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Boghog ( talk · contribs), if you're familiar with this synthesis/metabolism material, the content I just added could probably use copy-editing from a more chemistry-savvy editor than I am. I actually wasn't sure if some of the pathway-related enzymatic reactions were redundant. A lot of that content was bits and pieces from the pubchem compound page. Regards, Seppi333 ( talk) 05:39, 12 October 2013 (UTC)
(Outdent)
Sorry for the late follow up - been really busy outside of Wikipedia. I fixed the image, so let me know if it's good or there's still any flaws or potential improvements (no matter how small). Feel free to add whatever you want though - the more (on-topic/relevant) info, the more comprehensive, and hence the better the article. Also, I need to do the following two things for GA/FA improvements, but as I have no background in chem, it'd be a big help if you could review the content after I add it.
Regards, Seppi333 ( talk) 16:32, 22 October 2013 (UTC)
How's this look in the meantime? It's the best I could do with my limited knowledge of chemistry and chem editors (I actually used MS paint to make some of these). ;P
725x400 px image
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Seppi333 ( talk) 21:34, 24 October 2013 (UTC)
I hate to ask even more of you since I feel like you've already done a lot for me, but if you're willing and have a chance (this isn't even remotely urgent, so no rush), these three article I made could use a quick, cursory stupidity-filter/fact-check:
P-hydroxynorephedrine,
formetamide, and
User:Seppi333/P-hydroxyphenylacetone. Regards,
Seppi333 (
talk)
17:05, 28 October 2013 (UTC)
Hi everyone - I'm not 100% positive this is the same thing, so revert my edit if vaporization is a more general concept or "route" than smoking.
I came across this page from the EMC stating that, unlike meth, amphetamine (sulfate form) is insufficiently volatile to be smoked. http://www.emcdda.europa.eu/publications/drug-profiles/amphetamine
Regards, Seppi333 ( talk) 02:43, 15 October 2013 (UTC)
From the research I've done, and from prior knowledge, it would appear to me that Amphetamine's metabolism is almost entirely mediated by MAO-B. If that's the case, why shouldn't it be noted in the metabolism section on the right, that MAO-B plays a big part in Amphetamine metabolism? I know CYP2D9 does have some effect on amphetamine, however, the studies I've read claim that it's effects on Amphetamine metabolism is <10%.
So, before I add this into the article, am I missing something? It seems to me that this should already be here and the fact it isn't leads me to believe I may be misinterpreting something.
Regards SwampFox556 ( talk) 20:06, 15 October 2013 (UTC)
This section could use a general range of how long amphetamine is detectable by a typical test. That's a significant piece of information, and I'm sure many people come here looking for it. Exercisephys ( talk) 21:52, 25 October 2013 (UTC)
This article contains a lot of examples of long sentences being combined with semicolons. I would make the article more readable to leave them as separate sentences.
A study conducted soon before the cited Volkow study, which used similar methods, came to the opposite conclusion. The Volkow paper cites it. I don't have time to dig it up now, but I think in the spirit of neutrality it deserves a mention. I posted this here as a self-reminder, and as an offer to any WP:Gnomes that have a little free time. Thanks. Exercisephys ( talk) 02:33, 29 October 2013 (UTC)
A few months ago, I got Adderall moved to amphetamine mixed salts (medication). This was done because it is Wikipedia policy to name articles after the generic pharmaceutical name of drugs rather than the brand name. The fact that Adderall was one of the few lasting exceptions to this rule points out just how entrenched the brand name is. However, identical generic formulations exist, so the name "amphetamine mixed salts" should be used. However, it's probably a good idea for us to clarify that it's equivalent to Adderall often, as most people are only familiar with the latter term. Exercisephys ( talk) 00:44, 3 November 2013 (UTC)
Also, as a minor side-note, "Adderall" is capitalized. Exercisephys ( talk) 16:55, 3 November 2013 (UTC)
I also realized it was possible to check the number of users searching for Adderall vs using a wikilink directly to the page or searching the page itself. As of writing this, over the past 90 days, 70000 people searched for Adderall in the search bar or arrived there from outside wikipedia, since redirects to Adderall would just be moved to amph mixed salts by bots. Over that same 90 day period, 184 people arrived at "Amphetamine mixed salts" by searching that term directly or coming from outside wikipedia. The remainder of the 118000 people that viewed amphetamine mixed salts (medication) probably arrived there externally or by wikilink given that 184 (vs 70000 for Adderall) people searched the non-parenthetically disambiguated version. There's really only one conclusion to draw from those stats and the first item in WP:CRITERIA. :P Seppi333 ( talk) 12:23, 5 November 2013 (UTC)
Instead of replacing the "publisher" parameter with "work" parameter in citation templates as was done in this and removing the information that was in the work parameter, why don't we add publisher and work parameters to all cite web templates? According to the {{ cite web}} documentation, the "work" parameter contains the "title of the website; may be wikilinked; will display in italics" which is clearly different than the publisher. Boghog ( talk) 05:53, 4 November 2013 (UTC)
References
Regards,
Seppi333 (
talk)
23:38, 4 November 2013 (UTC)
I think the article would be of greater benefit to the internet if it was explained why Amphetamine (but all Dopaminergic stimulants apply) are the ideal treatment for ADHD? I'd also love to see a section about why Amphetamine is used to treat Narcolepsy.
The idea for the section I have in mind would explain what we know about the causing mechanism behind ADHD and why Amphetamines are the prototypical treatment for it. I'd also love to have the ladder explained for Narcolepsy as well.
I am seriously considering putting in the amount of time it would take to research everything in depth while only explaining it in a few paragraphs. I am willing to put in the time to do that, but I'm afraid someone might object and remove the new information. So I ask...
Would that be acceptable? It would be a subsection of the "uses" header at the top of the article. Let me know what you guys think.
Best regards, SwampFox556 ( talk) 00:30, 7 November 2013 (UTC)
The name of the study escapes me, but I read a very interesting study (that was actually a compilation of around 30 studies) that was able to make a very solid hypothesis that ADHD is caused by an over-expressed DAT1 gene. You seem pretty knowledgeable Seppi, so I'm sure you have already heard this before, however just in case you haven't...
The thesis was written up by Dr. Russell Barkley and published last year. He took many studies and formed a hypothesis from them. We have speculated for years that genes play a major part in the development of illness. However, it's incredibly difficult to understand mental illness due to the fact that we can't open up a human brain without killing that person. Anyways, my point is, we've always known that genes likely play a major role in the predisposition to developing illness, but its never been proven that one specific gene was the cause for an illness.
Dr. Russell Barkley's thesis stated this and he said that the study was start in order to attempt to determine "the genes" that cause ADHD. So he based the initial idea off of already published studies and using that information conducted other studies. His findings were quite interesting. He conducted more than one study and I'm not sure what each specific study was about to be honest, however, he summed it all up in his conclusion pretty well.
He said that they found that several things can lead to ADHD from birth, but all of these changes had to happen in the womb. However, he did mention that there was strong evidence to suggest that if a child sustains a concussion in the very early stages of after-birth development, it appeared that this could also lead to classic symptoms of ADHD.
Anyways, he said all of these things affect development in a different way but the end result is always the same.
The gene that controls the development of the Dopamine Uptake Transporters is called DAT1. It is located on chromosome 5p15. For one reason or another, this gene is mutated this causes the gene to become over-expressive thus resulting in a huge increase in Dopamine Uptake Transporters. The dopaminergic neurons release Dopamine like they should be, but the dopamine has no time to form a complex with a receptor before it gets uptaken. This results in incredibly small extracellular and postsynaptic Dopamine levels.
He found that this gene can already exist in some people and it doesn't have to be mutated. However, he found that introduction of a toxin can result in the mutation of this gene. Specifically, Nicotine and Ethanol.
Children, whose mothers drank or smoked during their pregnancy with the child, were something like 72% more likely to be born with ADHD. There is already a known correlation between ADHD and comorbidity, but he said that there was evidence to suggest that these children (children of mothers who had used a toxin at some point in their pregnancy) were even more likely to have a comorbid, psychiatric disorder diagnosed at some point in their life.
In the study, only Ethanol and Nicotine (well, all the extract of Tobacco) were used. However, both of these substances cause immense release of Dopamine through one mechanism or another. This was not said in the study, but the way he wrote it made it sound like he was alluding to this. The increased Dopamine levels causes the fetus to compensate in order to reach homeostasis. This compensation is the result of more DA transporters - either these transporters were created by the fetus as a means to get rid of extra Dopamine, or it's possible that the body could have mutated the gene so more DAT cells would be produced.
Again, he said none of that directly, but that's the idea I got from the thesis. I guess it doesn't matter how the extra uptake transporters were created, all they know is it happens. Also, I should add, they were actually able to prove this happens with extensive brain imaging. He also said that since the discovery of the over-expressed gene that causes more DA transporters to exist, many correlations between high amounts of these transporters and other illnesses have been seen.
He said that while he was conducting the rest of his thesis, another study came out (using his information) that the presence of this gene is a great indicator for later in life drug addiction. They also concluded that the substance that was most likely for the person to be addicted to at some point in their life was Nicotine. But other drugs were tested in this study and found that it also applies to Ethanol, Cocaine, and Methamphetamines. However, the study also said likelihood for addiction to dissociatives also appeared to be increased. The one tested specifically was Phencyclidine (PCP).
Anyways, to finish up Dr. Barkley's thesis - He found that the presence of this gene was a great indicator for how well you would respond to stimulant treatment. I don't remember how many people were tested (it was something like 11 or 14) but they were all tested for an over-expressed DAT1 gene - all tested positive. When they were asked to take Methylphenidate (I believe it was the minimum dose indicated for adult ADHD) they all responded very well to Methylphenidate. Attention was greatly improved, motivation was markedly improved, psychomotor agitation was markedly decreased, emotional stability was increased, impulsiveness was decreased, upon other things (those were just the one I remembered off the top of my head) and they all reported that there overall quality of life had been improved by Methylphenidate.
There are many videos of Dr. Russell Barkley explaining his finding on YouTube. One of the videos cited the thesis directly, but I can't seem to find it. Let me go back through my internet history and I'll post back.
Regards, SwampFox556 ( talk) 05:56, 7 November 2013 (UTC)
This is what I made reference to earlier. The paragraph is something I added a few months back and subsequently removed after becoming familiar with MEDRS:
Adhd & TAAR1
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With exception to the last 2 sentences which would need to be cut, every primary source in this paragraph could be replaced with one of the following 3 reviews: [1] [2] [3] In individuals with ADHD, there is significant evidence that phenethylamine (PEA) – an endogenous amphetamine homologue with analogous dopaminergic pharmacodynamics [4] [5] – metabolism is reduced compared to healthy individuals. [6] [7] [8] It is well documented that urinary excretion of PEA increases following administration of amphetamine and methylphenidate, and that urinary excretion of these drugs is highly correlated with urinary excretion of PEA; [9] [10] [11] moreover, studies on rodents show that brain PEA biosynthesis and metabolism greatly increases following amphetamine administration at therapeutic doses. [12] [13] There is also evidence that pharmacological depletion of PEA blocks the stimulant effects of amphetamine, suggesting that endogenous PEA plays an important role in mediating the effects of amphetamines. [14] [15] In spite of similar effects on catecholamines, unlike amphetamine, methamphetamine does not affect brain PEA levels, nor does PEA appear to mediate the effects of methamphetamine. [16]
References
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I apologies, that's not how I meant to present my point. I should have stated this above. What I meant to imply (and should have stated outright) was the fact that; whether or not it's "too many DA uptake pumps" or "too little endogenous Phenethylamine" the end result is always the same. Dopamine levels in the frontal lobe of the brain are lower than normal. This leads to all the motivational deficits, attention issues, emotional instability, etc seen in patients who have ADHD. I know there's a little more to it then just low dopamine, but that's pretty much the gist of it.
To get a little off topic, I remember reading some studies that suggested that there was a deficit in the levels of all the monoamine neurotransmitters in people with ADHD, but I'm not trying to get that far into it. Yes, I agree. Having all the above is a little overkill for just the Amphetamine article. But couldn't there be a very skimmed down version of both possible causes? Something like...
"Were not certain at this point in time what causes ADHD However, it's very widely accepted that the neurotransmitter Dopamine is found in much smaller quantities all over the Brain of someone with ADHD.(see "ADHD cause" article).
believe that genetics may play a major role in determining who will be susceptible to the illness. The gene located on chromosome 5p15, the gene itself is known as DAT1, has been identified as being responsible for the creation of the Dopamine Uptake Transporter. This transporter is responsible for removing dopamine from the synapticcleft and is an important part of dopamine regulation in the Brain. It was discovered *insert year here* that this gene appears to be overly expressed in people with ADHD. This means that many more DA transporters will be created. This would allow too much upregulation of dopamine and would result in much lower postsynaptic dopamine levels."
I didn't know how to summaries the lowered levels PEA paragraph. So in order to save time I didn't put it in in just a reply. But I'm thinking that after that paragraph is stated, that we could then briefly explain that amphetamines raise dopamine levels quite a bit?
would that be acceptable? — Preceding unsigned comment added by SwampFox556 ( talk • contribs) 22:08, 8 November 2013 (UTC)
Sorry for the late reply. I think adding something like that would be fine. I'll draft something tonight and post it here to see what you think. Seppi333 ( talk) 21:01, 9 November 2013 (UTC)
Actually, do you have a PMID for a MEDRS-quality review on DAT/ADHD (ideally, one published between Jan 2008 and today) handy that I can use to cite the first part? I've been a bit busy with ref editing for GA/FA to do a search for suitable papers to cite. The lack of ref on hand is really the only thing that's been holding me up from doing this. Seppi333 ( talk) 20:12, 11 November 2013 (UTC)
It took me a couple of hours, but I finally wrote up a section on the results of stimulant treatment in people with ADHD. Even though the information provided is entirely backup, by multiple clinical studies - this section will be controversial due to the fact that there are so many misconceptions out there about stimulants drugs in the treatment of ADHD that are potentiated by the scientologists and media.
I will revert any attempted edits to the section unless claims are backed up with legitimate medical proof. I imagine this section will receive an immense amount of vandalism but I will try to monitor the section as much as I can to revert this attempt to censor information.
If anyone has any problems with the section, and can provide medical proof to backup any claims, feel free to the edit the section at will. If anyone has any problems with the section as it is now, let me know and I'll edit the section in an attempt to comply with Wikipedia's rules as best as I can.
Best regards, SwampFox56 (Zeke Ortiz)
SwampFox556 ( talk) 23:30, 12 November 2013 (UTC)
I really like all of the edits. It sounds much more professional, and is better written than what I initially wrote. Thanks a lot for the work Seppi! It looks good :) There is one minor change I've decided to ahead and make though. "In particular, children with ADHD who use stimulant medications are generally more sociable." I feel like that implies that the child then becomes overly expressed socially, which isn't necessarily what the source said.
So I decided to change it to "In particular, children with ADHD who use stimulant medications, generally have better relationships with peers and family members." I also changed the sentence located after that one to "Children, also, generally perform better in school, are less distractible and impulsive, and have longer attention spans." In order to fit the above edits.
Anyways, again, everything looks great otherwise! :)
Regards,
SwampFox556 ( talk) 23:10, 15 November 2013 (UTC)
This is rather minor but it's mentioned a couple times in the article that Amphetamine "increases libido." I'm wondering if this should rather be stated as "change in libido" as it doesn't always cause an increase? I haven't researched the topic in depth yet, however, typical prescribing information lists "change in libido" and not that amphetamine will definitely increase libido.
http://www.rxlist.com/adderall-drug/side-effects-interactions.htm
http://pi.shirecontent.com/PI/PDFs/AdderallXR_USA_ENG.PDF
A libido decrease was noted by Shire in their prescribing information of 60 milligrams of Adderall or higher.
User reports I've read also indicate that amphetamine can both "increase sexual desire" or "decrease sexual desire." I know you can't base anything off of user reports - replicated clinical studies are the only way to be sure of anything. However, it seems to me that "increase in libido" is inappropriate.
If anyone has an opposition to me changing this, I won't make any fuss about it - it's not really that big of a deal anyways. However, I feel this minor edit would make the information in the article a bit more accurate.
SwampFox556 ( talk) 22:02, 16 November 2013 (UTC)
Apparently this page is protected so I can't edit it. Anyway, in the other relevant activities section it states that histamine is 'another monoamine' - only it isn't. It's a diamine, and as expected, it metabolized by diamine oxidase. 216.105.211.130 ( talk) 06:03, 26 November 2013 (UTC)
This is the current version of the article. I don't like the lede, it seems rather sloppily written and the "in spite of the significant health risks" is clearly tacked on. Not that it doesn't belong there, but the way it's included looks like the DARE van did a drive-by, so I'm going to edit it. The lede is usually the most contentious part of an article, especially one concerning a widely-abused drug, so I've gone ahead and created this section as a forum for the discussion and compromise that will probably be necessitated eventually. Zig Saw 07:28, 26 November 2013 (UTC)
Exercisephys, I know you're well aware of WP:MEDRS criteria - stop ignoring it. Asserting neurotoxicity is a medical claim. Since this is now a GA article and I went through a great deal of trouble to remove all the non-MEDRS sources to medical claims and then re-cite the text with MEDRS versions, I'm not going to accept anything but a MEDRS source for a neurotoxicity claim. I.E., use a review of literature or professional text published within the last 5 years. Moreover, the relevant material also needs to be on humans - not animals. All of that is explicitly stated in MEDRS for medical claims on actively studied topics.
