Wikipedia:Featured article candidates/Amphetamine/archive5

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 2¢ | 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 2¢ | Maintained) 08:59, 10 August 2014 (UTC)[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 2¢ | 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 2¢ | 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]

• 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 2¢ | Maintained) 19:06, 5 August 2014 (UTC)[reply]

• I've taken a shot at that; please do double-check to make sure it's accurate.

Looks good. Seppi333 (Insert 2¢ | Maintained) 08:59, 10 August 2014 (UTC)[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 2¢ | 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 2¢ | 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 2¢ | 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 2¢ | Maintained)

 Added - Diff Seppi333 (Insert 2¢ | 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.

• That's fine with me if you'd like to add this. Found a suitable ref, how's this look? Diff Seppi333 (Insert 2¢ | Maintained)

• 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]

 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 2¢ | Maintained) 16:00, 11 August 2014 (UTC)[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? :)

• There's actually a lot of discussion among the academic community about the use of performance enhancing agents in the general population (e.g., this paper elicited quite a lot of responses). It was only recently determined that low doses of ADHD psychostimulants improve cognitive control in everyone via their effect on dopamine D1 receptors in the prefrontal cortex.

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 2¢ | 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]

 Added – Seppi333 (Insert 2¢ | 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]

• 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 2¢ | 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]

 Done – Seppi333 (Insert 2¢ | Maintained)

Sorry for the late follow-up; I've been pretty busy this past week. I'll address these points momentarily! Regards, Seppi333 (Insert 2¢ | Maintained) 16:16, 9 August 2014 (UTC)[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 2¢ | Maintained) 14:19, 11 August 2014 (UTC)[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 2¢ | Maintained) 18:17, 12 August 2014 (UTC)[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]

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 2¢ | Maintained) 09:31, 13 August 2014 (UTC)[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]

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 2¢ | Maintained) 14:19, 11 August 2014 (UTC)[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 2¢ | Maintained) 18:17, 12 August 2014 (UTC)[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]

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]

 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 2¢ | Maintained) 18:19, 12 August 2014 (UTC)[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]

I'm not entirely sure to be honest. The enteric nervous system isn't well understood at the moment. Seppi333 (Insert 2¢ | Maintained) 20:47, 15 August 2014 (UTC)[reply]

Overdose 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]

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]

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 2¢ | Maintained) 03:37, 11 October 2014 (UTC)[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 2¢ | 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 2¢ | 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 2¢ | 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 2¢ | 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 2¢ | Maintained)

• “The most important transcription factors” I would suggest adding a note explaining the role of transcription factors in gene expression.

 In progress I need to find a MEDRS-quality source first, but I intend to do this. Seppi333 (Insert 2¢ | Maintained)

 Done Added this as a note next to the first use of the "transcription factor" phrase. Seppi333 (Insert 2¢ | 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 2¢ | Maintained)

• “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 2¢ | 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 2¢ | 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 2¢ | Maintained) 03:47, 11 October 2014 (UTC)[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 2¢ | Maintained) 03:47, 11 October 2014 (UTC)[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 2¢ | 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]

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 2¢ | 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 2¢ | Maintained) 01:25, 11 October 2014 (UTC)[reply]

Lead through Side effects Reading through these first few sections again I made a few tweaks to the prose, but I have a lot fewer comments than I did the first time around. Rather than 30-40 I've only got five. AmericanLemming (talk) 03:37, 23 December 2014 (UTC)[reply]

• Lead: “Amphetamine is also used as a performance and cognitive enhancer” So while using it as “a performance and cognitive enhancer” is almost always illegal, such use is not considered recreational?

Recreational use is really just using a drug for the pleasure it provides. Virtually all drugs that are used recreationally (except certain hallucinogens/deliriants) are rewarding and consequently produce some form of high or desirable feeling. That property unfortunately also makes them addictive drugs.
As for performance and cognitive enhancing use, anyone who is prescribed amphetamine pharmaceuticals can technically "misuse" it for such a purpose by taking it when it's needed for such a purpose as opposed to taking it a fixed number of times every day around the same time. It's also possible to acquire a prescription for an amphetamine without actually having a relevant medical condition... I'm not sure how common this is, but healthy individuals (often students) can feign symptoms of ADHD to acquire a prescription for amphetamine or methylphenidate for use as a cognitive enhancer. This technically is legal in spite of being a nonmedical use for a highly controlled (US schedule 2) substance. Seppi333 (Insert 2¢ | Maintained)

That is, are “illegal drug use” and “recreational drug use” usually but not always synonymous?

