Talk:Methylphenidate

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Article milestones Date Process Result January 27, 2010 Featured article candidate Not promoted

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Addiction and dependence are not signs of an overdose. Thus should not be a subheading of that. Doc James (talk · contribs · email) 05:53, 17 May 2019 (UTC)[reply]

In fact abuse and dependence are block box warnings. We include these under side effects generally.[1] Doc James (talk · contribs · email) 05:59, 17 May 2019 (UTC)[reply]

The original placement under the overdose heading was compliant with MOS:MED#Drugs, treatments, and devices. It is, therefore, acceptable. Also, the only reason that adverse effects is listed as a potential location for that section is that some drugs - and by some drugs I mean opiates (addiction and dependence) and benzos (dependence) - produce one or both of addiction and dependence at commonly prescribed doses for certain conditions (opiate addiction is really only a possibility in the case of end of life care though). I know for certain that this was the intended approach based upon the sectioning specified in the MOS because I'm the one who proposed listing "Adverse effects" and "Overdose" as potential locations for that subsection in the MOS way back when. Therefore, I'm moving it back.

The black box warning doesn't specify how methylphenidate addiction develops; don't read into something that's not there. Seppi333 (Insert 2¢) 06:06, 17 May 2019 (UTC)[reply]

No it does not make sense. Overdose is not simple just excessive usage. And actually placing under "Side effects" was fully compliant with WP:MEDMOS Doc James (talk · contribs · email) 06:32, 17 May 2019 (UTC)[reply]

First ref says "Our findings suggest that methylphenidate may be associated with a number of serious adverse events as well as a large number of non-serious adverse events in children "[3]

Second ref says "the low quality of the underpinning evidence means that we cannot be certain of the magnitude of the effects."[4]

The text was supported. Doc James (talk · contribs · email) 11:40, 1 November 2019 (UTC)[reply]

I've been made aware of a medication called Jornay PM (Methylphenidate HCl). It looks like an extended-release form of Methylphenidate but patients take it at night. It has FDA approval and is currently available in the US. Does it belong as a mention in Extended-release section? I'd add it myself but I'm having trouble finding the right references for how long it lasts and if it's available outside the US, etc. Wirewad (talk) 18:13, 5 December 2019 (UTC)[reply]

I can't find anyone summing it up with a single number or range, either. The chart on their FDA efficacy paperwork suggests a 12-hour active period (following the 8-10 hour delayed release) and their description of the active effect includes phrasing like "from morning until bedtime," but they don't interpret the chart for us. https://www.ironshorepharma.com/labeling.pdf

However, they do indicate that dosing can be increased to ensure that the medication remains effective until the end of the day. https://www.jornaypm-pro.com/dosing

Additionally, a review of the medication in Pharmacy Times suggests that Jornay PM takes advantage of existing ER technology, and that the innovation is simply the pairing of that with existing DR technology (delayed/extended release). So, it would be reasonable to assume that the ER piece of this is basically the same as other ER meds, and put down 8-12 hours as a broad range accounting for 2 standard deviations (or more) from the mean. https://www.pharmacytimes.com/view/stimulant-medication-with-evening-dosing-to-address-earlymorning-functioning-impairments-in-adhd

Regardless, Jornay PM is a very notable addition to existing options. I hope someone adds it to the page, even if they feel compelled to leave some of the sections on the table blank or simply quote the manufacture saying "all day" (or whatever exact phrasing) instead of putting a number. It's a shame to not see it here. 162.129.250.22 (talk) 16:58, 18 April 2022 (UTC)[reply]

Ref says "Stimulant medications cause a modest increase in average blood pressure (about 2-4 mmHg) and average heart rate (about 3-6 bpm), and individuals may have larger increases... Cardiac: angina, arrhythmia, palpitations, pulse increased or decreased, tachycardia"

Doc James (talk · contribs · email) 10:27, 29 January 2020 (UTC)[reply]

Support the 2019 proposal to merge to brand Daytrana to the generic name for the drug. Klbrain (talk) 17:34, 18 April 2020 (UTC)[reply]

• Support merge to generic. Doc James (talk · contribs · email) 23:32, 18 April 2020 (UTC)[reply]

Done Doc James (talk · contribs · email) 07:06, 21 May 2020 (UTC)[reply]

I am not able to contribute professional knowledge to this article, but I would like to share some personal experience. Methylphenidate was a psychiatric "magic bullet" for me. After decades of crippling clinical depression, my current psychiatric care provider (the most recent in a series of at least six) suggested it. The improvement in my symptoms was immediate, intense, and lasting. I had run through the gamut of conventional depression treatments prior to this, including ECT, with no relief, and did not know that methylphenidate was an option. I suspect that many of my former providers did not know either, or considered it a last resort.

