.
That's pretty fucked up considering: special:permalink/651517394#Medications - long term effects.
As the refs are all on "long-term" outcomes and not "over 2 years outcomes", we should be using the common language among them. Seppi333 (Insert  | Maintained) 18:48, 15 March 2015 (UTC)Reply[reply]
The reviews are looking at "long term outcomes" and they did not find good evidence of such. Doc James (talk · contribs · email) 19:27, 15 March 2015 (UTC)Reply[reply]
I agree with you that the 2013 review did not conclude "long-term" effectiveness - it didn't make an unambiguous statement about long-term pharmacotherapy one way or another, so I removed it altogether. I added the relevant excerpts to the quote parameter of the 2011 review and textbook ref, although these are both secondary to the conclusion of the 2015 review. Seppi333 (Insert  | Maintained) 23:12, 15 March 2015 (UTC)Reply[reply]

Content mispositioned

Second issue is that the "medical uses" section contains details that really belong in the mechanism of action / pharmacology section section including:

  1. "Current models of ADHD suggest that it is associated with functional impairments in some of the brain's neurotransmitter systems;[1] these functional impairments involve impaired dopamine neurotransmission in the mesocorticolimbic projection and norepinephrine neurotransmission in the locus coeruleus and prefrontal cortex.[1] Psychostimulants like methylphenidate and amphetamine are effective in treating ADHD because they increase neurotransmitter activity in these systems.[2][1][3]"
  2. "Long-term amphetamine exposure in some animal species is known to produce abnormal dopamine system development or nerve damage,[4][5] but, in humans with ADHD, pharmaceutical amphetamines appear to improve brain development and nerve growth.[6][7][8] Magnetic resonance imaging (MRI) studies suggest that long-term treatment with amphetamine decreases abnormalities in brain structure and function found in subjects with ADHD, and improves function in several parts of the brain, such as the right caudate nucleus of the basal ganglia.[6][7][8]"

As this is discussing how the medication may work. Doc James (talk · contribs · email) 14:17, 15 March 2015 (UTC)Reply[reply]

Again, this relates neuropsychology with clinical neuroscience. I'm not moving it. Seppi333 (Insert  | Maintained) 18:48, 15 March 2015 (UTC)Reply[reply]

References

  1. ^ a b c Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin". In Sydor A, Brown RY (ed.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York, USA: McGraw-Hill Medical. pp. 154–157. ISBN 9780071481274.{{cite book}}: CS1 maint: multiple names: authors list (link)
  2. ^ Cite error: The named reference Malenka_2009 was invoked but never defined (see the help page).
  3. ^ Bidwell LC, McClernon FJ, Kollins SH (August 2011). "Cognitive enhancers for the treatment of ADHD". Pharmacol. Biochem. Behav. 99 (2): 262–274. doi:10.1016/j.pbb.2011.05.002. PMC 3353150. PMID 21596055.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  4. ^ Cite error: The named reference pmid22392347 was invoked but never defined (see the help page).
  5. ^ Berman S, O'Neill J, Fears S, Bartzokis G, London ED (October 2008). "Abuse of amphetamines and structural abnormalities in the brain". Ann. N. Y. Acad. Sci. 1141: 195–220. doi:10.1196/annals.1441.031. PMC 2769923. PMID 18991959.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  6. ^ a b Hart H, Radua J, Nakao T, Mataix-Cols D, Rubia K (February 2013). "Meta-analysis of functional magnetic resonance imaging studies of inhibition and attention in attention-deficit/hyperactivity disorder: exploring task-specific, stimulant medication, and age effects". JAMA Psychiatry. 70 (2): 185–198. doi:10.1001/jamapsychiatry.2013.277. PMID 23247506.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  7. ^ a b Spencer TJ, Brown A, Seidman LJ, Valera EM, Makris N, Lomedico A, Faraone SV, Biederman J (September 2013). "Effect of psychostimulants on brain structure and function in ADHD: a qualitative literature review of magnetic resonance imaging-based neuroimaging studies". J. Clin. Psychiatry. 74 (9): 902–917. doi:10.4088/JCP.12r08287. PMC 3801446. PMID 24107764.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  8. ^ a b Frodl T, Skokauskas N (February 2012). "Meta-analysis of structural MRI studies in children and adults with attention deficit hyperactivity disorder indicates treatment effects". Acta psychiatrica Scand. 125 (2): 114–126. doi:10.1111/j.1600-0447.2011.01786.x. PMID 22118249. Basal ganglia regions like the right globus pallidus, the right putamen, and the nucleus caudatus are structurally affected in children with ADHD. These changes and alterations in limbic regions like ACC and amygdala are more pronounced in non-treated populations and seem to diminish over time from child to adulthood. Treatment seems to have positive effects on brain structure.