I put THREE sources to back the statement that you removed - two of which were MEDRS (1 review, 1 pharmacology textbook) and a primary source on HUMANS (not rats) to supplement the MEDRS review (also on HUMANS) and expand upon the material from that secondary source. I based all of that on what I found on a lit. search, pubchem, and drugbank.
I didn't counter your claims the last time. Since this is now annoying me, I'm going to support my position with MEDRS sources, specifically, NCBI's tertiary source on amphetamine (Pubchem Compound) - a "data encyclopedia" if-you-will.
Before I go into this, just in the event this isn't evident to you from the last time we went over this, the term substituted amphetamine (74 results) is a wikipedia construct. Almost all medical literature refers to the "class of amphetamines" as amphetamineS (again, notice the "s") (33467 results vs 9261 results for methamphetamine, an amph that's been researched more extensively than amph itself).
The massive Pubchem Human Toxicity Section on Amphetamine - notice the highly emphasized passage on direct toxicity in the human brain (i.e. neurotoxicity)
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Human Toxicity Excerpts [Emphasis added as bold, underlining, capitalizing an "S", and/or increased text size] The toxic dose of amphetamine varies widely. ... Severe reactions have occurred with 30 mg, yet doses of 400 to 500 mg are not uniformly fatal. Larger doses can be tolerated after chronic use of the drug. The acute toxic effects of amphetamine are usually extensions of its therapeutic actions and, as a rule, result from overdosage. The central effects commonly include restlessness, dizziness, tremor, hyperactive reflexes, talkativeness, tenseness, irritability, weakness, insomnia, fever, and sometimes euphoria. Confusion, assaultiveness, changes in libido, anxiety, delirium, paranoid hallucinations, panic states, and suicidal or homicidal tendencies occur, esp in mentally ill pt. However, these psychotic effects can be elicited in any individual if sufficient quantities of amphetamine are ingested for a prolonged period. Fatigue and depression usually follow central stimulation. Cardiovascular effects are common and include headache, chilliness, pallor or flushing, palpitation, cardiac arrhythmias, anginal pain, hypertension or hypotension, and circulatory collapse. Excessive sweating occurs. Symptoms referable to the GI system include dry mouth, metallic taste, anorexia, nausea, vomiting, diarrhea, and abdominal cramps. Fatal poisoning usually terminates in convulsions and coma, and cerebral hemorrhages are the main pathological findings. AMPHETAMINE GIVEN ORALLY RAISES BOTH SYSTOLIC & DIASTOLIC BLOOD PRESSURES. HEART RATE IS OFTEN REFLEXLY SLOWED; WITH LARGE DOSES, CARDIAC ARRHYTHMIAS MAY OCCUR. CARDIAC OUTPUT IS NOT ENHANCED BY THERAPEUTIC DOSES, & CEREBRAL BLOOD FLOW DOES NOT CHANGE MUCH. THE L-ISOMER IS SLIGHTLY MORE POTENT THAN THE D-ISOMER IN ITS CARDIOVASCULAR ACTIONS. IN GENERAL, SMOOTH MUSCLES RESPOND TO AMPHETAMINE AS THEY DO TO OTHER SYMPATHOMIMETIC AMINES. ... PAIN & DIFFICULTY IN MICTURITION OCCASIONALLY OCCUR. THE GI EFFECTS OF AMPHETAMINE ARE UNPREDICTABLE. IF ENTERIC ACTIVITY IS PRONOUNCED, AMPHETAMINE MAY CAUSE RELAXATION & DELAY THE MOVEMENT OF INTESTINAL CONTENTS; IF THE GUT IS ALREADY RELAXED, THE OPPOSITE EFFECT MAY OCCUR. THE RESPONSE OF THE HUMAN UTERUS VARIES, BUT USUALLY THERE IS AN INCREASE IN TONE. Because tolerance develops to the hyperthermic and cardiovascular effects of amphetamine, acute intoxication is more likely to occur in the neophyte. The syndrome includes dizziness, tremor, irritability, confusion, hallucinations, chest pain, palpitation, hypertension, sweating, and cardiac arrhythmias. There may be hyperpyrexia and convulsions. Death is usually preceded by hyperpyrexia, convulsions, and shock. Perivascular infiltration of amphetamineS can produce local necrosis, cellulitis, granulomas, & abscess formation. Intra-arterial injection causes intense vasospasm with distal cyanosis, ecchymosis, petechiae, edema, paresthesias, pain, weakness, necrosis, & decreased capillary filling. Immediate intense vasospasm is obvious after intra-arterial injections. Chronic intoxication with amphetamine causes symptoms similar to those of acute overdosage, but abnormal mental conditions are more common. Weight loss may be marked. A psychotic reaction with vivid hallucinations and paranoid delusions, often mistaken for schizophrenia, is the most common serious effect. Recovery usually is rapid after withdrawal of the drug, but occasionally the condition becomes chronic. In these persons, amphetamine may act as a precipitating factor hastening the onset of an incipient schizophrenia. Chronic use of high doses of amphetamineS has been reported to produce microvascular damage, neuronal chromatolysis (primarily in brain areas rich in adrenergic neurons), and profound and long lasting (or permanent) depletion of dopamine in the caudate nucleus. The psychic effects depend on the dose & the mental state & personality of the individual. The main results of an oral dose of 10-30 mg include wakefulness, alertness, & a decreased sense of fatigue; elevation of mood with increased initiative, self-confidence, & ability to concentrate; often, elation & euphoria; and increase in motor & speech activities. Performance of simple mental tasks is improved, but, although more work may be accomplished, the number of errors may increase. Physical performance - in athletes, for example - is improved, & the drug is often abused for this purpose. These effects are not invariable, & may be reversed by overdosage or repeated usage. Prolonged use or large doses are nearly always followed by depression & fatigue. Many individuals given amphetamine experience headache, palpitation, dizziness, vasomotor disturbances, agitation, confusion, dysphoria, apprehension, delirium, or fatigue. The fully developed toxic syndrome from amphetamine is characterized by vivid visual, auditory, and sometimes tactile hallucinations; picking and excoriation of the skin and delusions of parasitosis are not uncommon. There is also paranoid ideation, loosening of assoc, and changes in affect occurring in assoc with clear sensorium. In chronic users, there may be a striking paucity of sympathomimetic effects, and the blood pressure is not unduly elevated. It is often extremely difficult to differentiate this syndrome from a schizophrenic reaction. The syndrome may be seen as early as 36 to 48 hr after the ingestion of a single large dose of amphetamine; in apparently sensitive individuals, psychosis may be produced by 55 to 75 mg of dextroamphetamine. With high enough doses, psychosis can probably be induced in anyone. Unless the individual continues to use the drug, the psychosis usually clears within a week, the hallucinations being the first symptoms to disappear. Amphetamine ... in large doses systemically can dilate the pupils and cause slight blurring of near vision. Applied to the eye, amphetamine dilates the pupil and retracts the upper lid, but these actions are prevented by previous depletion of catecholamines such as is brought about by local guanethidine. Renal failure assoc with amphetamine use is usually the result of rhabdomyolysis, but it has also been found in patients without evidence of muscle damage or other apparent predisposing factors. Data on the effect of prenatal amphetamines, both prescribed and abused, are conflicting; however no consistent pattern of abnormalities has emerged. A large prospective evaluation of amphetamines prescribed during pregnancy found no incr in severe congenital malformations, but did report three cases of oral clefts. Another prospective study evaluating infants of amphetamine addicted women failed to demonstrate an incr in birth defects, but did note an incr in premature births, respiratory distress and jitteriness. The use of other drugs and alcohol may have confounded these findings. /Amphetamines/ In an acute poisoning in a child ... external stimuli precipitated increased hyperactivity. Abrupt discontinuation of amphetamines produces neither seizures nor life threatening symptoms, even in those patients who habitually consume large quantities. The abstinence syndrome assoc with chronic use of amphetamine ... is characterized by apathy, depression, lethargy, anxiety, & sleep disturbances. Myalgias, abdominal pain, voracious appetite, & a profound depression with suicidal tendencies may complicate the immediate postwithdrawal period & peak in 2-3 days. Symptoms persisting 6-7 days indicate an underlying disease process. During the early phases of iv use, 3 to 4 doses of 20 to 40 mg of amphetamine are usually considered sufficient /by abusers to produce euphoric effects/. In addition to the marked euphoria, the user experiences a sense of markedly enhanced physical strength & mental capacity, & feels little need for either sleep or food. Difficult to substantiate by objective means is the claim made by many users that orgasm in both male & female is delayed, permitting extended periods of sexual activity finally culminating in orgasms reported to be more intense & pleasurable. The sensation of "flash" or "rush" that immediately follows iv admin, while qualitatively distinct from the opioid "rush", is nevertheless described as being intensely pleasurable & somewhat akin to sexual orgasm. Many of those who use amphetamine ... are best described as "recreational" or occasional users, but some become dependent. A small percentage of the latter (eg, those taking the drugs for control of obesity) seem able to restrict drug intake & function productively (stabilized addicts). Others show progressive social & occupational deterioration, punctuated by periods of hospitalization for toxic psychosis. In terms of the compulsion to continue use, the degree to which a drug pervades the life of the user, & the tendency to relapse following withdrawal, some compulsive users of amphetamine ... are addicts. The risk of developing patterns of compulsive use is not limited to those who use drugs intravenously ... It is not clear whether the dependence syndromes caused by amphetamine ... are as persistent as that produced by opioids. In the US the waves of amphetamine use did not leave large numbers of chronic users in their wake. However, many iv users eventually became heroin users. ANOREXIA IS A COMMON FINDING /IN CHRONIC TOXICITY FROM ABUSE/. OCCASIONALLY IT MAY BE SO PRONOUNCED THAT THE AMPHETAMINE ABUSER EXPERIENCES CONSIDERABLE DIFFICULTY IN SWALLOWING. CHRONIC ABUSERS ARE REPORTED TO FORCE THEMSELVES TO EAT SMALL AMT OF HIGHLY NUTRITIOUS FOOD & TAKE VITAMIN SUPPLEMENTS TO COMPENSATE FOR DECR IN APPETITE. ... CONSTANT GRINDING OF TEETH IS ALSO A COMMON FINDING ... THE HISTORY, CHEMISTRY, PHARMACOLOGY, MEDICAL USE, ILLICIT USE & ADDICTION & TOLERANCE POTENTIAL OF AMPHETAMINES ARE PRESENTED. ALTHOUGH THERE ARE FEW PUBLISHED ACCOUNTS OF DEATH KNOWN TO RESULT DIRECTLY FROM AMPHETAMINES, DEATHS MAY RESULT INDIRECTLY FROM EFFECTS SUCH AS VIOLENT BEHAVIOR & HEPATITIS.[HART JB, WALLACE J; CLIN TOXICOL 8 (2): 179-90 (1975)] PubMed Abstract Few deaths have ... been attributed to amphetamine overdose. Amphetamines have a relatively low ratio of effective dose to fatal dose. Fatalities resulting from amphetamine use are usually the result of one of the following processes: 1) combinations with other drugs; 2) complications of iv injections, such as septicemia, bacterial endocarditis, or homicide, during withdrawal depression. Although comparable clinical data are lacking, hyperpyrexia has been noted as a frequent & prominent sign in acute human intoxication. During a grueling bicycle race a cyclist collapsed with symptoms closely resembling heat exhaustion, &, despite vigorous treatment, he died /after/ cardiovascular collapse; it was learned subsequently that he had consumed 105 mg of amphetamine during the race. Bleeding within the cranial vault is a rare but well-reported complication of amphetamine use. About 20 cases, which are about evenly divided between iv & oral exposures, have been reported in the American literature. Ages range from 16-60, & most patients are habitual & often multidrug abusers. However, intracranial hemorrhages have been reported after the ingestion of as few as 2-4 tablets of amphetamine or structurally related anorectic drugs ... The etiology of intracerebral & subarachnoid hemorrhages associated with amphetamine use appears multifactorial. Inflammation & necrosis of small cerebral arteries (ie, vasculitis) secondary to particulate foreign bodies or bacterial endocarditis can develop after iv drug use. Subsequently, the hypertension seen in amphetamine use may lead to vessel rupture & hemorrhage. However, vasculitis has occurred in the setting of oral acute dextroamphetamine overdose, amphetamine withdrawal, & therapeutic use as an anorectic drug. The presence of vasculitis after exposure by different routes suggests an immunopathological abnormality. Direct toxic damage to vessels seems unlikely because of the dilution that occurs before the drug reaches the cerebral circulation. Repetitive behavior may occur /from the use of amphetamines/ (e.g. repeatedly cleans dishes or continually grooms hair). Amphetamines also will extenuate hostile, aggressive, and antisocial behavior. Progression to paranoia, panic states, violence, and even suicide may occur. /Amphetamines/ Amphetamines used in large doses over a long period of time may lead to substantial weight loss, liver disease, hypertensive disorders, kidney damage, stroke, heart attack, nonhealing ulcers, and sores in the skin. /Amphetamines/ The abuse of amphetamines by combining the oral and inhalation routes of administration usually leads to a more intense effect and/or more toxic effect than if either was taken alone. /Amphetamines/ Doses as little as 2 mg, but more likely between 15 and 30 mg, may induce toxic effects. However, even doses of 400-500 mg are not uniformly fatal. Illicit maternal use /of amphetamines is/ associated with intrauterine growth retardation, premature birth, and increased fetal and newborn morbidity. /Amphetamines, from table/ Intrauterine ... amphetamine exposure may cause neonates to exhibit abnormal sleep patterns, tremors, poor feeding, hypotonia, fever, and vomiting. |
NCBI cited the amph article ref named "Westfall" for it's toxicity statements on the class of amphetamines. I cited Westfall too and not only covered what it said on amphetamine (oxidative damage from radical species), I also expanded upon it with the other two sources. Most of the WP:PAYWALLED refs cited in the article are hosted here, including other relevant sections of the Westfall ref that I didn't cite in the article.
With all that said, I'll just summarize and briefly state the issues:
If you add a WP:MEDRS secondary source demonstrating the existence of (singular) amphetamine neurotoxicity in humans, I would be happy to see and have it included in the article. If you add a source that falls short of what the policy requires, I will revert it, per the policy. If you change and of the language in that section such that it doesn't agree with the cited sources (hence causing at least WP:V and potentially WP:NPOV issues), I will revert it. WP policy practically dictates that I do this if I want to see this article reach FA.
Lastly, I also find it almost obnoxious, and it's completely illogical, to suggest that *I* am causing WP:NPOV problems with this article when you're citing animal studies to make claims about humans any skewing text-source integrity (the refs on humans stated only a single mechanism and you stated there were multiple). I'm not assuming bad faith on your part - now stop making assumptions and accusations about mine. Seppi333 ( talk) 18:12, 1 December 2013 (UTC)
This is ridiculous and unjustifiable. I'm going to have to bring more mediators in when I have the time. Exercisephys ( talk) 22:56, 1 December 2013 (UTC)
There are bad faith user warning templates for a reason. I normally avoid using them because, exactly like going off topic, personal attacks, or asserting bad faith intent of other users, it detracts from a conversation. So, once again, and I won't ask next time, please, stop saying I'm intentionally POV editing and focus on the actual issue: we need sources to directly support the text.
For 1: I've literally just asked you for a MEDRS source indicating other indirect mechanisms besides radical toxicity in humans or a source for any direct toxicity by amph in humans. You've just replied to this by restating this; it's a bit circular, but ignoring that, unfortunately, I don't think you are a MEDRS source. For 2: As I told you like a week ago via the user notification template in a thread currently on this page (SwampFox's thread, current the third section on this page as of this edit), I moved that material to the ADHD section. The paper is on neuroplasticity, not neurotoxicity. It's a more general concept. If anything, it belongs in the OD section, but since the study a study on human neuroplasticity is in that section, it MUST be there in order to not refute that source elsewhere in the article. I only kept it because you've been complaining I delete your material. If you didn't cite animal studies I probably wouldn't be trying to remove it.
[Related aside to this list item: I've said it over and over again, animal studies do not say anything about humans - extending the inference is spurious because the non-human sample in those studies is a nonprobability sample for human neurotoxicity. I can literally produce an analytic proof to demonstrate that any statistical model for a drug effect using nonprobability sampling (like animal studies with inference on humans) is spurious. In other words, I am literally stating that every animal study that has ever been conducted to detect the presence of any drug-related phenomenon in any (non-human) species yields invalid/spurious statistical inference in humans (the bolded terms are universal quantification in an analytic context). The fact that I can make that statement given that much scope is why representative sampling, like random sampling, is such a fundamental concept in statistics. Literally every stat textbook you might check for reference will tell you use "random" and "representative" samples. It's included in intro stats texts without rigorous justification simply because most people taking an intro stats course won't understand analytic proofs (i.e. the kind of argument in the collapse tabs of holder's inequality). In the event you don't have a solid background in math, just take it on faith - it's stated everywhere for a reason. This is the exact reason WP:MEDRS has a policy that says "don't use animal studies." The MEDRS policy is the justification for why I remove animal studies. This "aside" is an explanation of why that policy even exists.]