If someone could expand this section and include some links to academic or medical sources it would be of enormous value to other people who are struggling with treatment-resistant depression. It is difficult as a layman or patient to find information about this use of methylphenidate, and heathcare providers seem to be gun-shy about recommending it. 216.30.159.93 (talk) 23:38, 11 September 2020 (UTC)[reply]

depression treatment usually depends on monoamine theory. SSRI or other antidepressants(except atypicals and maoi's) increase monoamines but mostly serotonin basicly. Atypical depression and ADHD related depression (and some other types of depression) can be reversed by stimulants because of their distinct mechanism. But as a dopamine reuptake inhibitor methylphenidate mostly treats fatigue and anhedonia associated with depression or other medical conditions. my situation is same with you. ssri's can make depression worse if depression associated with other conditions. primary depression is more type of "melancholy" rather than "just anhedonia". but there is also some types of depression that depend on anhedonia but they respond ssri/snri's unlike those with ADHD. RoyaleKingdom78 (talk) 12:19, 9 December 2021 (UTC)[reply]

Adding some sources. The prescriber’s guide to classic MAO inhibitors (phenelzine, tranylcypromine, isocarboxazid) for treatment-resistant depression and MAOIs and CNS Stimulants

Currently it is: "It is not a Cocaine derivate nor analogue. Cocaine is analgesic and ligand channel blocker with SNDRI action while Methylphenidate is NDRI with 2-3 fold DAT selectivity over NET. Cocaine also more potent in SERT rather than NDRI site. [7]"

But it should be as follows: It is not a Cocaine derivate nor an analog. Cocaine is an analgesic and ligand channel blocker with SNDRI action while Methylphenidate is an NDRI with 2-3 fold DAT selectivity over NET. Cocaine is also more potent in SERT rather than NDRI sites. [7]"

(First time posting on wiki hope I did it right)

I noticed that too, upon a first reading of the article. I made the corrections that you suggested. Thank you! And yes, you posted correctly here on the talk page!--FeralOink (talk) 12:54, 2 January 2022 (UTC)[reply]

Not exactly "grammar", but in the Available Forms/Extended Release section, "Metadate ER" and "Methylin ER" are brand names, but appear in the Generic Names column.

This sentence under Other medical uses, "However, the use of stimulants such as methylphenidate in cases of treatment-resistant depression is controversial.[42]", references a journal article from 1992.

Kraus MF, Burch EA (October 1992). "Methylphenidate hydrochloride as an antidepressant: controversy, case studies, and review". Southern Medical Journal. 85 (10): 985–991. doi:10.1097/00007611-199210000-00012. PMID 1411740

30 years later, it's relatively common to use Methylphenidate to augment other medications in treatment-resistant depression. Therefore, I believe that either this sentence needs to be reevaluated for whether it's necessary, and/or more recent references are needed to back up this claim. Alteredtome (talk) 04:14, 12 April 2022 (UTC)[reply]

To all who contributed to writing this Article, all I can say is might just be the best article I’ve read on the entire site. Which is thousands so it’s saying a lot for me. Well done. 2601:644:8F83:D7A0:79B2:28C7:ECD2:4397 (talk) 01:08, 1 October 2022 (UTC)[reply]

Firstly this article reads in parts like an advert instead of a normal article on substances. Secondly, the delphic analyis which includes police and legal services is not useful in estimating addictive, deadly, or dangerous potential, rather it can only indicate attitudes instead of expert opinion due to the inclusion of police. Given that the police involved in this study are engaged in a drug war which generally treats pharmaceuticals as arbitrarily less dangerous, it's an obvious bias. This diagramm is misleading and should be deleted as should references to it. 77.188.117.198 (talk) 16:21, 23 January 2023 (UTC)[reply]

Are bupropion and methylphenidate TAAR-active? Requesting binding profile. --0dorkmann (talk) 08:16, 11 February 2023 (UTC)[reply]

No. Here is the relevant discussion from Dr. Faraone in 2018;

“The direct effects of MPH include inhibition of the DAT and NET (113, 114, 118, 120, 123, 128), an affinity for and agonist activity at the 5-HT_1A receptor (119, 120), and redistribution of VMAT-2 (88, 125). As a consequence of these interactions, MPH elevates extracellular DA and NE levels (58, 71, 94, 107). The enhanced efflux of DA and NE associated with MPH exposure results in increased availability of DA and NE to bind to their respective transporters (ie, the DAT or NET) or to DA or NE receptors, as evidenced by reductions in ligand binding in PET and SPECT studies (112, 113, 117, 122-124, 127).

Although increases in extracellular levels of striatal DA in rats measured using microdialysis are less pronounced with MPH than with AMP, both compounds have been shown to exhibit similar magnitude of effects with regard to reductions in DA binding potential as measured by PET in rodents and nonhuman primates (94). Multiple studies have demonstrated that MPH also directly interacts with adrenergic receptors (109, 115, 119, 120). Through activation of α₂adrenergic receptors, MPH has been demonstrated to stimulate cortical excitability (109). Further evidence for the interaction of MPH with α₂ adrenergic receptors comes from data indicating that the procognitive effects of MPH in a working memory task are blocked by the α₂ adrenergic antagonist idazoxan (115). The effects of MPH on α₂ adrenergic receptors are notable given that two α₂ adrenergic receptor agonist drugs (extended-release forms of guanfacine and clonidine) are indicated for the treatment of ADHD (196)”.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063758/ JoeBo82 (talk) 01:58, 8 July 2023 (UTC)[reply]

To me it seems superfluous and it might be found confusing to readers. Gutten på Hemsen (talk) 15:59, 15 April 2023 (UTC)[reply]

From Adverse Effects:

"Ophthalmologic adverse effects may include blurred vision caused by pupil dilatation and dry eyes, with less frequent reports of diplopia and mydriasis"

This seems to be saying that mydriasis is less common than dilated pupils. These terms are synonymous. Is this a syntactical issue I'm missing or is it contradictory? his seems to be saying that dilated pupils are less common than 2603:7081:1603:A300:2CC4:A198:82DB:C8BF (talk) 02:44, 28 September 2023 (UTC)[reply]