Semi-protected edit request on 30 March 2015

Please change "USFDA commissioned studies from 2011..." under Side Effects/Physical to "USFDA-commissioned studies from 2011..." It's a little confusing to read without the hyphen. mackdacre (talk) 22:38, 30 March 2015 (UTC)Reply[reply]

 DoneSeppi333 (Insert  | Maintained) 22:49, 30 March 2015 (UTC)Reply[reply]

Congratulations!

Congratulations to all the contributors to this featured article. You deserve a lot of applause, recognition and appreciation. What a wonderful article.

  Bfpage |leave a message  21:27, 3 April 2015 (UTC)Reply[reply]
Thanks! Took a lot of time, effort, and occasionally badgering Boghog for help to get it here. Seppi333 (Insert  | Maintained) 05:37, 4 April 2015 (UTC)Reply[reply]

Consistent representation

@Boghog: Hey, sorry to bother you again with an image request; I just noticed that every image that we've used in the article except COMMONS:File:Amphetamine Structural Formulae.png uses unspecified stereochemistry and the same positioning of the amine/methyl groups. That image reverses the groups, so I'd like to replace it with another image; I want to use COMMONS:File:racemic amphetamine.svg, but I wanted to ask if you'd be willing to move levoamph to the left and dextroamph to the right in the image. I figure it's more natural/intuitive to depict it this way because of what "levo-" and "dextro-" refer to. Seppi333 (Insert  | Maintained) 06:03, 5 April 2015 (UTC)Reply[reply]

 Done Good suggestion. Agreed swapping images makes sense. Boghog (talk) 06:15, 5 April 2015 (UTC)Reply[reply]
Thanks! Seppi333 (Insert  | Maintained) 06:27, 5 April 2015 (UTC)Reply[reply]

Merge discussion

The case for the merge is very simple. Any discussion of the properties of a mixture of enantiomers is made simpler if the similarities and differences of the individual enantiomers are also discussed. The stuctures of the two isomers are already shown in the section Amphetamine#Physical and chemical properties! Stereochemistry is important, even in articles on dugs, c.f. thalidomide.

Regarding the comments below, there is an argument for maintaining Dextroamphetamine as a separate article, but it is weak, as the separation results in a lot of unneccesary duplication. If the separation is retained the reason for retaining it needs to be explained in this article. The article on Levoamphetamine is short enough to make the merge easy.

If something is controversial, a Wikipedia article should present the cases for all sides of the controversy. Hopefully at some time in the future new experimental evidence will provide the basis for a resolution. Petergans (talk) 10:35, 5 April 2015 (UTC)Reply[reply]