Added by Seppi333 at 19:43, 7 December 2013 (UTC) - I made the policy shortcut WP:MEDANIMAL for your reference.
For 3: I revised the passage that I stated without citation. Sasata reviewed the content and asserted that all medical claims had adequate MEDRS citations yesterday in the concluding remarks to the GA review. He did an extremely thorough review to help this article with FA and I provided every single WP:PAYWALLED source in the GA-review (it's still linked in the GA archive with all the files still hosted in the link). I don't think he'd make that statement lightly.
I'm not asking you do to anything that any editor from WP:MED wouldn't ask of you.
If you state or even imply "some evidence of amphetamine neurotoxicity exists in humans" you need a source on amphetamine which states amphetamine is a neurotoxin. Stop using some paper on an entire class of substances, some of which have been proven to be neurotoxins in humans (meth). A paper on amphetamine human neurotoxicity would unequivocally support a statement about that - this ref is the ONLY THING you need (as well as what must be) cited to make that particular medical claim. That's the same standard for citing any medical claim. You need a ref making a definite statement which directly supports an included medical statement in the article. Every single source in the article CURRENTLY has a direct text-source relation like that, which is stated as what's required of a citation in WP:V. How do I know this? I checked all 100+ sources in the article when I did the WP:V check for GA. You only need to do this for a single source. It's not that hard. If the material you claim to be true exists, a paper on human amph neurotoxicity will be easy to produce (and it literally says this is true of the prevailing/majority viewpoint in WP:DUE. If it's not easy to find, you should be able to list a major proponent of the theory (ideally, someone who has done a case study demonstrating this). If you can't find a ref on amphetamine neurotoxicity, it shouldn't be on wikipedia, per WP:UNDUE. So once again, I'm not taking a position on content. I'm enforcing a policy that you know very well, as I've told you to use it CONSTANTLY in the last thread on this.
I want to emphasize these points so this thread isn't directed off on some random tangent again:
I figured I'd cite WP:MEDASSESS here and underline what the original claim of neurotoxicity is in this list:
Roughly in descending order of quality, lower-quality evidence in medical research comes from individual RCTs; other controlled studies; quasi-experimental studies; non-experimental, observational studies, such as cohort studies and case control studies, followed by cross-sectional studies (surveys), and other correlation studies such as ecological studies; and non-evidence-based expert opinion or clinical experience
Regards, Seppi333 ( talk) 19:50, 7 December 2013 (UTC)
The discussion concluded at [1].
Does this help at all with explaining the technical stuff in this section? (Copied from User:Seppi333/sandbox2#pharmacodynamics)
Seppi333 ( talk) 23:03, 11 December 2013 (UTC)
Metabolic pathways of amphetamine in humans
[sources 1]
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I put this in the article as well - same as before, but with winkilink annotations (citation errors not included ). I think that's all I can do with the images for now. Seppi333 ( Insert 2¢) 08:15, 13 December 2013 (UTC)
References
The simplest unsubstituted phenylisopropylamine, 1-phenyl-2-aminopropane, or amphetamine, serves as a common structural template for hallucinogens and psychostimulants. Amphetamine produces central stimulant, anorectic, and sympathomimetic actions, and it is the prototype member of this class (39). ... The phase 1 metabolism of amphetamine analogs is catalyzed by two systems: cytochrome P450 and flavin monooxygenase. ... Amphetamine can also undergo aromatic hydroxylation to p-hydroxyamphetamine. ... Subsequent oxidation at the benzylic position by DA β-hydroxylase affords p-hydroxynorephedrine. Alternatively, direct oxidation of amphetamine by DA β-hydroxylase can afford norephedrine.
Dopamine-β-hydroxylase catalyzed the removal of the pro-R hydrogen atom and the production of 1-norephedrine, (2S,1R)-2-amino-1-hydroxyl-1-phenylpropane, from d-amphetamine.
Hydroxyamphetamine was administered orally to five human subjects ... Since conversion of hydroxyamphetamine to hydroxynorephedrine occurs in vitro by the action of dopamine-β-oxidase, a simple method is suggested for measuring the activity of this enzyme and the effect of its inhibitors in man. ... The lack of effect of administration of neomycin to one patient indicates that the hydroxylation occurs in body tissues. ... a major portion of the β-hydroxylation of hydroxyamphetamine occurs in non-adrenal tissue. Unfortunately, at the present time one cannot be completely certain that the hydroxylation of hydroxyamphetamine in vivo is accomplished by the same enzyme which converts dopamine to noradrenaline.
Figure 1. Glycine conjugation of benzoic acid. The glycine conjugation pathway consists of two steps. First benzoate is ligated to CoASH to form the high-energy benzoyl-CoA thioester. This reaction is catalyzed by the HXM-A and HXM-B medium-chain acid:CoA ligases and requires energy in the form of ATP. ... The benzoyl-CoA is then conjugated to glycine by GLYAT to form hippuric acid, releasing CoASH. In addition to the factors listed in the boxes, the levels of ATP, CoASH, and glycine may influence the overall rate of the glycine conjugation pathway.
The biologic significance of the different levels of serum DβH activity was studied in two ways. First, in vivo ability to β-hydroxylate the synthetic substrate hydroxyamphetamine was compared in two subjects with low serum DβH activity and two subjects with average activity. ... In one study, hydroxyamphetamine (Paredrine), a synthetic substrate for DβH, was administered to subjects with either low or average levels of serum DβH activity. The percent of the drug hydroxylated to hydroxynorephedrine was comparable in all subjects (6.5-9.62) (Table 3).
In species where aromatic hydroxylation of amphetamine is the major metabolic pathway, p-hydroxyamphetamine (POH) and p-hydroxynorephedrine (PHN) may contribute to the pharmacological profile of the parent drug. ... The location of the p-hydroxylation and β-hydroxylation reactions is important in species where aromatic hydroxylation of amphetamine is the predominant pathway of metabolism. Following systemic administration of amphetamine to rats, POH has been found in urine and in plasma.
The observed lack of a significant accumulation of PHN in brain following the intraventricular administration of (+)-amphetamine and the formation of appreciable amounts of PHN from (+)-POH in brain tissue in vivo supports the view that the aromatic hydroxylation of amphetamine following its systemic administration occurs predominantly in the periphery, and that POH is then transported through the blood-brain barrier, taken up by noradrenergic neurones in brain where (+)-POH is converted in the storage vesicles by dopamine β-hydroxylase to PHN.
The metabolism of p-OHA to p-OHNor is well documented and dopamine-β hydroxylase present in noradrenergic neurons could easily convert p-OHA to p-OHNor after intraventricular administration.
@ Exercisephys: Following this conversation, these refs [1] [2] were added to ADHD to support the benefits of psychostimulants on the human brain. I'm notifying you for the sake of openness, because I'm now adding the refs to this article and their conclusions directly contradict what the animal studies that you added imply for humans. I also don't to give you the impression that I'm trying to subvert you again. This is the current paragraph in medical:
In studies of amphetamine exposure in nonhuman primates, some report no discernible adverse effects on behavior or dopamine system development, while others noted reductions to dopamine-associated structures and metabolites. [3] [4] In stark contrast for humans, recent literature reviews, including a meta-analysis and a systematic review, indicate that the long-term use of amphetamine at therapeutic doses for ADHD actually appears to produce beneficial changes in brain function and structure, such as an improvement in function of the right caudate nucleus. [1] [2]
Best regards, Seppi333 ( Insert 2¢) 06:44, 4 January 2014 (UTC)
References
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I was thinking about changing the drugbox image.
Does anyone have an objection to or support this change? Seppi333 ( talk) 22:24, 30 November 2013 (UTC)
I think that it could be presented in the chemistry section, but that the main drugbox should only contain the original. Exercisephys ( talk) 23:35, 1 December 2013 (UTC)
@ The Sceptical Chymist: I wanted to keep all these sections together for the archives - I hope this is ok with you; feel free to revert this edit if not. Best regards, Seppi333 ( Insert 2¢) 01:27, 11 January 2014 (UTC).
A contradiction in references. The article states "Amphetamine was first synthesized in 1887 in Germany by Romanian chemist Lazăr Edeleanu who named it phenylisopropylamine". On the other hand, a different reference, also used in the article (Heal DJ, Smith SL, Gosden J, Nutt DJ (June 2013). "Amphetamine, past and present – a pharmacological and clinical perspective") states: "racemic α-methylphenethylamine (amphetamine) was discovered by Barger and Dale in 1910, it was not until 1927 that this molecule was first synthesised by the chemist, G. A. Alles" The Sceptical Chymist ( talk) 03:44, 10 January 2014 (UTC)
Long quote
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Synthetic AMPH was invented in 1887 by Lazar Edeleanu (1862–1941, a.k.a. Edeleano), a Rumanian chemist who described its synthesis in his doctoral dissertation under A.W. Hofmann at the University of Berlin (Edeleano, 1887). Edeleanu later became famous for also inventing the method to distill petroleum using sulphur dioxide, providing the tell-tale odor of gasoline distilleries. AMPH was bequeathed its generic name from a contraction of α-methyl-phenethyl-amine. Some notion of the colorful history of this drug can be seen from the 1989 Merck Index listing, which lists 17 trade names, not even including such familiar trade names as Adderall, Benzedrine, and Dexedrine, or for that matter the myriad nicknames used by drug abusers. Of course, chemists have since developed an astonishing range of synthetic AMPH derivatives. Following work discussed below by Barger and Dale that introduced the concept of sympathomimetic amines (Section 3.1), researchers have examined a wide range of catecholamine-like derivatives for the ability to raise blood pressure and to relieve nasal and bronchial congestion from colds and hay fever. AMPH was independently resynthesized by Gordon Alles in 1927 in an effort toward developing synthetic sympathomimetics, and he and his coworkers are credited with the first report of its stimulant effects |
References
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Reference 17 - "Methamphetamine facts". DrugPolicy.org. - is probably not the best source, even for the history reference. It is a website of an advocacy organization. Accordingly, a better reference supporting the historical use of amphetamine for nasal congestion and obesity is needed. The Sceptical Chymist ( talk) 04:24, 10 January 2014 (UTC)
Reference 29 - Berman S, O'Neill J, Fears S, Bartzokis G, London ED (2008). "Abuse of amphetamines and structural abnormalities in the brain", at least according to the abstract is not relevant to amphetamine. It is about the abuse of amphetaminES, but amphetamine appears not to be among the drugs considered in the reviewed literature. From the abstract: "Ten studies compared controls to individuals who were exposed to methamphetamine. Three studies assessed individuals exposed to 3–4-methylenedioxymethamphetamine (MDMA)." The Sceptical Chymist ( talk) 04:38, 10 January 2014 (UTC)
References
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This wording seems to be too strong, considering the cautious way the results are summarized in the corresponding references:
I suggest the following re-wording of this paragraph:
The Sceptical Chymist ( talk) 13:49, 10 January 2014 (UTC)
In stark contrast for humans, literature reviews from 2013, including a meta-analysis and a systematic review, of magnetic resonance imaging studies indicate that long-term treatment of ADHD with amphetamine may decrease the abnormalities in brain structure and function in subjects with ADHD, such as an improvement in function of the right caudate nucleus.
In stark contrast for humans, literature reviews from 2013, including a meta-analysis and a systematic review, indicate that the long-term use of amphetamine at therapeutic doses for ADHD actually appears to produce beneficial changes in brain function and structure, such as an improvement in function of the right caudate nucleus.
References
"However, oral availability varies with gastrointestinal pH.[72] Amphetamine is a weak base with a pKa of 9–10;[3] consequently, when the pH is basic, more of the drug is in its lipid soluble free base form, and more is absorbed through the lipid-rich cell membranes of the gut epithelium.[3][72] Conversely, an acidic pH means the drug is predominantly in its water soluble cationic form, and less is absorbed.[3][72]"
The confusion stems from the fact that taking amphetamines with multiple grams (>10 g per day) of sodium bicarbonate (alkalyzer) or ammonium chloride (acidifier) does affect bioavailability of amphetamine. However, this is relevant only to research situations, and in practice no person would consume spoons of soda or ammonium chloride.
Next, there seem to be no evidence that large amounts of alkalizer of acidifier would change the absorption of amphetamine. It appears that they predominantly work through changing elimination (as described in he article below).
One of the strongest antacids (proton pump inhibitor) omeprazol also does not change bioavailability of amphetamine: "For MAS XR monotherapy, total amphetamine mean (SD) exposure was 36.6 (9.19) ng/mL and 640.8 (95.66) ng . h/mL; when coadministered with omeprazole it was 38.1 (7.35) ng/mL and 643.9 (143.16) ng . h/mL, for Cmax and AUCinf, respectively. The median Tmax was 5 hours and 2.75 hours without and with omeprazole, respectively; 57.1% to 61.9% of subjects receiving MAS XR and 25% receiving LDX showed an earlier (>or= 1 hour) Tmax with omeprazole" ( PMID 19820270)
And lastly, amphetamine has pKa of 9.9 according to the reference you cited; it is a strong organic base.
The Sceptical Chymist ( talk) 15:25, 16 January 2014 (UTC)
7 DRUG INTERACTIONS
7.1 Agents that Increase Blood Levels of Amphetamines
... Alkalinizing Agents
Gastrointestinal alkalinizing agents (e.g., sodium bicarbonate) increase absorption of amphetamines. Co-administration of ADDERALL XR and
gastrointestinal alkalinizing agents, such as antacids, should be avoided. Urinary alkalinizing agents (acetazolamide, some thiazides) increase the
concentration of the non-ionized species of the amphetamine molecule, thereby decreasing urinary excretion. Both groups of agents increase
blood levels and therefore potentiate the actions of amphetamines.
7.2 Agents that Lower Blood Levels of Amphetamines
Acidifying Agents
Gastrointestinal acidifying agents (e.g., guanethidine, reserpine, glutamic acid HCl, ascorbic acid) lower absorption of amphetamines. Urinary
acidifying agents (e.g., ammonium chloride, sodium acid phosphate, methenamine salts) increase the concentration of the ionized species of the
amphetamine molecule, thereby increasing urinary excretion. Both groups of agents lower blood levels and efficacy of amphetamines.
— Bottom of page 8 to the top of page 9 in the Rx info
Lead:
I will look at rest of sections as I go along. From reading lead, consider reducing verbosity. I have this problem too. When I read back over things I have written I find I can reduce the word count by about 40% through rewording, without losing any actual content. This will reduce the overall length of the article and make it more approachable for readers. The lead especially should be clear and concise (see WP:LEAD). I also noted that the images used in this article are not standardized to thumbnails. I think this is in the MOS, let me check. Lesion ( talk) 07:01, 1 December 2013 (UTC)
Does anyone agree that the lead could be a little shorter? We're currently at the maximum of four paragraphs mentioned in WP:Lead, but they're a little long (especially the first) and at times too thorough. Exercisephys ( talk) 22:58, 7 February 2014 (UTC)
I was looking for statistics like how much Amphetamine is produced/manufactured globally, legally, and an estimate of illegal production. I was unable to find this information in the article. Shouldn't this be included somewhere in the article ? -- Siddhant ( talk) 15:10, 19 February 2014 (UTC)
I think that the information presented in this article is sound; I would look more at the structure of the article. I feel that if the article was structured in more of a chronological order, it may be easier to interpret for those that don't know much about the content. Nicholas2015 ( talk) 12:57, 27 February 2014 (UTC)
@ Seppi333: I'm not trying to open old wounds here, but can you justify the continual distinction of "indirect neurotoxicity" from "direct neurotoxicity"? Also, I noticed that you used the term "indirect toxicity", which I find even further softened. I think that this phrasing is a bit of a POV-injection. Neurotoxicity is toxicity to neurons, no? I see the value in differentiating the two mechanisms, but I think that continually using the "indirect" qualifier suggests that it's less serious, or not "true" neurotoxicity. Exercisephys ( talk) 19:18, 24 February 2014 (UTC)
The section as it is basically says: low doses have a net positive cytoprotective/cytogenerative effect. High doses have a net cytotoxic effect. That seems exactly in line with what I would expect. If the compound were neurotoxic, it'd basically say low doses have a net cytotoxic effect. The page as is seems perfectly in line with clinical observations as well. Seppi333 ( Insert 2¢ | Maintained) 00:37, 25 February 2014 (UTC)
After going over my edit, all I did that could actually concern you is remove the word "systematic". I'm kind of dumbfounded that you're expressing any concern over this. Besides the fact that we don't have any evidence to cite, it's just padding. Seppi333 ( Insert 2¢ | Maintained) 00:45, 25 February 2014 (UTC)
@ Exercisephys: Look, ignoring the statistical definition, here's what those two concepts boil down to:
Water, all neurotransmitters, all minerals, all vitamins, etc are indirect neurotoxins. That 2 part definition prevents virtually every substance from being called a "neurotoxin" because the unqualified definition is literally just '"toxic" to a neuron.' Is this registering?