"In children over age 6 and adolescents, the short-term benefits and cost-effectiveness of methylphenidate are well established. A number of reviews have established the safety and effectiveness for individuals with ADHD over several years." Several narrative reviews, the newest of which is 12 years old, are cited in support of this passage. By contrast, a recent Cochrane review concludes that the quality of randomized controlled trials of methylphenidate is too poor to make conclusions about the effectiveness or harms of methylphenidate. This review is actually cited a paragraph below. It seems strange to leave up these contradictory statements. I would suggest that more information about the conclusions of the Cochrane review be included and the older text deleted. Feline negativity (talk) 18:12, 4 November 2023 (UTC)[reply]

Methylphenidate and amphetamines are still first-line treatment for ADHD so I don't think nothing's changed since that source. Not sure why you want a latest source when the scientific fact do not change/update. --WikiLinuz (talk) 05:45, 12 February 2024 (UTC)[reply]

WP:OLDSOURCES applies when newer evidence falsifies the older facts from the old source (but this doesn't seem to be the case here, unless I misunderstood what you mean). --WikiLinuz (talk) 05:48, 12 February 2024 (UTC)[reply]

The majority of the claims made in the two paragraphs removed are based on research from the early 2000s, in flawed (narrative) reviews which typically did not bother to review to quality of the trials on which they were based. Three separate Cochrane reviews of methylphenidate, by three different research groups, have found that the quality of the RCT evidence base is too poor to draw conclusions regarding the safety and efficacy of methylphenidate in the treatment of ADHD.

The same conclusion has been reached by the WHO Essential Medicines Committee, which has twice rejected methylphenidate from the list on the same grounds: namely, that safety, efficacy, and the harm-benefit ratio have not been adequately established. It therefore seems to me that the information on the page is indeed outdated, as it has been contradicted by newer, high-quality reviews. Why would outdated information from uncritical reviews be preferred to the reports of recent Cochrane systematic reviews, which have been supported by a WHO Committee? I believe it is Wikipedia policy to prefer the highest-quality recent systematic reviews on a medical topic. Feline negativity (talk) 22:17, 12 February 2024 (UTC)[reply]

I disagree with your removal of the two paragraphs in question. I am interpreting/reformulating your primary argument against the paragraphs and their sources as follows: "The sources cited are narrative reviews from over a decade ago that do not take into account the quality of the available evidence; more recent systematic reviews are superior in this aspect, and because the two source groups and their associated claims contradict each other, the more critical recent reviews should be given WP:DUEWEIGHT over the older ones." Is this an accurate representation of your argument?

Assuming it is, I have multiple issues with it. First of all, there are recent systematic reviews that take into account the evidence quality and nonetheless come to the conclusion that methylphenidate is an effective ADHD treatment (Cortese et al. 2018 Taking into account both efficacy and safety, evidence from this meta-analysis supports methylphenidate in children and adolescents...for the short-term treatment of ADHD, Elliott et al. 2020 Overall, we found that ADHD pharmacotherapies, as a class, improved clinical response relative to placebo; although the latter does not specifically state that specifically methylphenidate is effective, it was one of the medications looked at in the analysis). This suggests that it's a matter of disagreement between the sources on what conclusions can be made with the evidence, not which evidence was available (unless there was a drastic shift in available evidence in those few years between these sources and yours) nor whether the evidence quality was analyzed; in other words, different sources had mostly the same evidence, analyzed it in mostly the same way, and came to different conclusions on what could be said about the effectiveness of methylphenidate.

Second, the non-inclusion of a medication in the list of WHO essential medicines doesn't say much about whether a medication is effective or not; for the version of the list where it was rejected in the source you cite, only 460 medications made it onto the list at all (and even today it has just 591). The clue is in the name: only the most essential medicines for the most important needs of a healthcare system are included. Plenty of safe and effective medications aren't included, and this is by design. I don't have the full text, but from what I can tell about the WHO source, it is not a systematic review; this is fine, but by that token recent narrative reviews and clinical practice guidelines could be cited as well.

Thirdly, you seem to be implying either that there is a contradiction between the newer sources and the older paragraphs, that the claims of the newer sources are not given sufficient weight/coverage in the article, or both (correct me if I'm wrong though). As I understand it, the core issue of the newer sources – what they primarily dispute – is not the existence of such evidence but the quality of the evidence (see my first point). It's clear there is an effect, but as our article states itself (citing one of the newer critical sources): "[t]he precise magnitude of improvement in ADHD symptoms and quality of life produced by methylphenidate treatment remains uncertain" [emphasis mine]. The effect size and evidence quality are the two main loci of scientific debate. That's what those sources have investigated, and that's what's already in the article.

The problems with the two removed paragraphs are ultimately solvable with the use of more recent sources. On the other hand, their removal appears to slant the article's coverage away from the mainstream academic consensus regarding the effectiveness of ADHD medications. Coolclawcat (talk) 11:11, 13 February 2024 (UTC)[reply]

Thanks for your comments. I believe that the use of narrative reviews from the early 2000s is problematic (unfortunately they seem to be all over Wikipedia), as they were often written before journals had stringent COI policies, before peer-reviewers were well versed in the techniques of EBM, and before there was a widespread knowledge of the deeply flawed nature of many industry-sponsored drug trials. (Eminent medical historian Edward Shorter has described this period as the nadir of the corruption of academic medicine by industry.) I think that the language in the removed paragraphs was heavily promotional, based on an uncritical appraisal of the literature, and that the paragraphs should be replaced with similar information from newer and superior sources.