Oppose – The two enantiomers of amphetamine, Dextroamphetamine and Levoamphetamine have somewhat different rates of metabolism and pharmacological effects. Hence these two articles need to be kept separate from each other. Furthermore optically pure Dextroamphetamine and Adderall (75% dextroamphetamine salts and 25% levoamphetamine salts) both are prescribed pharmaceutical products and each deserves its own article. Finally the racemic mixture as well as the optically pure enantiomers have different registration numbers and external database entries hence merging of the infoboxes in each of these articles becomes impractical. Boghog (talk) 09:04, 5 April 2015 (UTC)Reply[reply]
  • Note: This issue has come up in the past on this and related pages (i.e., d-amph and Adderall). To summarize all the discussions, these pages haven't been merged mainly because there's a ton of distinct coverage of enantiopure d-amph vs a mixture of both isomers (Adderall) in medical literature and the lack of consensus regarding a merge of any of these articles. A lot of material from this page is transcluded to D-amph and Adderall simply because reviews generally conclude that there isn't much of a pharmacological or clinical difference between the two mixtures, resulting in analogous side effect profiles. Levoamphetamine exists partly because it would be odd to redirect it here while D-amph exists as a separate article and partly because there's distinct coverage of the racemate and L-amph in chemistry DBs.
    In a nutshell, this article is the primary parent article of levoamphetamine, dextroamphetamine, Adderall, and (for now) lisdexamfetamine, so the current relationship follows what is required in WP:SUMMARY STYLE. Most of the content on these pages (except levoamph) is either a slightly modified section transclusion from this page (via {{if pagename}} templates in this article) or a summary of this article and relevant parts of history and culture of substituted amphetamines. Levoamphetamine is sort of just off on its own because enantiopure L-amph hasn't been used as a pharmacotherapy in any country for anything for a while (i.e., it's not really a drug article so much as it is a chemistry article). Seppi333 (Insert  | Maintained) 09:31, 5 April 2015 (UTC)Reply[reply]
Unfortunately there doesn't seem to be a clean way to organize these related articles. Drugs that differ by stereochemical composition unless they rapidly interconvert are distinct. (Note that the regulatory position is that different stereochemical compositions of drugs are assumed to be different unless they are proven equivalent.) There are two distinct stereochemical drug compositions of amphetamine represented by Adderall and Dextroamphetamine (Dexedrine/Dextrostat). Hence separate articles should be devoted to each. At the same time, much of the material in this article is duplicated in Adderall and Dextroamphetamine which I think is unfortunately. However I do not see a better solution. Boghog (talk) 10:33, 5 April 2015 (UTC)Reply[reply]

I see that the merge tags have been removed. I am an inorganic chemist and don't feel qualified to do something about merging articles that are primarily pharmaceutical and biochemical. Nevertheless, the current situation is most unsatisfactory: there is considerable triplication in the three articles Levoamphetamine, Dextroamphetamine and adderall. I make these suggestions

  • This article becomes the "main" article of two
  • Merge Levoamphetamine with this article. This will be quite easy as the levo article is very short.
  • Merge Dextroamphetamine and adderall. These are essentially about the same substance. Aderall is just a trade name for a commercial pharmaceutical product containing the active ingredient..
  • Set up links so that the currently triplicated tables, diagrams and related text will be shown once, preferably in this article. The links could simply use the "main" template.

Petergans (talk) 09:09, 14 April 2015 (UTC)Reply[reply]