If you call amphetamine a neurotoxin, you can't explain to me why water isn't a neurotoxin given the way you're defining neurotoxicity. Seppi333 ( Insert 2¢ | Maintained) 04:08, 25 February 2014 (UTC)
@ Exercisephys: Defining a neurotoxin by relative toxic dose is completely arbitrary.
Hey, guys. I think there's a bug in the section-adder, as this title wasn't initially added. It's probably due to the fact that I tried to put Wikilinks in it. I'll report that.
Anyway, I guess the subject of this wasn't clear, as the facepalm of the ever respectful, dispassionate, and open-minded Seppi333 ( talk · contribs) noted.
Original post:
The toxicity section should also discuss these aspects. There's a good source here: http://link.springer.com/article/10.1007/s00204-012-0815-5/fulltext.html
If anyone needs access, let me know. Exercisephys ( talk) 15:59, 25 February 2014 (UTC)
Facepalm Seppi333 ( Insert 2¢ | Maintained) 17:18, 25 February 2014 (UTC)
Wait, I just realized that you removed the title, Seppi333 ( talk · contribs). Whydju do that? I'm just trying to improve this article, dude. Exercisephys ( talk) 16:25, 26 February 2014 (UTC)
I suggest before re-adding anything potentially controversial back into this article, we try to achieve consensus here on the talk page. I think both of you are making some good points. Toxicity is toxicity whether it is by a direct or indirect mechanism. On the other hand, toxicity is not clinically relevant if it occurs only at doses significantly higher than patents are likely to be exposed to. The key point of course is whether there are MEDRS compliant sources that would directly support a conclusion one way or the other. I am not at all familiar with the amphetamine toxicity literature. I will read through the available secondary literature and try to offer some suggestions. Boghog ( talk) 01:22, 1 March 2014 (UTC)
Seppi's response
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Bullshit
No, you just annoyed me to the point that I stopped caring about offending you by editing text you've added. You made it abundantly clear (with two sections from different occassions on my talk page) that you don't like it when I edit content you add to articles. Why did I delete a clause stating that amph and meth toxicity are indistinguishable? Because that comparison is nothing but trivia/textual padding to the 99.9% of readers that know nothing about meth addiction.
Besides the fact that I already acknowledged this months ago to WP:MED when I was a new editor, I don't see how this could possibly constitute a COI for ANY editor unless I/he/she were an addict. Perhaps you've completely missed the adverse effects and overdose sections, which are far more detailed than they were before I started working on this article.
No, I just never looked. |
Seppi333 ( Insert 2¢ | Maintained) 02:55, 1 March 2014 (UTC)
Also, Exercisephys, before you throw that source back at me, LOOK AT THE PAPERS ITS CITING WHEN IT SUGGESTS "XYZ IS NEUROTOXIC." I can't tell whether you're intentionally and knowingly trying to put POV in this article, or you just don't know any better, but I'm really running out of patience. -Seppi333
References
Neuroimaging studies have revealed that METH can indeed cause neurodegenerative changes in the brains of human addicts (Aron and Paulus, 2007; Chang et al., 2007). These abnormalities include persistent decreases in the levels of dopamine transporters (DAT) in the orbitofrontal cortex, dorsolateral prefrontal cortex, and the caudate-putamen (McCann et al., 1998, 2008; Sekine et al., 2003; Volkow et al., 2001a, 2001c). The density of serotonin transporters (5-HTT) is also decreased in the midbrain, caudate, putamen, hypothalamus, thalamus, the orbitofrontal, temporal, and cingulate cortices of METH-dependent individuals (Sekine et al., 2006) ...
Neuropsychological studies have detected deficits in attention, working memory, and decision-making in chronic METH addicts ...
There is compelling evidence that the negative neuropsychiatric consequences of METH abuse are due, at least in part, to drug-induced neuropathological changes in the brains of these METH-exposed individuals ...
Structural magnetic resonance imaging (MRI) studies in METH addicts have revealed substantial morphological changes in their brains. These include loss of gray matter in the cingulate, limbic and paralimbic cortices, significant shrinkage of hippocampi, and hypertrophy of white matter (Thompson et al., 2004). In addition, the brains of METH abusers show evidence of hyperintensities in white matter (Bae et al., 2006; Ernst et al., 2000), decreases in the neuronal marker, N-acetylaspartate (Ernst et al., 2000; Sung et al., 2007), reductions in a marker of metabolic integrity, creatine (Sekine et al., 2002) and increases in a marker of glial activation, myoinositol (Chang et al., 2002; Ernst et al., 2000; Sung et al., 2007; Yen et al., 1994). Elevated choline levels, which are indicative of increased cellular membrane synthesis and turnover are also evident in the frontal gray matter of METH abusers (Ernst et al., 2000; Salo et al., 2007; Taylor et al., 2007).
@
Exercisephys: I've been sure of it because I know that those three researchers all have an interest in various psychostimulant-related topics. I.e., I know for a fact that all three actively do research with amphetamine. Look for their publications (not the textbook) in this article if you don't believe me. Nestler in particular is purely focused on the genetic aspects of psychostimulant addiction. In any event, after I last posted, I started searching through toxicology databases for more information. I'm sure you'll be as pleased as I am after reading this:
http://projectreporter.nih.gov/project_info_description.cfm?aid=8429516&icde=0
It's oddly good timing and rather amusing that this study ended yesterday (This research started in 2009 and was initially slated to end April 2014, but was rescheduled to end Feb 28th 2014):
http://projectreporter.nih.gov/project_info_details.cfm?aid=8429516&icde=0
And lastly, this is a related paper he published on this topic in 2005:
http://jpet.aspetjournals.org/content/315/1/91.full
I'm going to email the researcher tomorrow and ask about the results ahead of any publications. His results will settle our content dispute.
Seppi333 (
Insert 2¢ |
Maintained)
06:44, 1 March 2014 (UTC)
@
Exercisephys: I'll email Drs. Nestler, Hyman, and Malenka about that statement while I'm at it.
Seppi333 (
Insert 2¢ |
Maintained)
06:52, 1 March 2014 (UTC)
Thanks @ Exercisephys: and @ Seppi333: for brining me up to speed. It seem to me that part of this dispute revolves around what exactly WP:MEDRS allows and disallows. I think everyone is in agreement that to the greatest extent possible, human studies should be cited in preference to animal or in vitro studies. However I think toxicology is a special case. For ethical reasons, humans toxicology data is generally not available (I think this and this discussion where it was proposed to modify MEDRS to specifically address toxicology is especially relevant). While animal toxicity experiments are imperfect models of human toxicity, they are often the best and only data we have. Hence I think including animal toxicology studies that are discussed in secondary sources should be allowed. Boghog ( talk) 19:45, 1 March 2014 (UTC)
After spending a stupid amount of time searching for and reading papers, I've basically discovered that there's evidence of indirect amphetamine neurotixicity in humans which is analogous, although milder, than methamphetamine neurotoxicity. What's interesting it that it only seems to manifest with cognitive dysfunction in addicts. Makes me wonder about just how deep the connection between neurotoxicity, (adverse) neuroplasticity and addiction are;† this is OR, but to give you an example of how interrelated these are, there's some clear connections in reviews, but I need to read more of the papers I spent hours sifting through and downloading before I add anything else to the article. I should emphasize that this is indirect neurotoxicity simply because therapeutic use of ADHD stimulants (incl. amph) produces the opposite histological and biomarker changes as methamphetamine neurotoxicity. (read the quote in the reflist) It DOES produce *some* of those changes in abuse conditions though, based upon what I've read so far. E.g., it can compromise the BBB through adverse effects on gene expression from heightened oxidative stress (meth apparently has a more direct impact on BBB integrity). Also can reduce gray matter volume in overdose (the reverse is evident at therapeutic doses - see the refs named "neuroplasticity" in the source). Amph sensitization also doesn't occur at therapeutic doses, which is additional evidence that it doesn't adversely affect the DA/NE neurotransmitter systems. I'm too lazy to cite specific papers, but if you're curious about a particular claim, just ask me for the ref. Seppi333 ( Insert 2¢ | Maintained) 10:50, 2 March 2014 (UTC)
@ Exercisephys:
http://www.ncbi.nlm.nih.gov/pubmed/23415394
This is very weak (and only marginally significant - p=.05) neurotoxicity given that:
Seppi333 ( Insert 2¢ | Maintained) 07:51, 5 March 2014 (UTC)
This study - PMID 17049170 - is very clearly asserting that the neurotoxic effects of amphetamine are dose-dependent above some threshold (as I've suggested since I wrote about it here), based upon their data. There's also a review, PMID 24440369, which cites it (the article/citation name itself supports the claim). Seppi333 ( Insert 2¢ | Maintained) 08:53, 5 March 2014 (UTC)
@
Exercisephys: Err...this was my bad. I thought I shared this with you like a week or two ago EP.
PMID
21886562. Added that to meth a while back. That's 1 reason it has a greater neurotoxic potential. Found another review showing detectable acute neurotoxicity in humans using large binge doses.
PMID
19897075
MPH is a sigma agonist as well. Amph has no detectable binding affinity for sigmas based upon Binding DB's data.
Seppi333 (
Insert 2¢ |
Maintained)
00:11, 24 March 2014 (UTC)
There's a plethora of clinical evidence on neuroplasticity and therapeutic ADHD psychostimulant use. I found another meta analysis to tack onto that section. Going to put it in when I expand toxicity. Busy irl lately. Seppi333 ( Insert 2¢ | Maintained) 20:04, 3 March 2014 (UTC)
Same here, to a frightening degree. I'll have some time in a few days. Exercisephys ( talk) 17:27, 5 March 2014 (UTC)Busy irl lately. - Seppi333
@ Dosenfant:, instead of edit-warring over the inclusion of this phenomenon, I'm starting this thread.
I'd be happy to give you a detailed explanation, with citation, of the toxicodynamics of amphetamine-induced serotonin toxidrome. [Edit/add: for a simple comparison, amphetamine acts analogously to an SSRI, except: it reduces postsynaptic 5-HT firing rate/action potentials (produces a less potent effect in comparison to SSRIs), but effluxes 5-HT into the synaptic cleft via PKC signaling (produces a more potent effect in comparison to SSRIs).] In any event, the relevant text from the body (not the abstract) of the paper from my recent revert is below (emphasis added):
2 Stimulants
2.1 Amphetamines
Amphetamine is the common name for the racemic mixture of b-phenylisopropylamine or a-methylphenylethylamine [11]. Substitutions of the phenylethylamine result in the creation of different amphetamine analogs, which are also described using the term ‘amphetamines’. Currently available prescription amphetamines include amphetamine, lisdexamphetamine, phentermine, phendimetrazine, and dextroamphetamine. Because lisdexamphetamine is rapidly converted to dextroamphetamine in the blood, it is reviewed in this section.
...2.1.2 Mechanism of Toxicity
The mechanism of toxicity of amphetamines is primarily related to excessive extracellular dopamine, norepinephrine, and serotonin [22, 23]. The most prominent clinical picture is alpha- and beta-adrenoreceptor-mediated sympathomimetic syndrome, with psychiatric symptoms and hyperthermia secondary to the dopamine and serotonin excess [23–26].
— Overdose of drugs for attention-deficit hyperactivity disorder: clinical presentation, mechanisms of toxicity, and management, PMID23757186
Seppi333 ( Insert 2¢ | Maintained) 17:04, 18 March 2014 (UTC)
Sigh...ok, look; I wrote that entire section, so I obviously read all these references, as I cited every review/medical source in that section ( in addition to the vast majority of the rest of the article...); I therefore know exactly what citation references each symptom. The above source asserts 5-HT overdose in a section titled "mechanisms of toxicity." I don't need anything more specific/direct to support that assertion because it's the definition of 5-ht toxicity syndrome, which is a toxic concentration of synaptic 5-ht. Seppi333 ( Insert 2¢ | Maintained) 18:58, 18 March 2014 (UTC)
Note:To keep this conversation in one place, reply at: WT:MED#WP:SYNTH on amphetamine articles
@
Shudde: Continue your review here.
Seppi333 (
Insert 2¢ |
Maintained)
06:55, 24 April 2014 (UTC)
@All: I've been procrastinating - I'll make the edits to pharmacology before Friday and repost here once I'm done simplifying what I can.
@ Shudde: I'm still sort of unsure about what your concerns were with the long-term evidence review, so I was wondering if you would be willing to read the cited section excerpt and give me your thoughts on how you'd phrase it:
Quoted from pages 122-123 of the Millichap text (Link inside tab).
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The author stated that the underlined study was both multicenter and placebo controlled, which makes it higher quality evidence than the other open placebo-controlled studies.
I uploaded
this newer review which indicated more or less the same continuation of benefits from 2 studies involving ~2 years of amphetamine use (Scroll down to table 2 or search for the term "amfetamine" to get there - the paper uses the amphetamine INN); these were open, placebo-controlled trials though. Millichap also pointed out the unusually exceptional benefits beyond just a continued therapeutic effect that were observed in that multicenter trial as well.
Any thoughts/advice/suggestions on communicating this material? Seppi333 ( Insert 2¢ | Maintained) 08:43, 30 April 2014 (UTC)
I followed Boghog's advice and put the simpler and more general pharmacodynamic information first. It currently summarizes the effect it has on catecholamines and the neural pathways in acts upon in the first paragraph. I don't think I can simplify the subsequent material more than using the graphic I made to illustrate the process though. It simply requires a technical background to understand.
In any event, I'm satisfied with this section now. If you could take a look at it and give me your thoughts, I'd appreciate it.
Seppi333 (
Insert 2¢ |
Maintained)
03:19, 4 May 2014 (UTC)
Per AWB, there's now at most 2 wikilinks for any given term in the article. Seppi333 ( Insert 2¢ | Maintained) 03:39, 4 May 2014 (UTC)
@ Shudde: Can you give me some feedback on the recent changes please? Seppi333 ( Insert 2¢ | Maintained) 03:45, 4 May 2014 (UTC)
Reviews of clinical stimulant research have established the safety and effectiveness of long-term amphetamine use for ADHD. [1] [2] An evidence review noted the findings of a randomized controlled trial of amphetamine treatment for ADHD in Swedish children following 9 months of amphetamine use. [3] During treatment, the children experienced improvements in attention, disruptive behaviors, and hyperactivity, and an average change of +4.5 in IQ. [3] It noted that the population in the study had a high rate of comorbid disorders associated with ADHD and suggested that other long-term amphetamine trials in people with less associated disorders could find greater functional improvements. [3]
Reviews of clinical stimulant research have established the safety and effectiveness of long-term amphetamine use for ADHD. [1] [4] Controlled trials spanning two years have demonstrated continuous treatment effectiveness and safety. [4] [3] One review highlighted a 9 month randomized controlled trial in children that found an average increase of 4.5 in the IQ and continued improvements in attention, disruptive behaviors, and hyperactivity. [3]
References
{{
cite journal}}
: CS1 maint: multiple names: authors list (
link)
{{
cite journal}}
: Unknown parameter |month=
ignored (
help)
The main changes were the removal and addition of a review, summary of both reviews, and merging two sentences. Minor copyedits too. How's it look now? Seppi333 ( Insert 2¢ | Maintained) 10:44, 5 May 2014 (UTC)
Eh, 4.5 points is roughly 5% of the average person's IQ. Seems sizeable to me, but I'll cut it if it's that much of an issue for you. I've made changes per your suggestion - the new section is reflected in the blockquote above. A minor detail, though the reviews cover 4 trials with durations of 9, 15, 24, and 24 months. Seppi333 ( Insert 2¢ | Maintained) 12:49, 5 May 2014 (UTC)
I believe that a good addition to this article would be adding a table that that includes Amphetamine's EC50, IC50, and dissociation constant (Ki) values. I think this table should include binding to the monoamine transporters (including VMAT), and receptor affinities (since amphetamine does have very minor, but notable) at some of the adrenergic receptors and dopamine receptors. Personally, I think that would pretty much complete this article.
What does everyone else think?
SwampFox556 ( talk) 02:29, 27 April 2014 (UTC)
Anyways, I'll check through my plethora of bookmarked studies and go from there ;). Good hunting!
SwampFox556 ( talk) 01:09, 29 April 2014 (UTC)
@ Boghog: The imine intermediate in method 5 is incorrectly named (2-nitroprop-1-en-1-yl)benzene. I'm guessing that was accidentally carried over from method 4?
Since it's a primary imine, I'm pretty sure you'd just call it 1-phenylpropan-2-imine. BlackstarX ( talk) 07:35, 1 May 2014 (UTC)
Cite error: There are <ref group=note>
tags on this page, but the references will not show without a {{reflist|group=note}}
template (see the
help page).