There is indeed another major recent systematic review on the topic, Cortese et al, which drew conclusions opposed to the review of Storebø et al. The crux of the matter is how the quality and risk of bias of the included trials are assessed. The two research groups behind the reviews have been going back and forth quarreling over which of them is doing this correctly for around 8 years now. This article has citations to all or most of their commentary on the Storebø review, and here are critical letters on Cortese's. Ultimately I believe Storebø's review is to be preferred, although a note about the controversy would certainly be warranted. Storebø et al. is more recent, underwent a very extensive peer-review for inclusion in the Cochrane Library, and was explicitly preferred by the Expert Committee and the peer-reviewers for the WHO, who received both meta-analyses for review. It is certainly true that methylphenidate doesn't have to be an "essential medicine" to be an effective one, but look at the commentary of the WHO as to why it was rejected: because the poor quality of the trials makes the efficacy, safety, and cost-effectiveness of methylphenidate unclear. Obviously this is not what the article had previously said: the section opened with very strong and positive assertions about the effects of methylphenidate, and relegated the assessment of the Cochrane review and the WHO to the role of a minor quibble, rather than calling into doubt the evidence base on which the preceding claims were made. Feline negativity (talk) 20:38, 13 February 2024 (UTC)[reply]

There is an interesting discussion of the WHO's decision and rationale in the pages of this month's Lancet Psychiatry. It is another point in Storebø's favor, in my view, that the authors do not have conflicts of interest, whereas many of the authors on the Cortese review and on the critical commentaries on Storebø have very extensive financial ties to industry, which has been shown to be a significant issue, including in systematic reviews. There is a useful review I have found of the issues involved in the dispute, which could provide some background for discussion here and could also be worth citing in the main article. Feline negativity (talk) 23:54, 13 February 2024 (UTC)[reply]

I've had the time now to take a look at the other systematic review you brought up, Elliott et al. This review actually extensively raises very similar concerns with regard to risk of bias as the Cochrane reviews of methylphenidate in adults by Cândido et al. and Boesen et al. The sentence you quote from the Discussion section continues, "however, the clinical importance of these changes is unclear, and when the analyses were restricted to studies at low risk of bias due to blinding, there was no significant difference between ADHD pharmacotherapy and placebo in the meta-analysis, and few differences were evident in the network meta-analyses...the certainty of the findings for all outcomes was very low to low." In Table 3 you can see that Elliott et al. have classified all the evidence for the various outcomes with methylphenidate as being of "very low" quality. It is perhaps worth noting that a previous Cochrane review on methylphenidate in adults was retracted for, amongst other reasons, an inadequate assessment of bias in the literature. Feline negativity (talk) 06:39, 14 February 2024 (UTC)[reply]

agree w/ Feline negativity--Ozzie10aaaa (talk) 13:57, 15 February 2024 (UTC)[reply]

Methylphenidate and MAOIs are perfectly safe to use concomitantly, despite common dogma to the contrary. MPH is not a releaser of norepinephrine unlike DEX and especially mixed AMP salts (due to the presence of levoamphetamines which have strong peripheral effects). There is virtually no risk of precipitating a hypertensive crisis if titrated/managed properly. The prescriber’s guide to classic MAO inhibitors (phenelzine, tranylcypromine, isocarboxazid) for treatment-resistant depression and MAOIs and CNS Stimulants 206.194.253.145 (talk) 04:44, 21 January 2024 (UTC)[reply]

Background

This article cites update of the controversial 2015 analysis by Storebø et al, who claim there is "very low" level of certainty about evidence that methylphenidate is safe and efficacious for reducing symptoms of ADHD. Together with the controversial 2021 meta-analysis by Golder & Junqueria, it is claimed "clinicians should consider whether it is appropriate to prescribe IR methylphenidate, given its limited efficacy and increased risk of harms". The article also cites a committee's decision to repeatedly exclude methylphenidate for ADHD from the WHO’s list of essential medicines for children, based on the above 2015 analysis. The committee responsible for this decision rejected an application by scientists for inclusion in 2019, and a second application backed by 51 professional groups in 2021; with further discourse occurring in 2024.

Such citations are evidently selective as they are well-refuted, flawed and omit crucial context. As a result, I feel a consensus needs to be reached on balancing the scientific information on this article.

The Evidence

Relying on Storebø and colleagues evaluation of research and clinical relevance is problematic for several reasons. That meta-analysis is flawed due to its idiosyncratic application of the Cochrane risk of bias tool and systematic errors, such as inappropriate study inclusion, incorrect downgrading of evidence based on the GRADE system, and incorrect data imputation. Their conclusions that the status of the evidence is uncertain is misplaced. For further details, see Banaschewski et al. (2016), Cortese et al. (2016), Hoekstra et al. (2016), Romanos et al (2017a) and Faraone et al. (2024).

Scientists are in global consensus that the results from randomised controlled clinical trials are clear: methylphenidate is not only safe and efficacious, it is among the most efficacious drugs in all of medicine. For references, see the International Consensus Statement on ADHD.

Additionally, all prior 15 systematic meta-analyses and reviews to the 2015 analysis, including the meta-analyses conducted by the National Institute of Clinical Excellence (NICE), unanimously report effect sizes between 0.8–1 for the efficacy of methylphenidate in terms of reducing the core symptoms of ADHD in children and adolescents of moderate to high quality, compared to the "very low quality" in Storebo and colleagues controversial analysis. For references, see Banaschewski et al.