There is no consensus for this merger. In fact, taking into account both the present and past discussions, the consensus is clearly against it. Contrary to what you have stated above, the argument against the merger is strong. Because different stereochemical isomers of a drug can have markedly different pharmacological effects, half-lives, toxicities, etc. drug regulatory agencies treat different drug stereoisomers as different. So should we. Boghog (talk) 09:38, 14 April 2015 (UTC)Reply[reply]
"So should we" Not so. There is a world of difference between a regulatory agency and Wikipedia. The audience for WP is universal and herein lies the dilemma. Conventions in the fields of pharmacy and chemistry have diverged. Chemistry students will be surprised to see enantiomers given separate articles. In fact, functional differences between enantiomers only appear in a biochemical context. Stereoisomers, on the other hand, can have quite different chemical properties, e.g. maleic acid and fumaric acid.
It is disappointing to see responses to my proposal from two editors only. As a chemistry person, I would not have been part of the "consensus", had I known of the discussion. Where can a vote on the previous merge discussion be found?. Petergans (talk) 09:15, 18 April 2015 (UTC)Reply[reply]
Chemistry ≠ Universe. The universe also includes pharmacology. Since the main interest in amphetamine is as a drug, pharmacological arguments trump chemical ones. The universe also includes regulatory authorities and Wikipedia drug articles must take into account the views of these authorities. The regulatory view is enantiomers of drugs are assumed to be different unless proven equivalent (e.g., the enantiomers rapidly epimerize). The enantiomers of amphetamine do not interconvert and have documented differences in pharmacology. It is also important to note that both enantiomers of amphetamine have pharmacological activity and that activity is similar but not identical. Hence merging Adderall (enantiomerically enriched dextroamphetamine that also contains pharmacologically active levoamphetamine) into dextroamphetamine doesn't make any sense. Levoamphetamine also contributes to the pharmacological activity of Adderall.
Functional differences between enantiomers only appear in a biochemical context – exactly. The main interest in the amphetamine article is its biological context, not its chemistry. Boghog (talk) 11:07, 18 April 2015 (UTC)Reply[reply]
Going through all the archives, I can see that the suggestion of a merge of L-amph, D-amph, and amphetamine only ever came up once on the dextroamphetamine talk page; it never gained any traction though. This merge proposal was never mentioned anywhere else. Frankly, I'm extremely disinclined to go through with a merge because of the amount of work it would require on my part to rewrite certain sections (e.g., medical uses) to tailor it to a specific page. I also have no clue what to title a page that combines both D-amph and Adderall, as they're distinct pharmaceutical products with different licence data. Both of those pages should exist anyway, as they're distinct pharmaceutical entities.
The normal venue for discussing a merge like this would be WP:Proposed mergers, but WT:PHARM+WT:CHEMICALS would likely be a better place to discuss this issue. Seppi333 (Insert ) 11:19, 18 April 2015 (UTC)Reply[reply]

Fair enough. I won't press this any further. Just two last (rhetorical) questions. i) Is the effect of a mixture of D- and L- isomers equal to the sum of the parts? ii) Is the D-isomer R- or S-? Petergans (talk) 19:35, 18 April 2015 (UTC)Reply[reply]

In answer to your questions: (i) To a first approximation, yes. (ii) Levo is R and Dextro is S. Boghog (talk) 20:06, 18 April 2015 (UTC)Reply[reply]

Reference notes

Why are the references grouped into "Reference notes" rather than linking to the citation directly? --Nbauman (talk) 11:27, 10 April 2015 (UTC)Reply[reply]

It is done when there are four or more references that need to be cited. Using the citations directly results in an excessively long number of citations. You would have to ask Seppi333 why all these citations are needed however. Sizeofint (talk) 15:06, 10 April 2015 (UTC)Reply[reply]
The first 4 refnotes cite entire paragraphs in the lead while the remainder group 4 or more references together for brevity, as Sizeofint stated. This was done because one individual complained incessantly about it during the FA nomination. Sentences which are cited by 4+ references are generally extremely broad statements which require multiple references to fully support the statement. Seppi333 (Insert ) 19:37, 10 April 2015 (UTC)Reply[reply]

Epigenetic mechanisms reviews

  • Review[1]
  • Review[2]
  • Review - already cited in the article[3]
  • Review[4]
  • 1st paper on psychostimulant HDACi (class I) efficacy[5]
  • 1st paper on alcoholism HDACi (class I) efficacy[6]
  • 1st paper on nicotine HDACi (class I) efficacy[7]