This is an archive of past discussions. Do not edit the contents of this page. If you wish to start a new discussion or revive an old one, please do so on the current talk page. |
Archive 1 | Archive 2 | Archive 3 | Archive 4 | Archive 5 | Archive 6 | → | Archive 8 |
Boghog ( talk · contribs), if you're familiar with this synthesis/metabolism material, the content I just added could probably use copy-editing from a more chemistry-savvy editor than I am. I actually wasn't sure if some of the pathway-related enzymatic reactions were redundant. A lot of that content was bits and pieces from the pubchem compound page. Regards, Seppi333 ( talk) 05:39, 12 October 2013 (UTC)
(Outdent)
Sorry for the late follow up - been really busy outside of Wikipedia. I fixed the image, so let me know if it's good or there's still any flaws or potential improvements (no matter how small). Feel free to add whatever you want though - the more (on-topic/relevant) info, the more comprehensive, and hence the better the article. Also, I need to do the following two things for GA/FA improvements, but as I have no background in chem, it'd be a big help if you could review the content after I add it.
Regards, Seppi333 ( talk) 16:32, 22 October 2013 (UTC)
How's this look in the meantime? It's the best I could do with my limited knowledge of chemistry and chem editors (I actually used MS paint to make some of these). ;P
725x400 px image
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Seppi333 ( talk) 21:34, 24 October 2013 (UTC)
I hate to ask even more of you since I feel like you've already done a lot for me, but if you're willing and have a chance (this isn't even remotely urgent, so no rush), these three article I made could use a quick, cursory stupidity-filter/fact-check:
P-hydroxynorephedrine,
formetamide, and
User:Seppi333/P-hydroxyphenylacetone. Regards,
Seppi333 (
talk)
17:05, 28 October 2013 (UTC)
Hi everyone - I'm not 100% positive this is the same thing, so revert my edit if vaporization is a more general concept or "route" than smoking.
I came across this page from the EMC stating that, unlike meth, amphetamine (sulfate form) is insufficiently volatile to be smoked. http://www.emcdda.europa.eu/publications/drug-profiles/amphetamine
Regards, Seppi333 ( talk) 02:43, 15 October 2013 (UTC)
From the research I've done, and from prior knowledge, it would appear to me that Amphetamine's metabolism is almost entirely mediated by MAO-B. If that's the case, why shouldn't it be noted in the metabolism section on the right, that MAO-B plays a big part in Amphetamine metabolism? I know CYP2D9 does have some effect on amphetamine, however, the studies I've read claim that it's effects on Amphetamine metabolism is <10%.
So, before I add this into the article, am I missing something? It seems to me that this should already be here and the fact it isn't leads me to believe I may be misinterpreting something.
Regards SwampFox556 ( talk) 20:06, 15 October 2013 (UTC)
This section could use a general range of how long amphetamine is detectable by a typical test. That's a significant piece of information, and I'm sure many people come here looking for it. Exercisephys ( talk) 21:52, 25 October 2013 (UTC)
This article contains a lot of examples of long sentences being combined with semicolons. I would make the article more readable to leave them as separate sentences.
A study conducted soon before the cited Volkow study, which used similar methods, came to the opposite conclusion. The Volkow paper cites it. I don't have time to dig it up now, but I think in the spirit of neutrality it deserves a mention. I posted this here as a self-reminder, and as an offer to any WP:Gnomes that have a little free time. Thanks. Exercisephys ( talk) 02:33, 29 October 2013 (UTC)
A few months ago, I got Adderall moved to amphetamine mixed salts (medication). This was done because it is Wikipedia policy to name articles after the generic pharmaceutical name of drugs rather than the brand name. The fact that Adderall was one of the few lasting exceptions to this rule points out just how entrenched the brand name is. However, identical generic formulations exist, so the name "amphetamine mixed salts" should be used. However, it's probably a good idea for us to clarify that it's equivalent to Adderall often, as most people are only familiar with the latter term. Exercisephys ( talk) 00:44, 3 November 2013 (UTC)
Also, as a minor side-note, "Adderall" is capitalized. Exercisephys ( talk) 16:55, 3 November 2013 (UTC)
I also realized it was possible to check the number of users searching for Adderall vs using a wikilink directly to the page or searching the page itself. As of writing this, over the past 90 days, 70000 people searched for Adderall in the search bar or arrived there from outside wikipedia, since redirects to Adderall would just be moved to amph mixed salts by bots. Over that same 90 day period, 184 people arrived at "Amphetamine mixed salts" by searching that term directly or coming from outside wikipedia. The remainder of the 118000 people that viewed amphetamine mixed salts (medication) probably arrived there externally or by wikilink given that 184 (vs 70000 for Adderall) people searched the non-parenthetically disambiguated version. There's really only one conclusion to draw from those stats and the first item in WP:CRITERIA. :P Seppi333 ( talk) 12:23, 5 November 2013 (UTC)
Instead of replacing the "publisher" parameter with "work" parameter in citation templates as was done in this and removing the information that was in the work parameter, why don't we add publisher and work parameters to all cite web templates? According to the {{ cite web}} documentation, the "work" parameter contains the "title of the website; may be wikilinked; will display in italics" which is clearly different than the publisher. Boghog ( talk) 05:53, 4 November 2013 (UTC)
References
Regards,
Seppi333 (
talk)
23:38, 4 November 2013 (UTC)
I think the article would be of greater benefit to the internet if it was explained why Amphetamine (but all Dopaminergic stimulants apply) are the ideal treatment for ADHD? I'd also love to see a section about why Amphetamine is used to treat Narcolepsy.
The idea for the section I have in mind would explain what we know about the causing mechanism behind ADHD and why Amphetamines are the prototypical treatment for it. I'd also love to have the ladder explained for Narcolepsy as well.
I am seriously considering putting in the amount of time it would take to research everything in depth while only explaining it in a few paragraphs. I am willing to put in the time to do that, but I'm afraid someone might object and remove the new information. So I ask...
Would that be acceptable? It would be a subsection of the "uses" header at the top of the article. Let me know what you guys think.
Best regards, SwampFox556 ( talk) 00:30, 7 November 2013 (UTC)
The name of the study escapes me, but I read a very interesting study (that was actually a compilation of around 30 studies) that was able to make a very solid hypothesis that ADHD is caused by an over-expressed DAT1 gene. You seem pretty knowledgeable Seppi, so I'm sure you have already heard this before, however just in case you haven't...
The thesis was written up by Dr. Russell Barkley and published last year. He took many studies and formed a hypothesis from them. We have speculated for years that genes play a major part in the development of illness. However, it's incredibly difficult to understand mental illness due to the fact that we can't open up a human brain without killing that person. Anyways, my point is, we've always known that genes likely play a major role in the predisposition to developing illness, but its never been proven that one specific gene was the cause for an illness.
Dr. Russell Barkley's thesis stated this and he said that the study was start in order to attempt to determine "the genes" that cause ADHD. So he based the initial idea off of already published studies and using that information conducted other studies. His findings were quite interesting. He conducted more than one study and I'm not sure what each specific study was about to be honest, however, he summed it all up in his conclusion pretty well.
He said that they found that several things can lead to ADHD from birth, but all of these changes had to happen in the womb. However, he did mention that there was strong evidence to suggest that if a child sustains a concussion in the very early stages of after-birth development, it appeared that this could also lead to classic symptoms of ADHD.
Anyways, he said all of these things affect development in a different way but the end result is always the same.
The gene that controls the development of the Dopamine Uptake Transporters is called DAT1. It is located on chromosome 5p15. For one reason or another, this gene is mutated this causes the gene to become over-expressive thus resulting in a huge increase in Dopamine Uptake Transporters. The dopaminergic neurons release Dopamine like they should be, but the dopamine has no time to form a complex with a receptor before it gets uptaken. This results in incredibly small extracellular and postsynaptic Dopamine levels.
He found that this gene can already exist in some people and it doesn't have to be mutated. However, he found that introduction of a toxin can result in the mutation of this gene. Specifically, Nicotine and Ethanol.
Children, whose mothers drank or smoked during their pregnancy with the child, were something like 72% more likely to be born with ADHD. There is already a known correlation between ADHD and comorbidity, but he said that there was evidence to suggest that these children (children of mothers who had used a toxin at some point in their pregnancy) were even more likely to have a comorbid, psychiatric disorder diagnosed at some point in their life.
In the study, only Ethanol and Nicotine (well, all the extract of Tobacco) were used. However, both of these substances cause immense release of Dopamine through one mechanism or another. This was not said in the study, but the way he wrote it made it sound like he was alluding to this. The increased Dopamine levels causes the fetus to compensate in order to reach homeostasis. This compensation is the result of more DA transporters - either these transporters were created by the fetus as a means to get rid of extra Dopamine, or it's possible that the body could have mutated the gene so more DAT cells would be produced.
Again, he said none of that directly, but that's the idea I got from the thesis. I guess it doesn't matter how the extra uptake transporters were created, all they know is it happens. Also, I should add, they were actually able to prove this happens with extensive brain imaging. He also said that since the discovery of the over-expressed gene that causes more DA transporters to exist, many correlations between high amounts of these transporters and other illnesses have been seen.
He said that while he was conducting the rest of his thesis, another study came out (using his information) that the presence of this gene is a great indicator for later in life drug addiction. They also concluded that the substance that was most likely for the person to be addicted to at some point in their life was Nicotine. But other drugs were tested in this study and found that it also applies to Ethanol, Cocaine, and Methamphetamines. However, the study also said likelihood for addiction to dissociatives also appeared to be increased. The one tested specifically was Phencyclidine (PCP).
Anyways, to finish up Dr. Barkley's thesis - He found that the presence of this gene was a great indicator for how well you would respond to stimulant treatment. I don't remember how many people were tested (it was something like 11 or 14) but they were all tested for an over-expressed DAT1 gene - all tested positive. When they were asked to take Methylphenidate (I believe it was the minimum dose indicated for adult ADHD) they all responded very well to Methylphenidate. Attention was greatly improved, motivation was markedly improved, psychomotor agitation was markedly decreased, emotional stability was increased, impulsiveness was decreased, upon other things (those were just the one I remembered off the top of my head) and they all reported that there overall quality of life had been improved by Methylphenidate.
There are many videos of Dr. Russell Barkley explaining his finding on YouTube. One of the videos cited the thesis directly, but I can't seem to find it. Let me go back through my internet history and I'll post back.
Regards, SwampFox556 ( talk) 05:56, 7 November 2013 (UTC)
This is what I made reference to earlier. The paragraph is something I added a few months back and subsequently removed after becoming familiar with MEDRS:
Adhd & TAAR1
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With exception to the last 2 sentences which would need to be cut, every primary source in this paragraph could be replaced with one of the following 3 reviews: [1] [2] [3] In individuals with ADHD, there is significant evidence that phenethylamine (PEA) – an endogenous amphetamine homologue with analogous dopaminergic pharmacodynamics [4] [5] – metabolism is reduced compared to healthy individuals. [6] [7] [8] It is well documented that urinary excretion of PEA increases following administration of amphetamine and methylphenidate, and that urinary excretion of these drugs is highly correlated with urinary excretion of PEA; [9] [10] [11] moreover, studies on rodents show that brain PEA biosynthesis and metabolism greatly increases following amphetamine administration at therapeutic doses. [12] [13] There is also evidence that pharmacological depletion of PEA blocks the stimulant effects of amphetamine, suggesting that endogenous PEA plays an important role in mediating the effects of amphetamines. [14] [15] In spite of similar effects on catecholamines, unlike amphetamine, methamphetamine does not affect brain PEA levels, nor does PEA appear to mediate the effects of methamphetamine. [16]
References
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I apologies, that's not how I meant to present my point. I should have stated this above. What I meant to imply (and should have stated outright) was the fact that; whether or not it's "too many DA uptake pumps" or "too little endogenous Phenethylamine" the end result is always the same. Dopamine levels in the frontal lobe of the brain are lower than normal. This leads to all the motivational deficits, attention issues, emotional instability, etc seen in patients who have ADHD. I know there's a little more to it then just low dopamine, but that's pretty much the gist of it.
To get a little off topic, I remember reading some studies that suggested that there was a deficit in the levels of all the monoamine neurotransmitters in people with ADHD, but I'm not trying to get that far into it. Yes, I agree. Having all the above is a little overkill for just the Amphetamine article. But couldn't there be a very skimmed down version of both possible causes? Something like...
"Were not certain at this point in time what causes ADHD However, it's very widely accepted that the neurotransmitter Dopamine is found in much smaller quantities all over the Brain of someone with ADHD.(see "ADHD cause" article).
believe that genetics may play a major role in determining who will be susceptible to the illness. The gene located on chromosome 5p15, the gene itself is known as DAT1, has been identified as being responsible for the creation of the Dopamine Uptake Transporter. This transporter is responsible for removing dopamine from the synapticcleft and is an important part of dopamine regulation in the Brain. It was discovered *insert year here* that this gene appears to be overly expressed in people with ADHD. This means that many more DA transporters will be created. This would allow too much upregulation of dopamine and would result in much lower postsynaptic dopamine levels."
I didn't know how to summaries the lowered levels PEA paragraph. So in order to save time I didn't put it in in just a reply. But I'm thinking that after that paragraph is stated, that we could then briefly explain that amphetamines raise dopamine levels quite a bit?
would that be acceptable? — Preceding unsigned comment added by SwampFox556 ( talk • contribs) 22:08, 8 November 2013 (UTC)
Sorry for the late reply. I think adding something like that would be fine. I'll draft something tonight and post it here to see what you think. Seppi333 ( talk) 21:01, 9 November 2013 (UTC)
Actually, do you have a PMID for a MEDRS-quality review on DAT/ADHD (ideally, one published between Jan 2008 and today) handy that I can use to cite the first part? I've been a bit busy with ref editing for GA/FA to do a search for suitable papers to cite. The lack of ref on hand is really the only thing that's been holding me up from doing this. Seppi333 ( talk) 20:12, 11 November 2013 (UTC)
It took me a couple of hours, but I finally wrote up a section on the results of stimulant treatment in people with ADHD. Even though the information provided is entirely backup, by multiple clinical studies - this section will be controversial due to the fact that there are so many misconceptions out there about stimulants drugs in the treatment of ADHD that are potentiated by the scientologists and media.
I will revert any attempted edits to the section unless claims are backed up with legitimate medical proof. I imagine this section will receive an immense amount of vandalism but I will try to monitor the section as much as I can to revert this attempt to censor information.
If anyone has any problems with the section, and can provide medical proof to backup any claims, feel free to the edit the section at will. If anyone has any problems with the section as it is now, let me know and I'll edit the section in an attempt to comply with Wikipedia's rules as best as I can.
Best regards, SwampFox56 (Zeke Ortiz)
SwampFox556 ( talk) 23:30, 12 November 2013 (UTC)
I really like all of the edits. It sounds much more professional, and is better written than what I initially wrote. Thanks a lot for the work Seppi! It looks good :) There is one minor change I've decided to ahead and make though. "In particular, children with ADHD who use stimulant medications are generally more sociable." I feel like that implies that the child then becomes overly expressed socially, which isn't necessarily what the source said.
So I decided to change it to "In particular, children with ADHD who use stimulant medications, generally have better relationships with peers and family members." I also changed the sentence located after that one to "Children, also, generally perform better in school, are less distractible and impulsive, and have longer attention spans." In order to fit the above edits.
Anyways, again, everything looks great otherwise! :)
Regards,
SwampFox556 ( talk) 23:10, 15 November 2013 (UTC)
This is rather minor but it's mentioned a couple times in the article that Amphetamine "increases libido." I'm wondering if this should rather be stated as "change in libido" as it doesn't always cause an increase? I haven't researched the topic in depth yet, however, typical prescribing information lists "change in libido" and not that amphetamine will definitely increase libido.
http://www.rxlist.com/adderall-drug/side-effects-interactions.htm
http://pi.shirecontent.com/PI/PDFs/AdderallXR_USA_ENG.PDF
A libido decrease was noted by Shire in their prescribing information of 60 milligrams of Adderall or higher.
User reports I've read also indicate that amphetamine can both "increase sexual desire" or "decrease sexual desire." I know you can't base anything off of user reports - replicated clinical studies are the only way to be sure of anything. However, it seems to me that "increase in libido" is inappropriate.
If anyone has an opposition to me changing this, I won't make any fuss about it - it's not really that big of a deal anyways. However, I feel this minor edit would make the information in the article a bit more accurate.