Safety and efficacy data have been reviewed extensively by medical regulators (e.g., the US Food and Drug Administration and the European Medicines Agency), the developers of evidence-based national guidelines (e.g., the UK National Institute for Health and Care Excellence and the American Academy of Pediatrics), and government agencies who have endorsed these guidelines (e.g., the Australian National Health and Medical Research Council). These professional groups all conclude, based on the scientific evidence, that methylphenidate is safe and effective and should be considered as a first-line treatment for ADHD.

The European ADHD Guidelines Group (EAGG) meta-analysis of RCTs of ADHD across the lifespan (Cortese et al., 2018) is based on a more advanced and precise meta-analytic method (network meta-analysis) compared with the standard approach (pairwise) used by Storebø and colleagues. This meta-analysis represents the most comprehensive evidence-base available, as it and the International Consensus Statement on ADHD (September 2021-2024) concluded. These show that considering all the included outcomes related to efficacy/safety, methylphenidate should be considered the first line pharmacological option for ADHD in children and adolescents. In Cortese et al.’s meta-analysis, the quality of the evidence of the RCTs on methylphenidate on the primary outcome (clinicians rating) was judged as moderate, as opposed to the very low quality of evidence reported by Storebø and colleagues. This difference stems from three primary sources. First, Storebø et al.’s use of the GRADE system for rating risk of bias deviates from established practice and guidelines. For example, they rated overall study bias as ‘high risk’ if only one item was uncertain. Guidelines for rating quality define ‘high risk’ if one item clearly indicates a high risk of bias, and this procedure was followed in Cortese et al and other systematic reviews and meta-analyses. Second, the rating of the quality of the evidence is based on the information available to the researchers who perform the rating. Cortese et al. gathered unpublished data after systematically contacting study authors and drug manufacturers. After including this information, which was not available to Storebø et al., the overall number of uncertain quality items across all items of the Risk of Bias decreased from 63.5% to 35.2%. Third, Storebø and colleagues make many gross systematic errors and misinterpretations as indicated by the citations cited above, thus (in addition to the above) disproving their results.

As for the committee, their decisions and claims are not consistent with the evidence and global scientific consensus, diverges from WHO’s own established guidelines/recommendations and stands in stark contrast to the decisions of many regulatory agencies and professional groups around the world. Although WHO has not yet agreed to include methylphenidate on the EML, they do paradoxically to this committee's claims support the use of methylphenidate as an acceptable and effective treatment for ADHD, including in non-specialist settings within low-income and middle-income countries. The 2023 WHO Mental Health Gap Action Programme guidelines for mental, neurological, and substance use disorders makes a clear recommendation that methylphenidate should be considered for children aged 6 years and older who have ADHD, noting specifically that, “methylphenidate treatment shows substantial effects on symptom reduction”9 - showing that this committee's claims are in spark contrast to WHO's own established guidelines and recommendations. Thus the committee responsible for excluding methylphenidate from WHO's Model list of Essential Medicines for ADHD no longer represents WHO since their most recent guidelines and recommendations disagree with their claims.

The committee responsible for the decision to exclude methylphenidate cited the disproven 2015 analysis by Storebo et al and cited the short duration of most supporting randomised controlled trials (RCTs) and indicated that an RCT of 52 weeks would be needed to support methylphenidate's inclusion. This requirement is perplexing, given the fact that WHO does not require long-term efficacy and safety data from RCTs for other medications in the EML. Because long term RCTs are not ethical, scientists rely on large, naturalistic population registry studies to assess longer term functional outcomes. These show that methylphenidate treatment for ADHD significantly reduces or even eliminates the elevated risks for obesity, accidental injuries, traumatic brain injury, substance abuse, cigarette smoking, educational underachievement, bone fractures, sexually transmitted infections, depression, suicide, criminal activity and teenage pregnancy, among others.ICS Their claim that there is no strong evidence for the long-term effectiveness of methylphenidate also ignores data from relapse prevention studies, which demonstrate the persistence of clinically meaningful benefits for people with ADHD with continued long-term methylphenidate treatment.Flore et al. (2019). As for their claims about tolerance being significant, the most comprehensive review of the topic (2022) found tolerance rate of 24.7% in a clinical study of days-weeks, and 2.7% over the course of 10 years in another. Although it concludes that tolerance exists, it is typically manageable, the rate is small and the data regarding actual physiologic tolerance is weak at best.Handelman et al. (2022)

Lastly, I want to attest that a crucial perspective missing from the article is the voice of people with lived experience of ADHD. Listening to what those with lived experience are saying is essential for evaluating evidence and determining policy. When preparing the latest WHO EML application and further, over 51 large lived-experience professional organisations and associations across the world endorsed the application and efforts in addition to the entire scientific community. These are unanimous in recognising the crucial role methylphenidate has in improving the lives of people with ADHD, and supporting inclusion of methylphenidate in the EML. We cannot ignore their message.

