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ADHD - links to related peer reviewed articles.

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    March 9, 2014 10:09:14 AM PDT

    Psychiatry Res. 1991 Feb;36(2):141-55.

    Methylphenidate and dextroamphetamine treatments of hyperactivity: are there true nonresponders?

    Author information

    Doses in this "double-blind crossover study" were safe and effective in children at Adderall 30 mg PO BID... 
    The FDA approved maximum dose for Adults is 40 mg PO Qday. However that is not the Standard of care according to the medical letter or UpToDate. Again, safety is the concern as neurologic abnrmalities may not occur in some until doses of up to 15000 mg.

    Abstract

    The response to stimulant drugs of 48 boys with attention deficit/hyperactivity disorder was measured following dextroamphetamine, methylphenidate, and placebo in a double-blind crossover study. To distinguish lack of behavioral improvement from adverse drug effects, a day hospital setting and a wide dose range were used. Both drugs were highly and equally efficacious for the group as a whole, and frequently one drug or the other was superior for an individual child, or adverse effects occurred only on one of the stimulants. Only one of the 48 boys (2%) was discharged without the recommendation for continued stimulant drug treatment. "Nonresponse" appears to be extremely rare when both stimulants and a wide range of doses are given.

    PMID: 2017529 

    ADHD pharmacotherapy has become a hot topic in the New York Times, and they bring up a very concerning topic regarding over diagnosis. In addition, there is a significant quantity of non-controlled studies reporting information and misinformation related to the treatment of ADHD.
    The FDA publishes reviews on various drugs by advisory committee's and reading them is very insightful. I encourage physicians and students who are interested in a medication to read the FDA's advisory committee reports in addition to peer-reviewed articles. The FDA reviews many articles and some unpublished data in their analysis, and they often produce cogent graphs, and illustrate the pharmacokinetics and pharmacodynamics of the drugs quite well.

    ADHD Drugs and Serious Cardiovascular Events in Children and Young Adults

    "This large study showed no evidence that current use of an ADHD drug was associated with an increased risk of serious cardiovascular events,"

    http://www.nejm.org/doi/full/10.1056/NEJMoa1110212

    FDA links related to ADHD and/or amphetamine or related medications.

    (1) FDA: 

    http://www.fda.gov/

    (2) ADHD Treatments: 

    http://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm283449.htm

    (3) Lisdexamfetamine or Vyvanse: 

    http://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/021977s000_MedR.pdf

    (4). Amphetamine: 

    http://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/11-522S030_Adderall_BioPharmr.pdf

    (5) Adderall XR Product Labeling: 

    http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/021303s005lbl.pdf

    Peer-reviewed articles not found on the FDA's website.

    (1) ADHD Adults:

    http://www.nejm.org/doi/full/10.1056/NEJMcp1212625
    (2) ADHD children:

    http://www.nejm.org/doi/full/10.1056/NEJMcp1307215


    This post was edited by DrSocial Admin at March 25, 2015 4:34:59 PM PDT
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    March 9, 2014 5:47:32 PM PDT

    Peer reviewed articles related to amphetamine for the treatment of several conditions. Listing does not mean that is currently a recommended therapy, but that there is peer-reviewed publications documenting its use in the conditions.

    (1a). Carotid sinus hypersensitivity: 20mg Amphetamine sulfate daily were reported to be used in two patients.

    http://www.nejm.org/doi/full/10.1056/NEJM193812292192604

    (1b) Orthostatic hypotension: 100-150mg of amphetamine daily reported in one patient. Systolic blood pressure increased from 55 to 75 in the standing position.  

    http://www.nejm.org/doi/full/10.1056/NEJM193812292192604


    This post was edited by DrSocial Admin at April 14, 2014 4:39:52 AM PDT
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    March 9, 2014 6:13:41 PM PDT

     

     

    Intentional Adderall Overdose

    Catheter Cardiovasc Interv. 2011 Nov 15;78(6):910-3. doi: 10.1002/ccd.23036. Epub 2011 May 12.
    Adderall induced inverted-Takotsubo cardiomyopathy.
    Abstract
    INTRODUCTION:

    Takotsubo Cardiomyopathy (TTC), also known as stress-induced cardiomyopathy, was initially described in Japan in 1990. Both illicit and prescription drugs have added to the growing list of insulting stressors. We describe an interesting case of atypical TTC triggered by adderall overdose.