SwampFox556 ( talk) 22:02, 16 November 2013 (UTC)
Apparently this page is protected so I can't edit it. Anyway, in the other relevant activities section it states that histamine is 'another monoamine' - only it isn't. It's a diamine, and as expected, it metabolized by diamine oxidase. 216.105.211.130 ( talk) 06:03, 26 November 2013 (UTC)
This is the current version of the article. I don't like the lede, it seems rather sloppily written and the "in spite of the significant health risks" is clearly tacked on. Not that it doesn't belong there, but the way it's included looks like the DARE van did a drive-by, so I'm going to edit it. The lede is usually the most contentious part of an article, especially one concerning a widely-abused drug, so I've gone ahead and created this section as a forum for the discussion and compromise that will probably be necessitated eventually. Zig Saw 07:28, 26 November 2013 (UTC)
Exercisephys, I know you're well aware of WP:MEDRS criteria - stop ignoring it. Asserting neurotoxicity is a medical claim. Since this is now a GA article and I went through a great deal of trouble to remove all the non-MEDRS sources to medical claims and then re-cite the text with MEDRS versions, I'm not going to accept anything but a MEDRS source for a neurotoxicity claim. I.E., use a review of literature or professional text published within the last 5 years. Moreover, the relevant material also needs to be on humans - not animals. All of that is explicitly stated in MEDRS for medical claims on actively studied topics.
I put THREE sources to back the statement that you removed - two of which were MEDRS (1 review, 1 pharmacology textbook) and a primary source on HUMANS (not rats) to supplement the MEDRS review (also on HUMANS) and expand upon the material from that secondary source. I based all of that on what I found on a lit. search, pubchem, and drugbank.
I didn't counter your claims the last time. Since this is now annoying me, I'm going to support my position with MEDRS sources, specifically, NCBI's tertiary source on amphetamine (Pubchem Compound) - a "data encyclopedia" if-you-will.
Before I go into this, just in the event this isn't evident to you from the last time we went over this, the term substituted amphetamine (74 results) is a wikipedia construct. Almost all medical literature refers to the "class of amphetamines" as amphetamineS (again, notice the "s") (33467 results vs 9261 results for methamphetamine, an amph that's been researched more extensively than amph itself).
The massive Pubchem Human Toxicity Section on Amphetamine - notice the highly emphasized passage on direct toxicity in the human brain (i.e. neurotoxicity)
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Human Toxicity Excerpts [Emphasis added as bold, underlining, capitalizing an "S", and/or increased text size] The toxic dose of amphetamine varies widely. ... Severe reactions have occurred with 30 mg, yet doses of 400 to 500 mg are not uniformly fatal. Larger doses can be tolerated after chronic use of the drug. The acute toxic effects of amphetamine are usually extensions of its therapeutic actions and, as a rule, result from overdosage. The central effects commonly include restlessness, dizziness, tremor, hyperactive reflexes, talkativeness, tenseness, irritability, weakness, insomnia, fever, and sometimes euphoria. Confusion, assaultiveness, changes in libido, anxiety, delirium, paranoid hallucinations, panic states, and suicidal or homicidal tendencies occur, esp in mentally ill pt. However, these psychotic effects can be elicited in any individual if sufficient quantities of amphetamine are ingested for a prolonged period. Fatigue and depression usually follow central stimulation. Cardiovascular effects are common and include headache, chilliness, pallor or flushing, palpitation, cardiac arrhythmias, anginal pain, hypertension or hypotension, and circulatory collapse. Excessive sweating occurs. Symptoms referable to the GI system include dry mouth, metallic taste, anorexia, nausea, vomiting, diarrhea, and abdominal cramps. Fatal poisoning usually terminates in convulsions and coma, and cerebral hemorrhages are the main pathological findings. AMPHETAMINE GIVEN ORALLY RAISES BOTH SYSTOLIC & DIASTOLIC BLOOD PRESSURES. HEART RATE IS OFTEN REFLEXLY SLOWED; WITH LARGE DOSES, CARDIAC ARRHYTHMIAS MAY OCCUR. CARDIAC OUTPUT IS NOT ENHANCED BY THERAPEUTIC DOSES, & CEREBRAL BLOOD FLOW DOES NOT CHANGE MUCH. THE L-ISOMER IS SLIGHTLY MORE POTENT THAN THE D-ISOMER IN ITS CARDIOVASCULAR ACTIONS. IN GENERAL, SMOOTH MUSCLES RESPOND TO AMPHETAMINE AS THEY DO TO OTHER SYMPATHOMIMETIC AMINES. ... PAIN & DIFFICULTY IN MICTURITION OCCASIONALLY OCCUR. THE GI EFFECTS OF AMPHETAMINE ARE UNPREDICTABLE. IF ENTERIC ACTIVITY IS PRONOUNCED, AMPHETAMINE MAY CAUSE RELAXATION & DELAY THE MOVEMENT OF INTESTINAL CONTENTS; IF THE GUT IS ALREADY RELAXED, THE OPPOSITE EFFECT MAY OCCUR. THE RESPONSE OF THE HUMAN UTERUS VARIES, BUT USUALLY THERE IS AN INCREASE IN TONE. Because tolerance develops to the hyperthermic and cardiovascular effects of amphetamine, acute intoxication is more likely to occur in the neophyte. The syndrome includes dizziness, tremor, irritability, confusion, hallucinations, chest pain, palpitation, hypertension, sweating, and cardiac arrhythmias. There may be hyperpyrexia and convulsions. Death is usually preceded by hyperpyrexia, convulsions, and shock. Perivascular infiltration of amphetamineS can produce local necrosis, cellulitis, granulomas, & abscess formation. Intra-arterial injection causes intense vasospasm with distal cyanosis, ecchymosis, petechiae, edema, paresthesias, pain, weakness, necrosis, & decreased capillary filling. Immediate intense vasospasm is obvious after intra-arterial injections. Chronic intoxication with amphetamine causes symptoms similar to those of acute overdosage, but abnormal mental conditions are more common. Weight loss may be marked. A psychotic reaction with vivid hallucinations and paranoid delusions, often mistaken for schizophrenia, is the most common serious effect. Recovery usually is rapid after withdrawal of the drug, but occasionally the condition becomes chronic. In these persons, amphetamine may act as a precipitating factor hastening the onset of an incipient schizophrenia. Chronic use of high doses of amphetamineS has been reported to produce microvascular damage, neuronal chromatolysis (primarily in brain areas rich in adrenergic neurons), and profound and long lasting (or permanent) depletion of dopamine in the caudate nucleus. The psychic effects depend on the dose & the mental state & personality of the individual. The main results of an oral dose of 10-30 mg include wakefulness, alertness, & a decreased sense of fatigue; elevation of mood with increased initiative, self-confidence, & ability to concentrate; often, elation & euphoria; and increase in motor & speech activities. Performance of simple mental tasks is improved, but, although more work may be accomplished, the number of errors may increase. Physical performance - in athletes, for example - is improved, & the drug is often abused for this purpose. These effects are not invariable, & may be reversed by overdosage or repeated usage. Prolonged use or large doses are nearly always followed by depression & fatigue. Many individuals given amphetamine experience headache, palpitation, dizziness, vasomotor disturbances, agitation, confusion, dysphoria, apprehension, delirium, or fatigue. The fully developed toxic syndrome from amphetamine is characterized by vivid visual, auditory, and sometimes tactile hallucinations; picking and excoriation of the skin and delusions of parasitosis are not uncommon. There is also paranoid ideation, loosening of assoc, and changes in affect occurring in assoc with clear sensorium. In chronic users, there may be a striking paucity of sympathomimetic effects, and the blood pressure is not unduly elevated. It is often extremely difficult to differentiate this syndrome from a schizophrenic reaction. The syndrome may be seen as early as 36 to 48 hr after the ingestion of a single large dose of amphetamine; in apparently sensitive individuals, psychosis may be produced by 55 to 75 mg of dextroamphetamine. With high enough doses, psychosis can probably be induced in anyone. Unless the individual continues to use the drug, the psychosis usually clears within a week, the hallucinations being the first symptoms to disappear. Amphetamine ... in large doses systemically can dilate the pupils and cause slight blurring of near vision. Applied to the eye, amphetamine dilates the pupil and retracts the upper lid, but these actions are prevented by previous depletion of catecholamines such as is brought about by local guanethidine. Renal failure assoc with amphetamine use is usually the result of rhabdomyolysis, but it has also been found in patients without evidence of muscle damage or other apparent predisposing factors. Data on the effect of prenatal amphetamines, both prescribed and abused, are conflicting; however no consistent pattern of abnormalities has emerged. A large prospective evaluation of amphetamines prescribed during pregnancy found no incr in severe congenital malformations, but did report three cases of oral clefts. Another prospective study evaluating infants of amphetamine addicted women failed to demonstrate an incr in birth defects, but did note an incr in premature births, respiratory distress and jitteriness. The use of other drugs and alcohol may have confounded these findings. /Amphetamines/ In an acute poisoning in a child ... external stimuli precipitated increased hyperactivity. Abrupt discontinuation of amphetamines produces neither seizures nor life threatening symptoms, even in those patients who habitually consume large quantities. The abstinence syndrome assoc with chronic use of amphetamine ... is characterized by apathy, depression, lethargy, anxiety, & sleep disturbances. Myalgias, abdominal pain, voracious appetite, & a profound depression with suicidal tendencies may complicate the immediate postwithdrawal period & peak in 2-3 days. Symptoms persisting 6-7 days indicate an underlying disease process. During the early phases of iv use, 3 to 4 doses of 20 to 40 mg of amphetamine are usually considered sufficient /by abusers to produce euphoric effects/. In addition to the marked euphoria, the user experiences a sense of markedly enhanced physical strength & mental capacity, & feels little need for either sleep or food. Difficult to substantiate by objective means is the claim made by many users that orgasm in both male & female is delayed, permitting extended periods of sexual activity finally culminating in orgasms reported to be more intense & pleasurable. The sensation of "flash" or "rush" that immediately follows iv admin, while qualitatively distinct from the opioid "rush", is nevertheless described as being intensely pleasurable & somewhat akin to sexual orgasm. Many of those who use amphetamine ... are best described as "recreational" or occasional users, but some become dependent. A small percentage of the latter (eg, those taking the drugs for control of obesity) seem able to restrict drug intake & function productively (stabilized addicts). Others show progressive social & occupational deterioration, punctuated by periods of hospitalization for toxic psychosis. In terms of the compulsion to continue use, the degree to which a drug pervades the life of the user, & the tendency to relapse following withdrawal, some compulsive users of amphetamine ... are addicts. The risk of developing patterns of compulsive use is not limited to those who use drugs intravenously ... It is not clear whether the dependence syndromes caused by amphetamine ... are as persistent as that produced by opioids. In the US the waves of amphetamine use did not leave large numbers of chronic users in their wake. However, many iv users eventually became heroin users. ANOREXIA IS A COMMON FINDING /IN CHRONIC TOXICITY FROM ABUSE/. OCCASIONALLY IT MAY BE SO PRONOUNCED THAT THE AMPHETAMINE ABUSER EXPERIENCES CONSIDERABLE DIFFICULTY IN SWALLOWING. CHRONIC ABUSERS ARE REPORTED TO FORCE THEMSELVES TO EAT SMALL AMT OF HIGHLY NUTRITIOUS FOOD & TAKE VITAMIN SUPPLEMENTS TO COMPENSATE FOR DECR IN APPETITE. ... CONSTANT GRINDING OF TEETH IS ALSO A COMMON FINDING ... THE HISTORY, CHEMISTRY, PHARMACOLOGY, MEDICAL USE, ILLICIT USE & ADDICTION & TOLERANCE POTENTIAL OF AMPHETAMINES ARE PRESENTED. ALTHOUGH THERE ARE FEW PUBLISHED ACCOUNTS OF DEATH KNOWN TO RESULT DIRECTLY FROM AMPHETAMINES, DEATHS MAY RESULT INDIRECTLY FROM EFFECTS SUCH AS VIOLENT BEHAVIOR & HEPATITIS.[HART JB, WALLACE J; CLIN TOXICOL 8 (2): 179-90 (1975)] PubMed Abstract Few deaths have ... been attributed to amphetamine overdose. Amphetamines have a relatively low ratio of effective dose to fatal dose. Fatalities resulting from amphetamine use are usually the result of one of the following processes: 1) combinations with other drugs; 2) complications of iv injections, such as septicemia, bacterial endocarditis, or homicide, during withdrawal depression. Although comparable clinical data are lacking, hyperpyrexia has been noted as a frequent & prominent sign in acute human intoxication. During a grueling bicycle race a cyclist collapsed with symptoms closely resembling heat exhaustion, &, despite vigorous treatment, he died /after/ cardiovascular collapse; it was learned subsequently that he had consumed 105 mg of amphetamine during the race. Bleeding within the cranial vault is a rare but well-reported complication of amphetamine use. About 20 cases, which are about evenly divided between iv & oral exposures, have been reported in the American literature. Ages range from 16-60, & most patients are habitual & often multidrug abusers. However, intracranial hemorrhages have been reported after the ingestion of as few as 2-4 tablets of amphetamine or structurally related anorectic drugs ... The etiology of intracerebral & subarachnoid hemorrhages associated with amphetamine use appears multifactorial. Inflammation & necrosis of small cerebral arteries (ie, vasculitis) secondary to particulate foreign bodies or bacterial endocarditis can develop after iv drug use. Subsequently, the hypertension seen in amphetamine use may lead to vessel rupture & hemorrhage. However, vasculitis has occurred in the setting of oral acute dextroamphetamine overdose, amphetamine withdrawal, & therapeutic use as an anorectic drug. The presence of vasculitis after exposure by different routes suggests an immunopathological abnormality. Direct toxic damage to vessels seems unlikely because of the dilution that occurs before the drug reaches the cerebral circulation. Repetitive behavior may occur /from the use of amphetamines/ (e.g. repeatedly cleans dishes or continually grooms hair). Amphetamines also will extenuate hostile, aggressive, and antisocial behavior. Progression to paranoia, panic states, violence, and even suicide may occur. /Amphetamines/ Amphetamines used in large doses over a long period of time may lead to substantial weight loss, liver disease, hypertensive disorders, kidney damage, stroke, heart attack, nonhealing ulcers, and sores in the skin. /Amphetamines/ The abuse of amphetamines by combining the oral and inhalation routes of administration usually leads to a more intense effect and/or more toxic effect than if either was taken alone. /Amphetamines/ Doses as little as 2 mg, but more likely between 15 and 30 mg, may induce toxic effects. However, even doses of 400-500 mg are not uniformly fatal. Illicit maternal use /of amphetamines is/ associated with intrauterine growth retardation, premature birth, and increased fetal and newborn morbidity. /Amphetamines, from table/ Intrauterine ... amphetamine exposure may cause neonates to exhibit abnormal sleep patterns, tremors, poor feeding, hypotonia, fever, and vomiting. |
NCBI cited the amph article ref named "Westfall" for it's toxicity statements on the class of amphetamines. I cited Westfall too and not only covered what it said on amphetamine (oxidative damage from radical species), I also expanded upon it with the other two sources. Most of the WP:PAYWALLED refs cited in the article are hosted here, including other relevant sections of the Westfall ref that I didn't cite in the article.
With all that said, I'll just summarize and briefly state the issues:
If you add a WP:MEDRS secondary source demonstrating the existence of (singular) amphetamine neurotoxicity in humans, I would be happy to see and have it included in the article. If you add a source that falls short of what the policy requires, I will revert it, per the policy. If you change and of the language in that section such that it doesn't agree with the cited sources (hence causing at least WP:V and potentially WP:NPOV issues), I will revert it. WP policy practically dictates that I do this if I want to see this article reach FA.
Lastly, I also find it almost obnoxious, and it's completely illogical, to suggest that *I* am causing WP:NPOV problems with this article when you're citing animal studies to make claims about humans any skewing text-source integrity (the refs on humans stated only a single mechanism and you stated there were multiple). I'm not assuming bad faith on your part - now stop making assumptions and accusations about mine. Seppi333 ( talk) 18:12, 1 December 2013 (UTC)
This is ridiculous and unjustifiable. I'm going to have to bring more mediators in when I have the time. Exercisephys ( talk) 22:56, 1 December 2013 (UTC)
There are bad faith user warning templates for a reason. I normally avoid using them because, exactly like going off topic, personal attacks, or asserting bad faith intent of other users, it detracts from a conversation. So, once again, and I won't ask next time, please, stop saying I'm intentionally POV editing and focus on the actual issue: we need sources to directly support the text.
For 1: I've literally just asked you for a MEDRS source indicating other indirect mechanisms besides radical toxicity in humans or a source for any direct toxicity by amph in humans. You've just replied to this by restating this; it's a bit circular, but ignoring that, unfortunately, I don't think you are a MEDRS source. For 2: As I told you like a week ago via the user notification template in a thread currently on this page (SwampFox's thread, current the third section on this page as of this edit), I moved that material to the ADHD section. The paper is on neuroplasticity, not neurotoxicity. It's a more general concept. If anything, it belongs in the OD section, but since the study a study on human neuroplasticity is in that section, it MUST be there in order to not refute that source elsewhere in the article. I only kept it because you've been complaining I delete your material. If you didn't cite animal studies I probably wouldn't be trying to remove it.