References

  1. ^ McCowan TJ, Dhasarathy A, Carvelli L (February 2015). "The Epigenetic Mechanisms of Amphetamine" (PDF). J. Addict. Prev. Avens Publishing Group (S1): 1–7. ISSN 2330-2178. Retrieved 30 April 2015. Epigenetic modifications caused by addictive drugs play an important role in neuronal plasticity and in drug-induced behavioral responses. Although few studies have investigated the effects of AMPH on gene regulation (Table 1), current data suggest that AMPH acts at multiple levels to alter histone/DNA interaction and to recruit transcription factors which ultimately cause repression of some genes and activation of other genes. Importantly, some studies have also correlated the epigenetic regulation induced by AMPH with the behavioral outcomes caused by this drug, suggesting therefore that epigenetics remodeling underlies the behavioral changes induced by AMPH. If this proves to be true, the use of specific drugs that inhibit histone acetylation, methylation or DNA methylation might be an important therapeutic alternative to prevent and/or reverse AMPH addiction and mitigate the side effects generate by AMPH when used to treat ADHD.
  2. ^ Walker DM, Cates HM, Heller EA, Nestler EJ (February 2015). "Regulation of chromatin states by drugs of abuse". Curr. Opin. Neurobiol. 30: 112–121. doi:10.1016/j.conb.2014.11.002. PMID 25486626. Studies investigating general HDAC inhibition on behavioral outcomes have produced varying results but it seems that the effects are specific to the timing of exposure (either before, during or after exposure to drugs of abuse) as well as the length of exposure
  3. ^ Nestler EJ (January 2014). "Epigenetic mechanisms of drug addiction". Neuropharmacology. 76 Pt B: 259–268. doi:10.1016/j.neuropharm.2013.04.004. PMC 3766384. PMID 23643695. Short-term increases in histone acetylation generally promote behavioral responses to the drugs, while sustained increases oppose cocaine's effects, based on the actions of systemic or intra-NAc administration of HDAC inhibitors. ... Genetic or pharmacological blockade of G9a in the NAc potentiates behavioral responses to cocaine and opiates, whereas increasing G9a function exerts the opposite effect (Maze et al., 2010; Sun et al., 2012a). Such drug-induced downregulation of G9a and H3K9me2 also sensitizes animals to the deleterious effects of subsequent chronic stress (Covington et al., 2011). Downregulation of G9a increases the dendritic arborization of NAc neurons, and is associated with increased expression of numerous proteins implicated in synaptic function, which directly connects altered G9a/H3K9me2 in the synaptic plasticity associated with addiction (Maze et al., 2010).
    G9a appears to be a critical control point for epigenetic regulation in NAc, as we know it functions in two negative feedback loops. It opposes the induction of ΔFosB, a long-lasting transcription factor important for drug addiction (Robison and Nestler, 2011), while ΔFosB in turn suppresses G9a expression (Maze et al., 2010; Sun et al., 2012a). ... Also, G9a is induced in NAc upon prolonged HDAC inhibition, which explains the paradoxical attenuation of cocaine's behavioral effects seen under these conditions, as noted above (Kennedy et al., 2013). GABAA receptor subunit genes are among those that are controlled by this feedback loop. Thus, chronic cocaine, or prolonged HDAC inhibition, induces several GABAA receptor subunits in NAc, which is associated with increased frequency of inhibitory postsynaptic currents (IPSCs). In striking contrast, combined exposure to cocaine and HDAC inhibition, which triggers the induction of G9a and increased global levels of H3K9me2, leads to blockade of GABAA receptor and IPSC regulation.