    CLINICAL CASE:

    A 19-year-old female was brought to the Emergency Department after ingesting 30 Adderall tablets. She was complaining of pressure like chest pain and shortness of breath. Her cardiac enzymes were elevated but the electrocardiogram was unremarkable. Echocardiography identified an ejection fraction (EF) of 25-30% with severe hypokinesis of the base and a preserved apex. Cardiac angiography demonstrated normal coronary arteries with an EF of 35%, hyperkinetic apex and akinetic base consistent with the diagnosis of inverted-TTC. Her symptoms resolved in 24 hrs. Repeat echocardiogram performed 3 days later showed an EF of 60% with no regional wall motion abnormalities.

    DISCUSSION:

    TTC can be identified as a rapid development of severe and reversible left ventricular dysfunction extending beyond the territory of a single epicardial coronary artery in the absence of coronary artery disease or pheochromocytoma. Clinical presentation can be challenging and very hard to distinguish from acute myocardial infarction. Medication induced-TTC has been reported. In our case, the patient overdosed on Adderall which is a sympathomimetic medication. Cardiac imaging identified wall motion abnormalities consistent with inverted type TTC. Restoration of left ventricular function within days confirms the diagnosis of TTC. In conclusion, this case offers an interesting insight into the pathophysiology of TTC

    ====================

     http://www.ncbi.nlm.nih.gov/pubmed/21567882

    ===========================

    Placebo controlled studies suggest amphetamine not beneficial in trained athletes. Article series http://bit.ly/1am2QRh 


    This post was edited by DrSocial Admin at March 25, 2015 4:38:46 PM PDT
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    Case report of a Purdue student who died during a biochemistry exam. The student was noted to be using amphetamine prior to the exam. http://bit.ly/1846eAu 

    September 9, 1939
    COLLAPSE WITH DEATH FOLLOWING THE USE OF AMPHETAMINE SULFATE
    Lowell C. Smith, M.D.
    JAMA. 1939;113(11):1022-1023. doi:10.1001/jama.1939.72800360001010.

    This post was edited by DrSocial Admin at March 25, 2015 4:32:01 PM PDT
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    March 26, 2014 8:50:07 PM PDT

    (1) Thirty tablets of Adderall resulted in chest pain & See photo. The patient had a complete return to functional baseline after her suicide attempt. 

    (2) Sixty milligrams per day of Adderall is the Typical* Upper Limit dose recommended for adults

    This is different than the FDA approval dose. 

    (3) Generic medications are FDA required to contain only 80% of the standard dose. Thus, in addition to ADHD medications being less effective in adults, a generic tablet of 30mg of Adderall may only contain ~23 mg of "Brand Adderall." 

    (4) http://www.uptodate.com/contents/pharmacotherapy-for-adult-attention-deficit-hyperactivity-disorder

    (5) Parenthetically, the necessary dose required to cause psychosis ranged from 55mg to 15,000 mg in humans http://www.ncbi.nlm.nih.gov/pubmed/1130936

    (6) Adderall's volume of distribution varies inversely with body weight. Using the doses that are effective in children in heavier adults is probably why ADHD medications are considered less effective in adults. http://www.ncbi.nlm.nih.gov/pubmed/14599383
    (7) In the 1975 article, published in JAMA psychiatry, they mention that doses, given intravenously of up to 10mg/kg (Comparable to 700 mg of Adderall given intravenously) did not result in neurologic abnormality, except in those with pre-existing disease. http://www.ncbi.nlm.nih.gov/pubmed/1130936

    (8) The people taking amphetamine in the NEJM study from 1938 were taking 100 - 150 mg per day for orthostatic hypotension.