Further evidence

Long-term meta-analyses and systematic reviews, as summarised in the International Consensus Statement on ADHD7, show that the medications used to treat ADHD are not associated with observed deficits in brain structure,13 14 15 16 17 but with improved brain development and functioning, most prominently in inferior frontal and striatal regions.18 19 20 21 22

It also identifies that systematic reviews, meta-analyses and large-scale studies show, except for the rare event of hypertension in one large-scale study, long-term methylphenidate use is not associated with statistically significant increased cardiac risks or events or all-cause death compared with placebo or controls.23 24 25 26 Subsequently, the most comprehensive meta-analysis available (19 studies with over 3.9 million participants) found "no statistically significant association between ADHD medications and the risk of cardiovascular events [and CVD] among children and adolescents, young and middle-aged adults, or older adults".27

Conclusion

It is evident that (a) the analyses cited in the article are flawed and well-refuted; (b) scientists, regulators, medical guidelines and governmental agencies are in global consensus, based on the scientific evidence, that methylphenidate is very safe and effective first-line treatment for ADHD; (c) the committee responsible for excluding methylphenidate from WHO's Model list of Essential Medicines for ADHD no longer represents WHO since their most recent guidelines and recommendations disagree with their claims. Димитрий Улянов Иванов (talk) 22:15, 29 April 2024 (UTC)[reply]

Hello, there has already been some discussion behind the motivation for using Storebø et al. on the talk page but we can discuss a bit more here. (Do in particular see the article by Swanson I’ve cited above, which explains the dispute over the review).

I would first note that a consensus statement in and of itself cannot “show” anything, aside from the opinions of those who authored/endorsed itself. It's only as good as the evidence it cites. (Setting aside the fact that the authors on the “International Consensus Statement” have extensive conflicts of interest [see Joseph Biederman, subject of a US Senate investigation] which may lead to a selective review of the literature - Cortese himself is an author on the statement, so it may not be surprising his analysis is cited.) Therefore I would prefer we discuss the relative merits of the systematic reviews we're considering.

I am aware that the Storebø et al. review was criticized by a number of authors after its publication. They have extensively replied to this criticism - I've given citations above which may help other readers orient themselves in the debate. It may be useful to observe that the Storebø review was primarily criticized by authors established within ADHD research - from the position of the sociology of science (taking into account the ecology of the way “expert niches” are formed) this is highly relevant. The authors of the Storebø review, by contrast, were primarily experts in EBM and have been authors on numerous systematic reviews. Their findings were criticized, but also supported in other corners, e.g. in this article in the Journal of the Norwegian Medical Association. Finally, another systematic review, published in PLOS One, again by independent authors, likewise found the evidence to be of "low or very low" quality. But you cannot really say that the Storebø review has in any sense been “disproven” - it has been criticized and the authors have replied to the criticism - but it’s a dispute over standards in the interpretation of evidence and not something which can be proven one way or the other. Also note that the Storebø review was updated in 2023, with partial corrections, but these did not affect the findings of the review.

The NICE analysis you mention has itself been criticized in an article in BMJ Evidence-Based Medicine. Network meta-analysis does not necessarily represent a more reliable or “advanced” method of analysis, and the particular meta-analytic technique used does not bear on the central point here regarding the quality of the trials. In their 2023 update Storebø et al. (p. 42) additionally note: "Indirect evidence differentiates network meta-analyses from conventional meta-analyses. Given the decreased interpretability of the indirect comparisons, there are no novel findings in this [Cortese et al.'s] network meta-analysis (Faltinsen 2018a; Storebø 2018a). In sum, the part of the network meta-analysis that is different from our review published in 2015 (Storebø 2015a), consists of evidence of low to very low certainty." Regulatory agency approval is often appealed to when the evidence for a drug is otherwise poor. It is worth bearing in mind that FDA approval requires only two positive trials, and is not any more reliable for assessing the efficacy of a drug than systematic reviews which consider the whole of the literature. For example, the regulatory process for the approval of XR methylphenidate has in particular been scrutinized by experts, who found that manufacturers had in some cases failed to turn over all relevant trials to regulators.

Ultimately, in my view, a Cochrane review (which will have been subjected to very stringent peer-review) authored by parties who do not have a particular interest in downplaying problems with the clinical trials is to be preferred to other systematic reviews. It seems to me that the researchers without conflicts of interest say one thing here, and researchers with COIs another. There is now a large literature on bias in clinical trials and it is considered best practice to take extensive account of it in contemporary systematic reviews. But more discussion is very much welcomed and it’d be good to hear more commentary on this from others. Feline negativity (talk) 20:52, 2 May 2024 (UTC)[reply]

Yes, can't see what the problem is here. The Cochrane review is a strong source not even making a very bold claims. It should certainly be cited. Bon courage (talk) 03:21, 3 May 2024 (UTC)[reply]

Thank you for your response. While I appreciate your effort to respond to my points, I doubt that they have been adequately addressed.

I address some briefly below:

It seems that you have rejected the global scientific consensus of all the world’s leading experts. You put the International Consensus in quotations, to apparently imply it is not really an international consensus, and claim that there are substantial conflict of interests.

The claim that the International Consensus Statement on ADHD merely represents “opinions” and “cannot show anything" is wrong. The evidence is contained in the research put forward that the scientific consensus is based on, not by any one or group of scientists stating the consensus. As it concluded: “To challenge misconceptions, we curated findings with strong evidence base”.

The status of the International Consensus Statement on ADHD is approved by 80 leading scientists who authored it from 27 countries and 6 continents, and it’s contents are endorsed by 403 experts (primarily active scientists), worldwide, and by many professional associations, organisations and agencies globally, not to mention extensive peer-review.

Indeed, it represents the global scientific consensus on ADHD.