[Related aside to this list item: I've said it over and over again, animal studies do not say anything about humans - extending the inference is spurious because the non-human sample in those studies is a nonprobability sample for human neurotoxicity. I can literally produce an analytic proof to demonstrate that any statistical model for a drug effect using nonprobability sampling (like animal studies with inference on humans) is spurious. In other words, I am literally stating that every animal study that has ever been conducted to detect the presence of any drug-related phenomenon in any (non-human) species yields invalid/spurious statistical inference in humans (the bolded terms are universal quantification in an analytic context). The fact that I can make that statement given that much scope is why representative sampling, like random sampling, is such a fundamental concept in statistics. Literally every stat textbook you might check for reference will tell you use "random" and "representative" samples. It's included in intro stats texts without rigorous justification simply because most people taking an intro stats course won't understand analytic proofs (i.e. the kind of argument in the collapse tabs of holder's inequality). In the event you don't have a solid background in math, just take it on faith - it's stated everywhere for a reason. This is the exact reason WP:MEDRS has a policy that says "don't use animal studies." The MEDRS policy is the justification for why I remove animal studies. This "aside" is an explanation of why that policy even exists.]
Added by Seppi333 at 19:43, 7 December 2013 (UTC) - I made the policy shortcut WP:MEDANIMAL for your reference.
For 3: I revised the passage that I stated without citation. Sasata reviewed the content and asserted that all medical claims had adequate MEDRS citations yesterday in the concluding remarks to the GA review. He did an extremely thorough review to help this article with FA and I provided every single WP:PAYWALLED source in the GA-review (it's still linked in the GA archive with all the files still hosted in the link). I don't think he'd make that statement lightly.
I'm not asking you do to anything that any editor from WP:MED wouldn't ask of you.
If you state or even imply "some evidence of amphetamine neurotoxicity exists in humans" you need a source on amphetamine which states amphetamine is a neurotoxin. Stop using some paper on an entire class of substances, some of which have been proven to be neurotoxins in humans (meth). A paper on amphetamine human neurotoxicity would unequivocally support a statement about that - this ref is the ONLY THING you need (as well as what must be) cited to make that particular medical claim. That's the same standard for citing any medical claim. You need a ref making a definite statement which directly supports an included medical statement in the article. Every single source in the article CURRENTLY has a direct text-source relation like that, which is stated as what's required of a citation in WP:V. How do I know this? I checked all 100+ sources in the article when I did the WP:V check for GA. You only need to do this for a single source. It's not that hard. If the material you claim to be true exists, a paper on human amph neurotoxicity will be easy to produce (and it literally says this is true of the prevailing/majority viewpoint in WP:DUE. If it's not easy to find, you should be able to list a major proponent of the theory (ideally, someone who has done a case study demonstrating this). If you can't find a ref on amphetamine neurotoxicity, it shouldn't be on wikipedia, per WP:UNDUE. So once again, I'm not taking a position on content. I'm enforcing a policy that you know very well, as I've told you to use it CONSTANTLY in the last thread on this.
I want to emphasize these points so this thread isn't directed off on some random tangent again:
I figured I'd cite WP:MEDASSESS here and underline what the original claim of neurotoxicity is in this list:
Roughly in descending order of quality, lower-quality evidence in medical research comes from individual RCTs; other controlled studies; quasi-experimental studies; non-experimental, observational studies, such as cohort studies and case control studies, followed by cross-sectional studies (surveys), and other correlation studies such as ecological studies; and non-evidence-based expert opinion or clinical experience
Regards, Seppi333 ( talk) 19:50, 7 December 2013 (UTC)
The discussion concluded at [1].
Does this help at all with explaining the technical stuff in this section? (Copied from User:Seppi333/sandbox2#pharmacodynamics)
Seppi333 ( talk) 23:03, 11 December 2013 (UTC)
Metabolic pathways of amphetamine in humans
[sources 1]
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I put this in the article as well - same as before, but with winkilink annotations (citation errors not included ). I think that's all I can do with the images for now. Seppi333 ( Insert 2¢) 08:15, 13 December 2013 (UTC)
References
The simplest unsubstituted phenylisopropylamine, 1-phenyl-2-aminopropane, or amphetamine, serves as a common structural template for hallucinogens and psychostimulants. Amphetamine produces central stimulant, anorectic, and sympathomimetic actions, and it is the prototype member of this class (39). ... The phase 1 metabolism of amphetamine analogs is catalyzed by two systems: cytochrome P450 and flavin monooxygenase. ... Amphetamine can also undergo aromatic hydroxylation to p-hydroxyamphetamine. ... Subsequent oxidation at the benzylic position by DA β-hydroxylase affords p-hydroxynorephedrine. Alternatively, direct oxidation of amphetamine by DA β-hydroxylase can afford norephedrine.
Dopamine-β-hydroxylase catalyzed the removal of the pro-R hydrogen atom and the production of 1-norephedrine, (2S,1R)-2-amino-1-hydroxyl-1-phenylpropane, from d-amphetamine.
Hydroxyamphetamine was administered orally to five human subjects ... Since conversion of hydroxyamphetamine to hydroxynorephedrine occurs in vitro by the action of dopamine-β-oxidase, a simple method is suggested for measuring the activity of this enzyme and the effect of its inhibitors in man. ... The lack of effect of administration of neomycin to one patient indicates that the hydroxylation occurs in body tissues. ... a major portion of the β-hydroxylation of hydroxyamphetamine occurs in non-adrenal tissue. Unfortunately, at the present time one cannot be completely certain that the hydroxylation of hydroxyamphetamine in vivo is accomplished by the same enzyme which converts dopamine to noradrenaline.
Figure 1. Glycine conjugation of benzoic acid. The glycine conjugation pathway consists of two steps. First benzoate is ligated to CoASH to form the high-energy benzoyl-CoA thioester. This reaction is catalyzed by the HXM-A and HXM-B medium-chain acid:CoA ligases and requires energy in the form of ATP. ... The benzoyl-CoA is then conjugated to glycine by GLYAT to form hippuric acid, releasing CoASH. In addition to the factors listed in the boxes, the levels of ATP, CoASH, and glycine may influence the overall rate of the glycine conjugation pathway.
The biologic significance of the different levels of serum DβH activity was studied in two ways. First, in vivo ability to β-hydroxylate the synthetic substrate hydroxyamphetamine was compared in two subjects with low serum DβH activity and two subjects with average activity. ... In one study, hydroxyamphetamine (Paredrine), a synthetic substrate for DβH, was administered to subjects with either low or average levels of serum DβH activity. The percent of the drug hydroxylated to hydroxynorephedrine was comparable in all subjects (6.5-9.62) (Table 3).
In species where aromatic hydroxylation of amphetamine is the major metabolic pathway, p-hydroxyamphetamine (POH) and p-hydroxynorephedrine (PHN) may contribute to the pharmacological profile of the parent drug. ... The location of the p-hydroxylation and β-hydroxylation reactions is important in species where aromatic hydroxylation of amphetamine is the predominant pathway of metabolism. Following systemic administration of amphetamine to rats, POH has been found in urine and in plasma.
The observed lack of a significant accumulation of PHN in brain following the intraventricular administration of (+)-amphetamine and the formation of appreciable amounts of PHN from (+)-POH in brain tissue in vivo supports the view that the aromatic hydroxylation of amphetamine following its systemic administration occurs predominantly in the periphery, and that POH is then transported through the blood-brain barrier, taken up by noradrenergic neurones in brain where (+)-POH is converted in the storage vesicles by dopamine β-hydroxylase to PHN.
The metabolism of p-OHA to p-OHNor is well documented and dopamine-β hydroxylase present in noradrenergic neurons could easily convert p-OHA to p-OHNor after intraventricular administration.
@ Exercisephys: Following this conversation, these refs [1] [2] were added to ADHD to support the benefits of psychostimulants on the human brain. I'm notifying you for the sake of openness, because I'm now adding the refs to this article and their conclusions directly contradict what the animal studies that you added imply for humans. I also don't to give you the impression that I'm trying to subvert you again. This is the current paragraph in medical:
In studies of amphetamine exposure in nonhuman primates, some report no discernible adverse effects on behavior or dopamine system development, while others noted reductions to dopamine-associated structures and metabolites. [3] [4] In stark contrast for humans, recent literature reviews, including a meta-analysis and a systematic review, indicate that the long-term use of amphetamine at therapeutic doses for ADHD actually appears to produce beneficial changes in brain function and structure, such as an improvement in function of the right caudate nucleus. [1] [2]
Best regards, Seppi333 ( Insert 2¢) 06:44, 4 January 2014 (UTC)
References
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I was thinking about changing the drugbox image.
Does anyone have an objection to or support this change? Seppi333 ( talk) 22:24, 30 November 2013 (UTC)
I think that it could be presented in the chemistry section, but that the main drugbox should only contain the original. Exercisephys ( talk) 23:35, 1 December 2013 (UTC)
@ The Sceptical Chymist: I wanted to keep all these sections together for the archives - I hope this is ok with you; feel free to revert this edit if not. Best regards, Seppi333 ( Insert 2¢) 01:27, 11 January 2014 (UTC).
A contradiction in references. The article states "Amphetamine was first synthesized in 1887 in Germany by Romanian chemist Lazăr Edeleanu who named it phenylisopropylamine". On the other hand, a different reference, also used in the article (Heal DJ, Smith SL, Gosden J, Nutt DJ (June 2013). "Amphetamine, past and present – a pharmacological and clinical perspective") states: "racemic α-methylphenethylamine (amphetamine) was discovered by Barger and Dale in 1910, it was not until 1927 that this molecule was first synthesised by the chemist, G. A. Alles" The Sceptical Chymist ( talk) 03:44, 10 January 2014 (UTC)
Long quote
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Synthetic AMPH was invented in 1887 by Lazar Edeleanu (1862–1941, a.k.a. Edeleano), a Rumanian chemist who described its synthesis in his doctoral dissertation under A.W. Hofmann at the University of Berlin (Edeleano, 1887). Edeleanu later became famous for also inventing the method to distill petroleum using sulphur dioxide, providing the tell-tale odor of gasoline distilleries. AMPH was bequeathed its generic name from a contraction of α-methyl-phenethyl-amine. Some notion of the colorful history of this drug can be seen from the 1989 Merck Index listing, which lists 17 trade names, not even including such familiar trade names as Adderall, Benzedrine, and Dexedrine, or for that matter the myriad nicknames used by drug abusers. Of course, chemists have since developed an astonishing range of synthetic AMPH derivatives. Following work discussed below by Barger and Dale that introduced the concept of sympathomimetic amines (Section 3.1), researchers have examined a wide range of catecholamine-like derivatives for the ability to raise blood pressure and to relieve nasal and bronchial congestion from colds and hay fever. AMPH was independently resynthesized by Gordon Alles in 1927 in an effort toward developing synthetic sympathomimetics, and he and his coworkers are credited with the first report of its stimulant effects |
References
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Reference 17 - "Methamphetamine facts". DrugPolicy.org. - is probably not the best source, even for the history reference. It is a website of an advocacy organization. Accordingly, a better reference supporting the historical use of amphetamine for nasal congestion and obesity is needed. The Sceptical Chymist ( talk) 04:24, 10 January 2014 (UTC)
Reference 29 - Berman S, O'Neill J, Fears S, Bartzokis G, London ED (2008). "Abuse of amphetamines and structural abnormalities in the brain", at least according to the abstract is not relevant to amphetamine. It is about the abuse of amphetaminES, but amphetamine appears not to be among the drugs considered in the reviewed literature. From the abstract: "Ten studies compared controls to individuals who were exposed to methamphetamine. Three studies assessed individuals exposed to 3–4-methylenedioxymethamphetamine (MDMA)." The Sceptical Chymist ( talk) 04:38, 10 January 2014 (UTC)
References
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This wording seems to be too strong, considering the cautious way the results are summarized in the corresponding references:
I suggest the following re-wording of this paragraph:
The Sceptical Chymist ( talk) 13:49, 10 January 2014 (UTC)
In stark contrast for humans, literature reviews from 2013, including a meta-analysis and a systematic review, of magnetic resonance imaging studies indicate that long-term treatment of ADHD with amphetamine may decrease the abnormalities in brain structure and function in subjects with ADHD, such as an improvement in function of the right caudate nucleus.
In stark contrast for humans, literature reviews from 2013, including a meta-analysis and a systematic review, indicate that the long-term use of amphetamine at therapeutic doses for ADHD actually appears to produce beneficial changes in brain function and structure, such as an improvement in function of the right caudate nucleus.
References
"However, oral availability varies with gastrointestinal pH.[72] Amphetamine is a weak base with a pKa of 9–10;[3] consequently, when the pH is basic, more of the drug is in its lipid soluble free base form, and more is absorbed through the lipid-rich cell membranes of the gut epithelium.[3][72] Conversely, an acidic pH means the drug is predominantly in its water soluble cationic form, and less is absorbed.[3][72]"
The confusion stems from the fact that taking amphetamines with multiple grams (>10 g per day) of sodium bicarbonate (alkalyzer) or ammonium chloride (acidifier) does affect bioavailability of amphetamine. However, this is relevant only to research situations, and in practice no person would consume spoons of soda or ammonium chloride.
Next, there seem to be no evidence that large amounts of alkalizer of acidifier would change the absorption of amphetamine. It appears that they predominantly work through changing elimination (as described in he article below).
One of the strongest antacids (proton pump inhibitor) omeprazol also does not change bioavailability of amphetamine: "For MAS XR monotherapy, total amphetamine mean (SD) exposure was 36.6 (9.19) ng/mL and 640.8 (95.66) ng . h/mL; when coadministered with omeprazole it was 38.1 (7.35) ng/mL and 643.9 (143.16) ng . h/mL, for Cmax and AUCinf, respectively. The median Tmax was 5 hours and 2.75 hours without and with omeprazole, respectively; 57.1% to 61.9% of subjects receiving MAS XR and 25% receiving LDX showed an earlier (>or= 1 hour) Tmax with omeprazole" ( PMID 19820270)
And lastly, amphetamine has pKa of 9.9 according to the reference you cited; it is a strong organic base.
The Sceptical Chymist ( talk) 15:25, 16 January 2014 (UTC)
7 DRUG INTERACTIONS
7.1 Agents that Increase Blood Levels of Amphetamines
... Alkalinizing Agents
Gastrointestinal alkalinizing agents (e.g., sodium bicarbonate) increase absorption of amphetamines. Co-administration of ADDERALL XR and
gastrointestinal alkalinizing agents, such as antacids, should be avoided. Urinary alkalinizing agents (acetazolamide, some thiazides) increase the
concentration of the non-ionized species of the amphetamine molecule, thereby decreasing urinary excretion. Both groups of agents increase
blood levels and therefore potentiate the actions of amphetamines.
7.2 Agents that Lower Blood Levels of Amphetamines
Acidifying Agents
Gastrointestinal acidifying agents (e.g., guanethidine, reserpine, glutamic acid HCl, ascorbic acid) lower absorption of amphetamines. Urinary
acidifying agents (e.g., ammonium chloride, sodium acid phosphate, methenamine salts) increase the concentration of the ionized species of the
amphetamine molecule, thereby increasing urinary excretion. Both groups of agents lower blood levels and efficacy of amphetamines.
— Bottom of page 8 to the top of page 9 in the Rx info
Lead:
I will look at rest of sections as I go along. From reading lead, consider reducing verbosity. I have this problem too. When I read back over things I have written I find I can reduce the word count by about 40% through rewording, without losing any actual content. This will reduce the overall length of the article and make it more approachable for readers. The lead especially should be clear and concise (see WP:LEAD). I also noted that the images used in this article are not standardized to thumbnails. I think this is in the MOS, let me check. Lesion ( talk) 07:01, 1 December 2013 (UTC)
Does anyone agree that the lead could be a little shorter? We're currently at the maximum of four paragraphs mentioned in WP:Lead, but they're a little long (especially the first) and at times too thorough. Exercisephys ( talk) 22:58, 7 February 2014 (UTC)
I was looking for statistics like how much Amphetamine is produced/manufactured globally, legally, and an estimate of illegal production. I was unable to find this information in the article. Shouldn't this be included somewhere in the article ? -- Siddhant ( talk) 15:10, 19 February 2014 (UTC)
I think that the information presented in this article is sound; I would look more at the structure of the article. I feel that if the article was structured in more of a chronological order, it may be easier to interpret for those that don't know much about the content. Nicholas2015 ( talk) 12:57, 27 February 2014 (UTC)
@ Seppi333: I'm not trying to open old wounds here, but can you justify the continual distinction of "indirect neurotoxicity" from "direct neurotoxicity"? Also, I noticed that you used the term "indirect toxicity", which I find even further softened. I think that this phrasing is a bit of a POV-injection. Neurotoxicity is toxicity to neurons, no? I see the value in differentiating the two mechanisms, but I think that continually using the "indirect" qualifier suggests that it's less serious, or not "true" neurotoxicity. Exercisephys ( talk) 19:18, 24 February 2014 (UTC)
The section as it is basically says: low doses have a net positive cytoprotective/cytogenerative effect. High doses have a net cytotoxic effect. That seems exactly in line with what I would expect. If the compound were neurotoxic, it'd basically say low doses have a net cytotoxic effect. The page as is seems perfectly in line with clinical observations as well. Seppi333 ( Insert 2¢ | Maintained) 00:37, 25 February 2014 (UTC)
After going over my edit, all I did that could actually concern you is remove the word "systematic". I'm kind of dumbfounded that you're expressing any concern over this. Besides the fact that we don't have any evidence to cite, it's just padding. Seppi333 ( Insert 2¢ | Maintained) 00:45, 25 February 2014 (UTC)
@ Exercisephys: Look, ignoring the statistical definition, here's what those two concepts boil down to:
Water, all neurotransmitters, all minerals, all vitamins, etc are indirect neurotoxins. That 2 part definition prevents virtually every substance from being called a "neurotoxin" because the unqualified definition is literally just '"toxic" to a neuron.' Is this registering?