    (9) In 1812, NEJM first reported, in great detail aand with great accuracy, the symptoms of angina from coronary vascular disease. The 1938 article in NEJM may be considered an "old article," by many, but in reality, we have many decades of safety experience with adderall. Some children do have ischemia from Adderall and they should not receive it. 


    This post was edited by DrSocial Admin at April 14, 2014 4:40:25 AM PDT
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    March 26, 2014 8:50:10 PM PDT

     Photo reference:

     Klawans, HL; Margolin, DI (June 1975). "Amphetamine-induced dopaminergic hypersensitivity in guinea pigs. Implications in psychosis and human movement disorders.". Archives of GeneralPsychiatry 32 (6): 725–32. PMID 1130936.


    This post was edited by Brett Snodgrass at April 6, 2014 7:47:30 PM PDT
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    April 6, 2014 7:49:22 PM PDT

    This is from the Centers for Disease Control.


    This post was edited by Brett Snodgrass at April 6, 2014 10:26:41 PM PDT
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    April 6, 2014 10:23:11 PM PDT

    These are the results from a blinded study of person with #ADHD and the administration of #adderall. They were noted to lack energy, politely help others, have a diminshed capability in their studies and more findings discordant with the majority of other reports in the medical literature. The blinded portion of the study began around October 15, 2010. The last documentation for the study was 05 23 2011 and included inability to follow-through on long-term tasks. Unfortunatley, there was no example reported in this study, but the assessment is assumed to be reliable. 

    The mixed amphetamine salt extended release DECREASED anxiety #PubMed - #NCBI http://www.ncbi.nlm.nih.gov/pubmed/21432593 (Above text in caps because of highly prevalent misperception).
    This post was edited by Brett Snodgrass at April 9, 2014 8:48:53 PM PDT
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    April 9, 2014 8:50:17 PM PDT
    The mixed amphetamine salt extended release DECREASED anxiety #PubMed - #NCBI http://www.ncbi.nlm.nih.gov/pubmed/21432593 (Above text in caps because of highly prevalent misperception).

    The mixed amphetamine salt extended release (Adderall XR, Max-XR) as an adjunctive to SSRIS or SNRIS in the treatment of adult ADHD patients with comorbid partially responsive generalized anxiety: an open-label study.

    Authors
    Gabriel A.
    Journal
    Atten Defic Hyperact Disord. 2010 Jun;2(2):87-92. doi: 10.1007/s12402-010-0025-z. Epub 2010 May 4.

    Affiliation
    Abstract
    To examine the changes in partially responsive anxiety symptoms utilizing adjunctive treatment with the mixed amphetamine salt extended release (Adderall XR, MAX-XR) in the treatment of adult ADHD patients, with comorbid refractory anxiety. Consenting adult patients (n = 32) with confirmed diagnosis of generalized anxiety (GA) and comorbid (ADHD) participated in this open-label study. All patients had significant comorbid anxiety symptoms (HAM-A > 7) and failed to respond to 8-week trials of Serotonin Reuptake Inhibitors (SSRIs) or Norepinephrine Reuptake inhibitors (SNRIs). All patients were treated with the "Mixed Amphetamine salts Extended Release Adderall XR, (MAS-XR), as adjunctive to SSRIs or to SNRIs and were followed for at least 12 weeks. The primary effectiveness measure was the Clinical Global Impression severity subscale (CGI-S). Other scales included the Hamilton Anxiety Scale (HAM-A), the adult ADHD Self-Report Scale (ASRS-v1.1) symptom checklist, and Sheehan's disability scale. Baseline measures prior to the treatment with MAS-XR were compared to those at 4, 8, and at 12 weeks of treatment. Monitoring for pulse, blood pressure, and weight changes was carried out at baseline and at end point. All patients completed this open-label trial. There was significant and robust resolution of symptoms of all effectiveness measures, including the symptoms of anxiety, as shown by changes from baseline in HAM-A, ASRS-v1.1, and CGI at 8 weeks. Also there was significant reduction in the disability score at 12 weeks. Patients tolerated the treatment, and there were no significant cardiovascular changes at 12 weeks. There was decrease in mean weight at 12 weeks by 2.2 kg (P < .001). Mixed amphetamine salts MAS-XR can be used in adult patients with ADHD and comorbid anxiety symptoms. Larger controlled studies are needed to support the effectiveness of mixed amphetamine salts in patients with comorbid anxiety symptoms. Treatments need to include the targeting of the ADHD symptoms effectively in order to achieve better resolution of anxiety symptoms.
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    April 10, 2014 2:33:04 AM PDT