The concerns expressed regarding COIs are unfounded. Disclosure statements of unrelated funding sources by some scientists only create the potential for a conflict, it does not assure such a conflict of interests, especially when the payments for speaking or consulting are so small relative to one's salary from their medical centre or university. Others may receive small grants from drug firms but that income is directed to the university, not the professional. In any case, one evaluates the International Consensus Statement for their accuracy in reflecting the status of the scientific literature regardless of who writes it. Anyone can check it for its veracity of its conclusions by doing literature searches and especially looking at the meta-analyses published now in many topic areas in ADHD.

So just because some authors, and not others, have received minor unrelated company fees for speaking or consulting doesn't automatically lead to dismissal of the conclusions in the reports i.e., the systematic reviews and meta-analysed. The most recent consensus statement is, in fact, a summation of all conclusions supported by MAs and SRs on various topics and so reflects the most robust, well supported findings in the field.

It's also important to clarify that the vast majority of meta-analyses and systematic reviews are not supported by pharma companies. One simply has to look at the disclosure statement accompanying these articles to see that they are supported either by federal government research grants or grants from guidelines groups or foundations or the medical centre or university itself. So any such assertions of COIS are unfounded.

The systematic review and network meta-analysis published by The European ADHD Guidelines Group (2018), along with the International Consensus Statement (Sept 2021-2024), concluded: 'Our findings represent the most comprehensive available evidence base to inform patients, families, clinicians, guideline developers, and policymakers on the choice of ADHD medications across age groups. Taking into account both efficacy and safety, evidence from this meta-analysis supports methylphenidate in children and adolescents, and amphetamines in adults, as preferred first-choice medications for the short-term treatment of ADHD.'

Network meta-analyses facilitate estimation of the comparative efficacy and tolerability of two or more interventions, even when they have not been investigated head-to-head in randomised controlled trials. (Cipriani et al. 2013). Thus, compared with standard pairwise meta-analyses, network meta-analyses have been found to increase the precision of the estimates (Cipriani et al. 2013).

More specifically, in fact, the network meta-analytic approach of Cortese et al. is also deemed more precise than the standard (pairwise) employed by Storebø and colleagues as endorsed by 51 professional groups (1).

Summation of the scientific literature

I do not intend to enter into further dialogue about the specifics of published research as it is unlikely to lead to consensus. My above points are aimed more at establishing the reputability of publications that were contended here. However, @WhatamIdoing announced a good idea to contrast the results of two analyses initially cited with the majority of research on the topic, per Wikipedia:Due weight:

A systematic review and network meta-analysis found stimulants to be highly effective in reducing the symptoms of ADHD: methylphenidate with large improvements in youths (9 studies, 2677 participants) and moderate ones in adults (11 studies, 2909 participants). Taking side effects into account, the medications with the best benefit-to-risk ratios were methylphenidate for children and adolescents, and amphetamines for adults, and concluded that its findings represents the most comprehensive evidence-base available to date (Cortese et al., 2018).

A systematic review and meta-analysis of 18 studies and 4868 patients concluded: "[Methylphenidate]/MPH is a very effective treatment for ADHD but there are concerns about potential adverse effects of extended treatment on several systems, including growth." (Carucci et al., 2021).

A meta-analysis of 4 studies with 216 patients found methylphenidate to be nearly as effective as mixed amphetamine salts; with moderate-to-large reductions in ADHD symptoms (Faraone et al., 2002).

A meta-analysis found a methylphenidate derivative strongly reduced ADHD symptoms relative to placebo (seven studies, almost 1500 participants), and had three times the clinical response rate (four studies, over 600 participants) (Maneeton et al., 2015).

A meta-analysis of 11 studies found that methylphenidate is effective and concluded that it should be considered as a first-line treatment option in most patients with ADHD (Liu et al., 2018).

A systematic review and meta-analysis of 13 studies with over 2200 adults found that methylphenidate led to small-to-moderate reductions in ADHD emotional-dysregulation symptoms (Lenzi et al., 2018).

A systematic review and meta-analysis of 8 studies and 423 patients found moderate-to-strong improvements in ADHD symptoms with methylphenidate in ADHD patients (Sun et al., 2019).

A systematic review and meta-analysis of nine studies with over 1300 participants found methylphenidate to be highly effective in reducing aggression, oppositional behaviour, and conduct problems in youths with ADHD (with and without oppositional defiant disorder) and conduct disorder, as measured by teachers, and moderately effective as measured by parents (Pringsheim et al., 2015).

A network meta-analysis found that extended-release methylphenidate is significantly effective for reducing ADHD symptoms; equivalent to atomoxetine (Bushe et al., 2016).

A meta-analysis of 7 studies and 1368 patients found that methylphenidate is significantly effective for reducing ADHD symptoms; comparable to atomoxetine (Hazell et al., 2011).

A long-term systematic review and meta-analysis of 7 studies found that immediate-release methylphenidate sustains its efficaciousness for ADHD for periods longer than 12 weeks (Maia et al., 2016).

Two systematic reviews (of 29 studies and 36 studies respectively) found that methylphenidate was effective; more than non-stimulant medications, but less than lisdexamfetamine, for reducing ADHD symptoms (Joseph A et al., 2014) (Joseph A et al., 2017).

A meta- and-network meta-analysis of 73 studies with 15,025 patients concluded: "The stimulants LDX and MPH are still highly recommended because they are highly effective and are tolerated well by patients"(Luan et al., 2017).

A meta-analysis of 21 studies found that methylphenidate effectively improves the executive functioning deficits in ADHD (Pievsky & McGrath, 2019).