If you call amphetamine a neurotoxin, you can't explain to me why water isn't a neurotoxin given the way you're defining neurotoxicity. Seppi333 ( Insert 2¢ | Maintained) 04:08, 25 February 2014 (UTC)
@ Exercisephys: Defining a neurotoxin by relative toxic dose is completely arbitrary.
Hey, guys. I think there's a bug in the section-adder, as this title wasn't initially added. It's probably due to the fact that I tried to put Wikilinks in it. I'll report that.
Anyway, I guess the subject of this wasn't clear, as the facepalm of the ever respectful, dispassionate, and open-minded Seppi333 ( talk · contribs) noted.
Original post:
The toxicity section should also discuss these aspects. There's a good source here: http://link.springer.com/article/10.1007/s00204-012-0815-5/fulltext.html
If anyone needs access, let me know. Exercisephys ( talk) 15:59, 25 February 2014 (UTC)
Facepalm Seppi333 ( Insert 2¢ | Maintained) 17:18, 25 February 2014 (UTC)
Wait, I just realized that you removed the title, Seppi333 ( talk · contribs). Whydju do that? I'm just trying to improve this article, dude. Exercisephys ( talk) 16:25, 26 February 2014 (UTC)
I suggest before re-adding anything potentially controversial back into this article, we try to achieve consensus here on the talk page. I think both of you are making some good points. Toxicity is toxicity whether it is by a direct or indirect mechanism. On the other hand, toxicity is not clinically relevant if it occurs only at doses significantly higher than patents are likely to be exposed to. The key point of course is whether there are MEDRS compliant sources that would directly support a conclusion one way or the other. I am not at all familiar with the amphetamine toxicity literature. I will read through the available secondary literature and try to offer some suggestions. Boghog ( talk) 01:22, 1 March 2014 (UTC)
Seppi's response
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Bullshit
No, you just annoyed me to the point that I stopped caring about offending you by editing text you've added. You made it abundantly clear (with two sections from different occassions on my talk page) that you don't like it when I edit content you add to articles. Why did I delete a clause stating that amph and meth toxicity are indistinguishable? Because that comparison is nothing but trivia/textual padding to the 99.9% of readers that know nothing about meth addiction.
Besides the fact that I already acknowledged this months ago to WP:MED when I was a new editor, I don't see how this could possibly constitute a COI for ANY editor unless I/he/she were an addict. Perhaps you've completely missed the adverse effects and overdose sections, which are far more detailed than they were before I started working on this article.
No, I just never looked. |
Seppi333 ( Insert 2¢ | Maintained) 02:55, 1 March 2014 (UTC)
Also, Exercisephys, before you throw that source back at me, LOOK AT THE PAPERS ITS CITING WHEN IT SUGGESTS "XYZ IS NEUROTOXIC." I can't tell whether you're intentionally and knowingly trying to put POV in this article, or you just don't know any better, but I'm really running out of patience. -Seppi333
References
Neuroimaging studies have revealed that METH can indeed cause neurodegenerative changes in the brains of human addicts (Aron and Paulus, 2007; Chang et al., 2007). These abnormalities include persistent decreases in the levels of dopamine transporters (DAT) in the orbitofrontal cortex, dorsolateral prefrontal cortex, and the caudate-putamen (McCann et al., 1998, 2008; Sekine et al., 2003; Volkow et al., 2001a, 2001c). The density of serotonin transporters (5-HTT) is also decreased in the midbrain, caudate, putamen, hypothalamus, thalamus, the orbitofrontal, temporal, and cingulate cortices of METH-dependent individuals (Sekine et al., 2006) ...
Neuropsychological studies have detected deficits in attention, working memory, and decision-making in chronic METH addicts ...
There is compelling evidence that the negative neuropsychiatric consequences of METH abuse are due, at least in part, to drug-induced neuropathological changes in the brains of these METH-exposed individuals ...
Structural magnetic resonance imaging (MRI) studies in METH addicts have revealed substantial morphological changes in their brains. These include loss of gray matter in the cingulate, limbic and paralimbic cortices, significant shrinkage of hippocampi, and hypertrophy of white matter (Thompson et al., 2004). In addition, the brains of METH abusers show evidence of hyperintensities in white matter (Bae et al., 2006; Ernst et al., 2000), decreases in the neuronal marker, N-acetylaspartate (Ernst et al., 2000; Sung et al., 2007), reductions in a marker of metabolic integrity, creatine (Sekine et al., 2002) and increases in a marker of glial activation, myoinositol (Chang et al., 2002; Ernst et al., 2000; Sung et al., 2007; Yen et al., 1994). Elevated choline levels, which are indicative of increased cellular membrane synthesis and turnover are also evident in the frontal gray matter of METH abusers (Ernst et al., 2000; Salo et al., 2007; Taylor et al., 2007).
@
Exercisephys: I've been sure of it because I know that those three researchers all have an interest in various psychostimulant-related topics. I.e., I know for a fact that all three actively do research with amphetamine. Look for their publications (not the textbook) in this article if you don't believe me. Nestler in particular is purely focused on the genetic aspects of psychostimulant addiction. In any event, after I last posted, I started searching through toxicology databases for more information. I'm sure you'll be as pleased as I am after reading this:
http://projectreporter.nih.gov/project_info_description.cfm?aid=8429516&icde=0
It's oddly good timing and rather amusing that this study ended yesterday (This research started in 2009 and was initially slated to end April 2014, but was rescheduled to end Feb 28th 2014):
http://projectreporter.nih.gov/project_info_details.cfm?aid=8429516&icde=0
And lastly, this is a related paper he published on this topic in 2005:
http://jpet.aspetjournals.org/content/315/1/91.full
I'm going to email the researcher tomorrow and ask about the results ahead of any publications. His results will settle our content dispute.
Seppi333 (
Insert 2¢ |
Maintained)
06:44, 1 March 2014 (UTC)
@
Exercisephys: I'll email Drs. Nestler, Hyman, and Malenka about that statement while I'm at it.
Seppi333 (
Insert 2¢ |
Maintained)
06:52, 1 March 2014 (UTC)
Thanks @ Exercisephys: and @ Seppi333: for brining me up to speed. It seem to me that part of this dispute revolves around what exactly WP:MEDRS allows and disallows. I think everyone is in agreement that to the greatest extent possible, human studies should be cited in preference to animal or in vitro studies. However I think toxicology is a special case. For ethical reasons, humans toxicology data is generally not available (I think this and this discussion where it was proposed to modify MEDRS to specifically address toxicology is especially relevant). While animal toxicity experiments are imperfect models of human toxicity, they are often the best and only data we have. Hence I think including animal toxicology studies that are discussed in secondary sources should be allowed. Boghog ( talk) 19:45, 1 March 2014 (UTC)
After spending a stupid amount of time searching for and reading papers, I've basically discovered that there's evidence of indirect amphetamine neurotixicity in humans which is analogous, although milder, than methamphetamine neurotoxicity. What's interesting it that it only seems to manifest with cognitive dysfunction in addicts. Makes me wonder about just how deep the connection between neurotoxicity, (adverse) neuroplasticity and addiction are;† this is OR, but to give you an example of how interrelated these are, there's some clear connections in reviews, but I need to read more of the papers I spent hours sifting through and downloading before I add anything else to the article. I should emphasize that this is indirect neurotoxicity simply because therapeutic use of ADHD stimulants (incl. amph) produces the opposite histological and biomarker changes as methamphetamine neurotoxicity. (read the quote in the reflist) It DOES produce *some* of those changes in abuse conditions though, based upon what I've read so far. E.g., it can compromise the BBB through adverse effects on gene expression from heightened oxidative stress (meth apparently has a more direct impact on BBB integrity). Also can reduce gray matter volume in overdose (the reverse is evident at therapeutic doses - see the refs named "neuroplasticity" in the source). Amph sensitization also doesn't occur at therapeutic doses, which is additional evidence that it doesn't adversely affect the DA/NE neurotransmitter systems. I'm too lazy to cite specific papers, but if you're curious about a particular claim, just ask me for the ref. Seppi333 ( Insert 2¢ | Maintained) 10:50, 2 March 2014 (UTC)
@ Exercisephys:
http://www.ncbi.nlm.nih.gov/pubmed/23415394
This is very weak (and only marginally significant - p=.05) neurotoxicity given that:
Seppi333 ( Insert 2¢ | Maintained) 07:51, 5 March 2014 (UTC)
This study - PMID 17049170 - is very clearly asserting that the neurotoxic effects of amphetamine are dose-dependent above some threshold (as I've suggested since I wrote about it here), based upon their data. There's also a review, PMID 24440369, which cites it (the article/citation name itself supports the claim). Seppi333 ( Insert 2¢ | Maintained) 08:53, 5 March 2014 (UTC)
@
Exercisephys: Err...this was my bad. I thought I shared this with you like a week or two ago EP.
PMID
21886562. Added that to meth a while back. That's 1 reason it has a greater neurotoxic potential. Found another review showing detectable acute neurotoxicity in humans using large binge doses.
PMID
19897075
MPH is a sigma agonist as well. Amph has no detectable binding affinity for sigmas based upon Binding DB's data.
Seppi333 (
Insert 2¢ |
Maintained)
00:11, 24 March 2014 (UTC)
There's a plethora of clinical evidence on neuroplasticity and therapeutic ADHD psychostimulant use. I found another meta analysis to tack onto that section. Going to put it in when I expand toxicity. Busy irl lately. Seppi333 ( Insert 2¢ | Maintained) 20:04, 3 March 2014 (UTC)
Same here, to a frightening degree. I'll have some time in a few days. Exercisephys ( talk) 17:27, 5 March 2014 (UTC)Busy irl lately. - Seppi333
@ Dosenfant:, instead of edit-warring over the inclusion of this phenomenon, I'm starting this thread.
I'd be happy to give you a detailed explanation, with citation, of the toxicodynamics of amphetamine-induced serotonin toxidrome. [Edit/add: for a simple comparison, amphetamine acts analogously to an SSRI, except: it reduces postsynaptic 5-HT firing rate/action potentials (produces a less potent effect in comparison to SSRIs), but effluxes 5-HT into the synaptic cleft via PKC signaling (produces a more potent effect in comparison to SSRIs).] In any event, the relevant text from the body (not the abstract) of the paper from my recent revert is below (emphasis added):
2 Stimulants
2.1 Amphetamines
Amphetamine is the common name for the racemic mixture of b-phenylisopropylamine or a-methylphenylethylamine [11]. Substitutions of the phenylethylamine result in the creation of different amphetamine analogs, which are also described using the term ‘amphetamines’. Currently available prescription amphetamines include amphetamine, lisdexamphetamine, phentermine, phendimetrazine, and dextroamphetamine. Because lisdexamphetamine is rapidly converted to dextroamphetamine in the blood, it is reviewed in this section.
...2.1.2 Mechanism of Toxicity
The mechanism of toxicity of amphetamines is primarily related to excessive extracellular dopamine, norepinephrine, and serotonin [22, 23]. The most prominent clinical picture is alpha- and beta-adrenoreceptor-mediated sympathomimetic syndrome, with psychiatric symptoms and hyperthermia secondary to the dopamine and serotonin excess [23–26].
— Overdose of drugs for attention-deficit hyperactivity disorder: clinical presentation, mechanisms of toxicity, and management, PMID23757186
Seppi333 ( Insert 2¢ | Maintained) 17:04, 18 March 2014 (UTC)
Sigh...ok, look; I wrote that entire section, so I obviously read all these references, as I cited every review/medical source in that section ( in addition to the vast majority of the rest of the article...); I therefore know exactly what citation references each symptom. The above source asserts 5-HT overdose in a section titled "mechanisms of toxicity." I don't need anything more specific/direct to support that assertion because it's the definition of 5-ht toxicity syndrome, which is a toxic concentration of synaptic 5-ht. Seppi333 ( Insert 2¢ | Maintained) 18:58, 18 March 2014 (UTC)
Note:To keep this conversation in one place, reply at: WT:MED#WP:SYNTH on amphetamine articles
@
Shudde: Continue your review here.
Seppi333 (
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Maintained)
06:55, 24 April 2014 (UTC)
@All: I've been procrastinating - I'll make the edits to pharmacology before Friday and repost here once I'm done simplifying what I can.
@ Shudde: I'm still sort of unsure about what your concerns were with the long-term evidence review, so I was wondering if you would be willing to read the cited section excerpt and give me your thoughts on how you'd phrase it:
Quoted from pages 122-123 of the Millichap text (Link inside tab).
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The author stated that the underlined study was both multicenter and placebo controlled, which makes it higher quality evidence than the other open placebo-controlled studies.
I uploaded
this newer review which indicated more or less the same continuation of benefits from 2 studies involving ~2 years of amphetamine use (Scroll down to table 2 or search for the term "amfetamine" to get there - the paper uses the amphetamine INN); these were open, placebo-controlled trials though. Millichap also pointed out the unusually exceptional benefits beyond just a continued therapeutic effect that were observed in that multicenter trial as well.
Any thoughts/advice/suggestions on communicating this material? Seppi333 ( Insert 2¢ | Maintained) 08:43, 30 April 2014 (UTC)
I followed Boghog's advice and put the simpler and more general pharmacodynamic information first. It currently summarizes the effect it has on catecholamines and the neural pathways in acts upon in the first paragraph. I don't think I can simplify the subsequent material more than using the graphic I made to illustrate the process though. It simply requires a technical background to understand.
In any event, I'm satisfied with this section now. If you could take a look at it and give me your thoughts, I'd appreciate it.
Seppi333 (
Insert 2¢ |
Maintained)
03:19, 4 May 2014 (UTC)
Per AWB, there's now at most 2 wikilinks for any given term in the article. Seppi333 ( Insert 2¢ | Maintained) 03:39, 4 May 2014 (UTC)
@ Shudde: Can you give me some feedback on the recent changes please? Seppi333 ( Insert 2¢ | Maintained) 03:45, 4 May 2014 (UTC)
Reviews of clinical stimulant research have established the safety and effectiveness of long-term amphetamine use for ADHD. [1] [2] An evidence review noted the findings of a randomized controlled trial of amphetamine treatment for ADHD in Swedish children following 9 months of amphetamine use. [3] During treatment, the children experienced improvements in attention, disruptive behaviors, and hyperactivity, and an average change of +4.5 in IQ. [3] It noted that the population in the study had a high rate of comorbid disorders associated with ADHD and suggested that other long-term amphetamine trials in people with less associated disorders could find greater functional improvements. [3]
Reviews of clinical stimulant research have established the safety and effectiveness of long-term amphetamine use for ADHD. [1] [4] Controlled trials spanning two years have demonstrated continuous treatment effectiveness and safety. [4] [3] One review highlighted a 9 month randomized controlled trial in children that found an average increase of 4.5 in the IQ and continued improvements in attention, disruptive behaviors, and hyperactivity. [3]
References
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The main changes were the removal and addition of a review, summary of both reviews, and merging two sentences. Minor copyedits too. How's it look now? Seppi333 ( Insert 2¢ | Maintained) 10:44, 5 May 2014 (UTC)
Eh, 4.5 points is roughly 5% of the average person's IQ. Seems sizeable to me, but I'll cut it if it's that much of an issue for you. I've made changes per your suggestion - the new section is reflected in the blockquote above. A minor detail, though the reviews cover 4 trials with durations of 9, 15, 24, and 24 months. Seppi333 ( Insert 2¢ | Maintained) 12:49, 5 May 2014 (UTC)
I believe that a good addition to this article would be adding a table that that includes Amphetamine's EC50, IC50, and dissociation constant (Ki) values. I think this table should include binding to the monoamine transporters (including VMAT), and receptor affinities (since amphetamine does have very minor, but notable) at some of the adrenergic receptors and dopamine receptors. Personally, I think that would pretty much complete this article.
What does everyone else think?
SwampFox556 ( talk) 02:29, 27 April 2014 (UTC)
Anyways, I'll check through my plethora of bookmarked studies and go from there ;). Good hunting!
SwampFox556 ( talk) 01:09, 29 April 2014 (UTC)
@ Boghog: The imine intermediate in method 5 is incorrectly named (2-nitroprop-1-en-1-yl)benzene. I'm guessing that was accidentally carried over from method 4?
Since it's a primary imine, I'm pretty sure you'd just call it 1-phenylpropan-2-imine. BlackstarX ( talk) 07:35, 1 May 2014 (UTC)
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