    Note the change in disruptive behavior in the Adderall (Adderall XR) group. Disruptive, talking fast, sending E-mail?

    http://www.ncbi.nlm.nih.gov/pubmed/10585981


    This post was edited by DrSocial Admin at April 14, 2014 4:41:03 AM PDT
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    April 10, 2014 2:33:12 AM PDT

    At therapeutic doses, such as 0.3 mg/kg BID, placebo controlled, blinded studies showed that
    there was MORE tics & worry/anxiety in the PLACEBO arm http://www.ncbi.nlm.nih.gov/pubmed/10585981


    This post was edited by DrSocial Admin at April 14, 2014 4:41:25 AM PDT
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    A nine-year-old boy was diagnosed with attentention deficit hyperactivity disorder and treated with methylphenidate for six weeks. Suddenly his skin broke out in pustule and there was no sign of infection and suberythroderma. When the patient was seen by dermatology, the boy had additionally developed severe itching, chills, and an increased teperature. 

    A presumably presumptive diagnosis of "Acute Generalized Exanthematous Pustulosis," (AGEP) was diagnosed clinically. A skin biopsy revealed intra-corneal fragmented neutrophils. 

    When the neutrophils are collected in an area, such as the stratum corneum, the term "pustule," is applied. The biopsy confirmed the presumptive clinical diagnosis, but the complete pathogenetic picture is not elucidated without additional evidence that "Ritalin did it." 

    -------

    The question remains what is the underlying pathophysiology in this case. Is methylphenidate just an innocent bystander?

    The authors (dermatologists), performed allergogolic testing. Is the patient allergic to Ritalin (methylphenidate)? 

    "The LTT was performed with the pure substance
    from the Ritalin capsule 8 weeks after the reaction
    and discontinuation of drug intake. It showed a
    clear proliferation with dose-related stimulation indices
    of up to 10.1 at 10 μg/mL of methylphenidate hydrochloride
    (normal cutoff, 2) (Table). In 3 control subjects
    exposed to methylphenidate for more than a year
    without any history of drug reaction, the LTT did not
    show any substantial proliferation.

    Comment. Acute generalized exanthematous pustulosis
    is a T-cell–dependent, type IV drug reaction induced
    by antibiotics, anticonvulsants, and nonsteroidal antiinflammatory
    drugs"

    http://www.ncbi.nlm.nih.gov/pubmed/21768498

    T-cell receptors are reported as stimulated directly by the drug "methylphenidate," (Ritalin), and this induces secretion of cytokines and increased inflammation. 

    --------------------------------------------------------------

    http://onlinelibrary.wiley.com/doi/10.1111/j.1398-9995.2004.00547.x/pdf

    "

    T-cell recognition of drugs
    T cells are able to be stimulated by small chemicals such
    as drugs. As drugs were considered to be too small to be
    immunogenic per se, immunogenicity was thought to
    rely on their ability to bind to larger molecules-like
    proteins or peptides (1–4, 14). This implies that the drug
    acts like a hapten and binds covalently to a peptide or
    protein, which makes it immunogenic. For a long time it
    was a enigma and the main reason for a certain
    scepticism against the LTT that a chemical inert drug,
    unable to act as hapten, cannot stimulate T cells in a
    specific way. Thus, positive reactions were seen as an
    in vitro artefact because of some stimulatory action by
    the drug. However, this could not explain that the drug
    was only stimulatory in certain patients. Moreover,
    newer findings proved that the LTT detects drug-
    specific T cells:
    • Persons tolerating the drug do norm"