  4. ^ Biliński P, Wojtyła A, Kapka-Skrzypczak L, Chwedorowicz R, Cyranka M, Studziński T (2012). "Epigenetic regulation in drug addiction". Ann. Agric. Environ. Med. 19 (3): 491–496. PMID 23020045. For these reasons, ΔFosB is considered a primary and causative transcription factor in creating new neural connections in the reward centre, prefrontal cortex, and other regions of the limbic system. This is reflected in the increased, stable and long-lasting level of sensitivity to cocaine and other drugs, and tendency to relapse even after long periods of abstinence. These newly constructed networks function very efficiently via new pathways as soon as drugs of abuse are further taken ... In this way, the induction of CDK5 gene expression occurs together with suppression of the G9A gene coding for dimethyltransferase acting on the histone H3. A feedback mechanism can be observed in the regulation of these 2 crucial factors that determine the adaptive epigenetic response to cocaine. This depends on ΔFosB inhibiting G9a gene expression, i.e. H3K9me2 synthesis which in turn inhibits transcription factors for ΔFosB. For this reason, the observed hyper-expression of G9a, which ensures high levels of the dimethylated form of histone H3, eliminates the neuronal structural and plasticity effects caused by cocaine by means of this feedback which blocks ΔFosB transcription
  5. ^ Kennedy PJ, Feng J, Robison AJ, Maze I, Badimon A, Mouzon E, Chaudhury D, Damez-Werno DM, Haggarty SJ, Han MH, Bassel-Duby R, Olson EN, Nestler EJ (April 2013). "Class I HDAC inhibition blocks cocaine-induced plasticity by targeted changes in histone methylation". Nat. Neurosci. 16 (4): 434–440. doi:10.1038/nn.3354. PMC 3609040. PMID 23475113. While acute HDAC inhibition enhances the behavioral effects of cocaine or amphetamine1,3,4,13,14, studies suggest that more chronic regimens block psychostimulant-induced plasticity3,5,11,12. ... The effects of pharmacological inhibition of HDACs on psychostimulant-induced plasticity appear to depend on the timecourse of HDAC inhibition. Studies employing co-administration procedures in which inhibitors are given acutely, just prior to psychostimulant administration, report heightened behavioral responses to the drug1,3,4,13,14. In contrast, experimental paradigms like the one employed here, in which HDAC inhibitors are administered more chronically, for several days prior to psychostimulant exposure, show inhibited expression3 or decreased acquisition of behavioral adaptations to drug5,11,12. The clustering of seemingly discrepant results based on experimental methodologies is interesting in light of our present findings. Both HDAC inhibitors and psychostimulants increase global levels of histone acetylation in NAc. Thus, when co-administered acutely, these drugs may have synergistic effects, leading to heightened transcriptional activation of psychostimulant-regulated target genes. In contrast, when a psychostimulant is given in the context of prolonged, HDAC inhibitor-induced hyperacetylation, homeostatic processes may direct AcH3 binding to the promoters of genes (e.g., G9a) responsible for inducing chromatin condensation and gene repression (e.g., via H3K9me2) in order to dampen already heightened transcriptional activation. Our present findings thus demonstrate clear cross talk among histone PTMs and suggest that decreased behavioral sensitivity to psychostimulants following prolonged HDAC inhibition might be mediated through decreased activity of HDAC1 at H3K9 KMT promoters and subsequent increases in H3K9me2 and gene repression.
  6. ^ Simon-O'Brien E, Alaux-Cantin S, Warnault V, Buttolo R, Naassila M, Vilpoux C (July 2015). "The histone deacetylase inhibitor sodium butyrate decreases excessive ethanol intake in dependent animals". Addict Biol. 20 (4): 676–689. doi:10.1111/adb.12161. PMID 25041570. Altogether, our results clearly demonstrated the efficacy of NaB in preventing excessive ethanol intake and relapse and support the hypothesis that HDACi may have a potential use in alcohol addiction treatment.
  7. ^ Castino MR, Cornish JL, Clemens KJ (April 2015). "Inhibition of histone deacetylases facilitates extinction and attenuates reinstatement of nicotine self-administration in rats". PLoS ONE. 10 (4): e0124796. doi:10.1371/journal.pone.0124796. PMC 4399837. PMID 25880762. treatment with NaB significantly attenuated nicotine and nicotine + cue reinstatement when administered immediately ... These results provide the first demonstration that HDAC inhibition facilitates the extinction of responding for an intravenously self-administered drug of abuse and further highlight the potential of HDAC inhibitors in the treatment of drug addiction.