Dextromethorphan (brand: Robitussin - where the phrase "robo tripping" comes from) is an OTC recreational drug, so uncontrolled/OTC recreational drugs do exist. This example is actually covered in detail at Recreational use of dextromethorphan. Seppi333 (Insert 2¢ | Maintained)

• Lead: “which includes prominent substances such as bupropion, cathinone, MDMA (ecstasy), and methamphetamine.” Can all these compounds be synthesized from amphetamine and/or are they commonly synthesized from amphetamine? We might want to mention that.

They're not really synthesized, per se. They represent a compound which contains amphetamine in its skeletal structure (i.e., if you look at a structure diagram of one of these chemicals, the amphetamine skeletal structure is contained within it as a substructure. You can think of substituted amphetamines as any chemical that can be formed ("described" might be a better term) by adding chemical groups onto the amphetamine compound. I don't think it's even possible to synthesize methamphetamine from amphetamine - Boghog expanded the chemistry section since I'm really not chem-savvy. Seppi333 (Insert 2¢ | Maintained)

• Lead: “Unlike methamphetamine, amphetamine's salts lack sufficient volatility to be smoked.” What exactly is the significance of this statement? That is, why is it in the lead? Does it make amphetamine less practical for recreational use than methamphetamine?

IIRC, smoking methamphetamine is the most common route of administration for taking methamphetamine recreationally. This basically says amphetamine salts can't be smoked, only the volatile liquid freebase can be (amphetamine is almost never stored as the freebase), making it much more difficult to smoke. If you think it's not worth including, we can delete it. Seppi333 (Insert 2¢ | Maintained)

I've removed it. The general reader isn't going to be able to make sense of it without context, and given space constraints in the lead, we don't have room for that context. It's also somewhat off-topic; the article's about amphetamine, not methamphetamine. AmericanLemming (talk) 09:32, 9 January 2015 (UTC)[reply]

• Medical: “Therapeutic doses of amphetamine improve cortical network efficiency,” as in the mesocorticolimbic pathway?

The ref indicates that it improves efficiency in the dorsolateral prefrontal cortex (which is part of that pathway) and the posterior parietal cortex (which isn't part of that pathway). These are included in the reference's quote parameter, so I imagine if someone is curious about which cortices become more efficient, they'd probably look there and see the quote. Seppi333 (Insert 2¢ | Maintained)

• Contradictions: Um, aren’t hypertension and elevated blood pressure the same thing? I ask because the whole “These agencies also state that anyone with…elevated blood pressure, etc.,” makes it sound like there’s some difference between them.

Fixed that by changing it to hypertension. Seppi333 (Insert 2¢ | Maintained)

Overdose I just finished going through all of my old comments from this section and looking at your changes and responses. I'm now satisfied with the organization and comprehensiveness of the section, but the prose still needs some tweaking, some of which I can take care of and some of which I'll need to ask you about. I really like the table, by the way; it does a much better job of presenting the same information. Also, I think you should reread the section to make sure I haven't oversimplified anything in my relentless quest to make the article accessible to the general public. AmericanLemming (talk) 08:41, 25 December 2014 (UTC)[reply]

• I’m not comfortable with the second paragraph. I think it does a pretty good job of summarizing the section, but I wrote almost all of it, so I’m not sure how accurate it is.

I tweaked it a tiny bit when I added some detail on how ΔFosB expression affects addictive behavior, but it looked fine. Seppi333 (Insert 2¢ | Maintained)

• I’ve reworded every sentence in this section (it feels like I have, anyway), and I’m worried that I’ve traded accuracy for readability in some places. You may want to read over the whole thing to make sure the facts are still straight.

I looked over the whole section. Most of the revisions were accurate; I added a little more detail in some cases. Seppi333 (Insert 2¢ | Maintained)

• “Increases in nucleus accumbens ΔJunD expression using viral vectors can reduce many of the neural and behavioral alterations seen in chronic drug abuse (i.e., the changes caused by ΔFosB); large enough increases may block these changes altogether.” So it sounds like we have/could have a drug that cures addiction, more or less. I suppose it’s still in animal trials/has extremely severe side effects?

Basically, yes. It's almost correct to say that ΔFosB overexpression alone causes addiction, though it's a little more technical because ΔFosB interacts with other proteins differently and different addictive drugs/behaviors have variable effects on those interacting proteins. It is crucial for an addiction though, so repressing ΔFosB in the nucleus accumbens will result in marked reductions in compulsive reward-seeking/addictive behavior. Seppi333 (Insert 2¢ | Maintained)

• About these sex addictions again. So they only happen if you’re addicted to amphetamine? That is, these are highly unlikely at typical therapeutic doses?