    This post was edited by DrSocial Admin at March 25, 2015 4:40:01 PM PDT
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    April 10, 2014 2:33:28 AM PDT

    1% amphetamine sulfate was previously used as a nasal spray 

    The mother of a girl 20 months was being treated with a 1 per cent amphetamine sulfate solution used as a nasal spray. There was no caution on the label that this might be toxic if taken internally.

    At 3:30 p. m., before the parents realized what was happening , the child had worked off the top of the container and had drunk a quantity of the contents of the bottle. 

    The child became restless and recovered within 1 day with supportive measures including intravenous fluids. 

    August 7, 1943, Vol 122, No. 15 >
    ARTICLE | August 7, 1943
    AMPHETAMINE SULFATE POISONING IN A CHILD OF TWENTY MONTHS
    Harold A. Rosenbaum, M.D.
    JAMA. 1943;122(15):1011. doi:10.1001/jama.1943.72840320001008.


    This post was edited by DrSocial Admin at March 25, 2015 4:40:52 PM PDT
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    Mixed effects of amphetamine on performance. 
    20 mg Amphetamine sulfate Helped
    1. Running
        1a) Improve running 3 kilometers in fatigued soliders. (Faster than when not fatigured with  
              amphetamine). It is not specified whether this reached a p<0.05.
        1b) Fatigued soliders who did the repeat run for comparison to before fatigue, were slower. Makes sense, they run  3Km --> then work hard for two days with little sleep --> then run the course again, ---> slower than before 
    2. Reading - Bourdon Test
         2a. Improved reading rapidity 
         2b. Improved reading accuracy
    3. Math performance: 
        3a. Well rested soldiers: worse performance, especially with respect to more complex
                     math probems.
        3b. Fatigued soliders: 
                 3bi.  Improved performance with amphetamine in the morning. 
                 3bii. No Change in math performance with amphetamine in afternoon.
    EFFECT OF AMPHETAMINE SULFATE ON PHYSICAL AND PSYCHIC PERFORMANCE  
    In Alwall's experiments1 large groups of soldiers were thoroughly fatigued by two or three nights of marching and exercises during the intervening one or two days, with little opportunity to sleep. In the course of the experiment the men marched 125 kilometers over a partly swampy ground with the temperature of the air being about 41 F. The men slept on an average three and one-fifth hours in the course of the entire experiment. On the termination of the fatigue exercises some of the men were given tablets containing 20 mg. of amphetamine sulfate, while others were given placebo tablets. Two and one-half hours later both groups were made to run 3 kilometers. Compared with the initial record established by the two groups just before they were subjected to the fatigue experiment, the postfatigue 3 kilometers
    Other Articles | December 16, 1944
    Current Comment
    JAMA. 1944;126(16):1031-1032. doi:10.1001/jama.1944.02850510039012.

    This post was edited by DrSocial Admin at March 25, 2015 4:42:41 PM PDT
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    May 4, 2014 6:35:57 PM PDT

    According to placebo controlled trials, the amount of "worry," (1 study), and the amount of "anxiety," experienced by persons with [ADHD &  who received treatment with Adderall XR was 

    A. More 

    B. Less

    C. Equal 

    to that of those without adderall? 

    Ans:  B

    ------------------------

    Classification of Anxiety disorders pers the DSMVAnxiety disorders per DSMV


    This post was edited by DrSocial Admin at April 6, 2015 6:39:07 AM PDT
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    May 4, 2014 6:36:15 PM PDT
    Although the enzymes involved in amphetamine metabolism have not been clearly defined, CYP2D6 is known to be involved with formation of 4-hydroxy-amphetamine. Since CYP2D6 is genetically polymorphic, population variations in amphetamine metabolism are a possibility.