@Boghog: This journal isn't pubmed indexed, so I can't use your cite tool to autoformat this citation; should the journal title be converted to sentence case? I'm also not really sure what to do about the issue parameter, since S(1) is used in the journal and (S1) is as much as I can get in the template output. Seppi333 (Insert ) 07:16, 30 April 2015 (UTC)Reply[reply]

Hi Seppi. Looks fine as is. I assume "S1" is short for "Supplement 1". Either will work as the |issue= value. Ideally the journal title should in title case. I know that tool presently does not do this. I will see if I can tweak it to do this. Boghog (talk) 09:15, 30 April 2015 (UTC)Reply[reply]
I feel stupid for not typo checking what I wrote... what I meant to ask was should the article title – |title=The Epigenetic Mechanisms of Amphetamine – be converted to sentence case? So far as I can tell, all the current cite journal templates in the amphetamine article have the title parameter in sentence case. Seppi333 (Insert ) 14:13, 30 April 2015 (UTC)Reply[reply]


These reviews + primary research papers actually suggest that chronic pretreatment (not concurrent use) with HDAC class I inhibitors (e.g., butyric acid/sodium butyrate) would be an effective drug treatment for stimulant (cocaine/amphetamine) all addictions by promoting NAcc G9a expression... Face-surprise.svg Seppi333 (Insert ) 23:17, 7 May 2015 (UTC)Reply[reply]

Issues

Article states "Cochrane reviews on the use of amphetamine following a stroke or acute traumatic brain injury indicated that it may improve recovery, but further research is needed to confirm this"

  • But the Cochrane reviews conclusions is "At present, too few patients have been studied to draw any definite conclusions about the effects of amphetamine treatment on recovery from stroke" [1]
  • The second review found just animal evidence [2]
  • And the third ref states "On the basis of current findings amphetamine after brain injury cannot be recommended" [3]

First of all this is research and not clinical use and thus should go at the end in a research section. Second we have misrepresented the sources. Doc James (talk · contribs · email) 12:37, 4 June 2015 (UTC)Reply[reply]

Then delete the sentence. Seppi333 (Insert ) 12:38, 4 June 2015 (UTC)Reply[reply]
Those were good sources. The content just needs to be reworded to acurate reflect the sources and placed in a second on research. Doc James (talk · contribs · email) 12:41, 4 June 2015 (UTC)Reply[reply]

This is also research "A review of clinical trials that used lisdexamfetamine as an adjunct therapy with a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) for treatment-resistant depression indicated that this adjunct therapy is no more effective than the use of an SSRI or SNRI alone.[1] This observation is consistent with previous findings that serotonin–norepinephrine–dopamine reuptake inhibitors (SNDRIs) demonstrate no additional efficacy over SSRIs and SNRIs for the treatment of major depressive disorder.[1]" Doc James (talk · contribs · email) 12:41, 4 June 2015 (UTC)Reply[reply]

What's your concern with that content? Seppi333 (Insert ) 12:44, 4 June 2015 (UTC)Reply[reply]
It should go under research. It is not a medical use. As should a proper summary of the previous sources. It is important that their is not good human evidence for use in stroke and that it is not recommended in brain trauma. It is interesting that their is some tentative animal data. Doc James (talk · contribs · email) 12:52, 4 June 2015 (UTC)Reply[reply]
If I had added a preclinical research section, it would be enormous to comply with the FA comprehensiveness criteria (e.g., the medications in the reviews in the above section), which is why I never included one when writing this article. I'm okay with putting the SSRI statements in a research section though. Seppi333 (Insert ) 13:03, 4 June 2015 (UTC)Reply[reply]
It just needs to be the highlights. A comprehensive list here would be undue weight. One could have a subpage if people are interested. Doc James (talk · contribs · email) 19:22, 4 June 2015 (UTC)Reply[reply]

concur with DocJames, logic indicates it should go under research section --Ozzie10aaaa (talk) 13:09, 4 June 2015 (UTC)Reply[reply]

I've deleted the remaining content from this page. It's now only in the LDX article. Seppi333 (Insert ) 17:55, 4 June 2015 (UTC)Reply[reply]

References

  1. ^ a b Dale E, Bang-Andersen B, Sánchez C (May 2015). "Emerging mechanisms and treatments for depression beyond SSRIs and SNRIs". Biochem. Pharmacol. 95 (2): 81–97. doi:10.1016/j.bcp.2015.03.011. PMID 25813654.