It's more likely to occur than an amphetamine addiction if an individual engages in both frequent sexual activity and frequent amphetamine use. It's still uncommon though. That said, because the rewarding effects of sex and amphetamine cross-sensitize bidirectionally, it's technically possible to see a "sex-induced amphetamine addiction", though I haven't read about one in humans. Seppi333 (Insert 2¢ | Maintained)

• “chronic acquisition of these rewards can result in a similar pathological state of addiction.” Most people eat every day, but very few of them become addicted to food. By “chronic acquisition” do you mean excessive/abnormal/more than usual?

ΔFosB isn't normally produced upon acute (a single) exposure to an addictive stimulus; it requires repeated exposure at some minimum intensity (e.g., frequent drug use a above some threshold dose or the amount/frequency of food intake). The more excessive and more frequent the exposure to an addictive stimulus, the more likely it is that ΔFosB will begin to be expressed. This actually is the reason why it's not possible to become addicted to anything upon a single exposure to it, no matter how "intensely" (e.g., the severity of an overdose) it is experienced. Back to food though, only sweet and fatty foods are addictive, since these are perceived as being palatable/tasty (rewarding). You'd have to frequently consume a lot of these types of foods to start eating them compulsively; I can't imagine most people have that type of diet anyway. :P Seppi333 (Insert 2¢ | Maintained)

• “increased activation of dopamine receptors and co-localized NMDA receptors” So these receptors are located in the same cells?

Same neurons to be more precise, but yes. I actually illustrated this on template:psychostimulant addiction. Their occurrence together along that plasma membrane makes them co-localized. Seppi333 (Insert 2¢ | Maintained)

• Diagram and caption: “trigger internal signaling events through a cAMP pathway and calcium-dependent pathway that ultimately result in increased CREB phosphorylation.” So I take it these are two different pathways?

It's basically referring to the signaling that starts at the dopamine receptors (the cAMP pathway) and the signaling that originates from the calcium channel/NMDA receptor (calcium-dependent pathway). These pathways intersect/merge once they reach/signal to CREB (as shown in the diagram). Seppi333 (Insert 2¢ | Maintained)

• Diagram and caption: “Phosphorylated CREB increases levels of ΔFosB, which in turn represses the c-fos gene with the help of corepressors.” What does repressing the c-fos gene do? I understand it’s implicated in many types of cancer and plays an important role in the cell, but what is its importance here?

Well... because c-fos is an immediate early gene, it does a lot of things. ΔFosB actually has other immediate targets (unlike c-fos, it increases the expression of some of them); I just didn't have a lot of drawing room to show more. The primary diagram I used as a reference simply stopped at that point anyway, so it's probably not losing anything significant by omitting all of them except c-fos. :P Seppi333 (Insert 2¢ | Maintained)

Edit: this is a more useful answer to your question: accumbal ΔFosB targets/effects table. Seppi333 (Insert 2¢ | Maintained)

• Psychosis and toxicity: “as a result of increased oxidative stress from reactive oxygen species and autoxidation of dopamine.” What exactly does this mean? Does amphetamine indirectly cause oxidative stress by increasing synaptic dopamine levels, which then increases the production of free oxygen radicals? AmericanLemming (talk) 07:00, 1 January 2015 (UTC)[reply]

That's exactly what it means. A direct toxicity would mean that amphetamine itself is toxic to neurons. This form of indirect toxicity means that the toxic compounds are the reactive oxygen species and autoxidized dopamine radicals. The main difference between a direct and an indirect toxicity is that an indirect toxicity has a threshold dose for when the compounds begins to produce toxicity. All substances, including salt and water, are indirect neurotoxins. Seppi333 (Insert 2¢ | Maintained)

Interactions

• “Inhibitors of the enzymes that metabolize amphetamine…will prolong its elimination half-life” What the clinical significance of having amphetamine in your system longer? Does that make it easier to overdose on it?

Eh... an increased elimination half-life doesn't do much more than extend the amount of time the drug is active (going about its business). It could contribute to an overdose if it is used frequently enough, though I've never read of an unintentional amphetamine overdose arising solely from half-life manipulations. Seppi333 (Insert 2¢ | Maintained)

• “increase plasma catecholamines” I know we’re mentioned it in the lead, but adding “(i.e. norepinephrine and dopamine)” after catecholamines may be helpful for the general reader. AmericanLemming (talk) 08:11, 15 December 2014 (UTC)[reply]

I added this in. Seppi333 (Insert 2¢ | Maintained)