    Drugs.com

    EricTopol says individualized, aka personalized medicine is coming. Indeed it is already here, but this is relevant.
    This post was edited by Brett Snodgrass at June 3, 2014 7:17:14 PM PDT
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    May 4, 2014 6:36:59 PM PDT

    This space is reserved for neuropsychological testing in both ADHD and ADD. 

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    May 4, 2014 6:38:33 PM PDT
    Amphetamine Adderall decreased addiction
    Other Articles | June 3, 1939

    AMPHETAMINE IN CHRONIC ALCOHOLISM

    Tracy J. Putnam, M.D.
    JAMA. 1939;112(22):2346. doi:10.1001/jama.1939.02800220112025.

     

    To the Editor:—  The reply which recently appeared in Queries and Minor Notes to a letter relative to the use of amphetamine (benzedrine) in the treatment of chronic alcoholism as recommended by Dr. Wilfred Bloomberg might easily give rise to a regrettable misunderstanding. Dr. Bloomberg made the suggestion only after long experience with the drug in other conditions, for he (with Prinzmetal) was the first to report its effectiveness in the treatment of narcolepsy. He has further, in preparation, a detailed study of the effects of large doses given over a period of three years to some of his early patients and a careful survey of all the cases in which ill effects are reported to have followed the use of the drug. This study has led him to the belief that its use under medical supervision is entirely justified when dealing with such serious diseases as narcolepsy and chronic



    http://jama.jamanetwork.com/article.aspx?articleid=289190&


    This post was edited by DrSocial Admin at April 6, 2015 6:40:49 AM PDT
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    May 4, 2014 6:41:02 PM PDT

    Subsequent study. Please note that this forum is not a peer-reviewed journal that is indexed by pubmed. In time, however it is public and comments and suggestions are welcome.

    In addition, we link to multiple peer-reviewed publications. 

    Amphetamine is not working very well for the treatment of alcoholism. Indeed, nothing is working well for the treatment thereof, and the data is not robust enough, nor the methods sufficiently described to compare to the current studies, such as the recent trial reported by JAMA.Amphetamine Woefully inadequate for Alcoholism


    This post was edited by DrSocial Admin at March 25, 2015 4:44:51 PM PDT
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    May 4, 2014 6:42:02 PM PDT

    Space reserved for peer-reviewed literature, not (expert opinion), for expert opinion, without careful analysis of the study methods used in the clinical trials and literature, is probably more consistent with Eminence-based medicine. 

    There is an idiom: "The devil is in the details," and this idiom emphasizes the importance of finding data, studies, analyzing their methods, looking for bias, etc, when evaluating peer-reviewed literature. 

    Space is reserved for peer-reviewed literature, not what the text book says.


    This post was edited by DrSocial Admin at March 25, 2015 4:33:53 PM PDT
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    May 4, 2014 6:54:44 PM PDT

    Amphetamine sulfate has been shown to cause an atopic dermatitis-like skin eruption. Amphetamine atopic dermatitis

    http://jama.jamanetwork.com/article.aspx?articleid=263886 Toxic Eruption Due to Amphetamine Sulfate JAMA. 1943;123(3):161. doi:10.1001/jama.1943.02840380037015. September 18, 1943

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    May 4, 2014 11:03:04 PM PDT

    Photo reference:

    Klawans, HL; Margolin, DI (June 1975). "Amphetamine-induced dopaminergic hypersensitivity in guinea pigs. Implications in psychosis and human movement disorders.". Archives of GeneralPsychiatry 32 (6): 725–32. PMID 1130936.

     

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    • Moderator
    • 1955 posts
    May 25, 2014 4:25:28 PM PDT

    Here is another article on alcoholism from pubmed central 

     

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1634168/bin/calwestmed00304-0050.tifChronic Alcoholism PubMed Central

    • 445 posts
    March 25, 2015 4:30:38 PM PDT

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