A literature review concluded: 'There is substantial body of evidence to suggest that MPH is an effective and safe treatment option for adults with ADHD.' (Jaeschke et al., 2021).

The analysis by Storebo and colleagues (2015) contradicts all 15 previous systematic reviews and meta-analyses; which, including the meta-analyses conducted by the National Institute of Clinical Excellence (NICE) (King et al., 2006), unanimously report effect sizes between 0.8–1 for the efficacy of methylphenidate in terms of reducing the core symptoms of ADHD in children and adolescents (Bloch 2009; Charach, 2011; Charach, 2013; Faraone, 2002; Faraone, 2006; Faraone, 2009; Faraone, 2010; Hanwella, 2011; Kambeitz, 2014; King, 2006; Maia, 2010; Punja, 2013; Reichow, 2013; Schachter, 2001; Van der Oord, 2008). To save time adding all links, see: Banaschewski et al. (2016) for clickable references.

Methylphenidate treatment in the long-term significantly reduces or eliminates many ADHD symptomatic impairments including the elevated risks for obesity, accidental injuries, traumatic brain injury, substance abuse, cigarette smoking, educational underachievement, bone fractures, sexually transmitted infections, depression, suicide, criminal activity, teenage pregnancy, vehicle crashes, burn injuries and overall-cause mortality, as indicated by an extensive amount of research. For references, see section 12.2 of the ICS.

The International Consensus Statement on ADHD (Sept 2021-2024) concluded that methylphenidate is safe and very effective for treating ADHD, based on the results of many systematic reviews and meta-analyses and reviews of regulators, the developers of evidence-based medical guidelines and agencies who endorse said guidelines.

Relapse prevention studies also demonstrate the persistence of clinically meaningful and neuropsychological benefits for people with ADHD with continued long-term methylphenidate treatment (Matthijssen et al., 2019; Rosenau et al., 2021).

Conclusion

The vast majority of the scientific literature (e.g. systematic reviews and meta-analyses), including the global scientific consensus, shows that methylphenidate is certainly safe and very effective for reducing the symptoms of ADHD. It thus adheres to guidelines. For these reasons, and the presence of systematic errors and idiosyncratic methods for assessing evidence-quality, I am once again faced with the problem that the article's reliance on the two controversial analyses has to be considered flawed and even inadmissible. Димитрий Улянов Иванов (talk) 21:07, 3 May 2024 (UTC)[reply]

Hi, I think we're in agreement that the consensus statement is as good as the evidence it cites, so to return to that: There are, as best I can tell, three major recent systematic reviews which assess the efficacy of methylphenidate in children/adolescents: Storebø et al. 2023, Cortese et al. 2018, and Catalá-López et al. 2017. Storebø et al. deem the evidence to be of "very low" quality and Catalá-López et al. rate it "low" (Table 1). The quality assessment of Cortese et al. is less transparent. They appear to rate the quality of evidence as "low" for methylphenidate v. placebo, teacher's rating of ADHD symptoms (supplementary file, Table S22, p. 590) and "moderate" for clinician's rating (p. 598). The article should make it clear that the quality of the evidence base for methylphenidate appears to be poor, with due weight given to the Cochrane review in this area. If there is a relevant systematic review on the efficacy of methylphenidate I have missed, please let me know.

Most of the other meta-analyses you mention above are either old, small, or looking only at particular questions. For instance, Carucci et al. doesn't look at the efficacy of methylphenidate, it's an analysis of adverse effects relating to growth.

As for the efficacy of methylphenidate in adults, there are two other Cochrane reviews of methylphenidate (by different research groups) in the adult population, Cândido et al. 2021 and Boesen et al. 2022. All three Cochrane reviews of methylphenidate conclude that the quality of the evidence assessed was very low. The other recent major systematic review I have seen, Elliott et al. 2020, again looking at methylphenidate in adults, assesses the quality of the evidence as being "very low to low."

Due weight with regard to the relevant literature here seems clear. Feline negativity (talk) 23:51, 3 May 2024 (UTC)[reply]

Hi, apologies if my tone seems abrupt, but as time is limited I must be direct. I do not agree that the International Consensus Statement on ADHD is only as good as the evidence it cites, which seems to have been substantially ignored here. A small amount of publications are fallible, the global scientific consensus is usually much less so; in comparison and in the context of disagreement. From what I've read in Wikipedia Guidelines previously, referencing scientific consensus is profoundly relevant. As it concludes, methylphenidate is not only efficacious, it is among the most efficacious drugs in all of medicine.

I really must emphasise this point. I have not seen a compelling reason for this article to be completely against the global scientific consensus, and I'm not even sure there can be one.

Cortese et al. concluded a)

'Our findings represent the most comprehensive available evidence base to inform patients, families, clinicians, guideline developers, and policymakers on the choice of ADHD medications across age groups. Taking into account both efficacy and safety, evidence from this meta-analysis supports methylphenidate in children and adolescents, and amphetamines in adults, as preferred first-choice medications for the short-term treatment of ADHD.'

And for quality of evidence, b)

"Whereas previous pairwise or network meta-analyses of ADHD medications rated all comparisons as low or very low quality, attributable in part to unpublished information that we gathered and a more nuanced assessment, we could rate some comparisons as high or moderate quality. Of note, these comparisons included the most commonly used drugs for ADHD (ie, methylphenidate and amphetamines). Additionally, our stringent criteria for the risk of bias (ie, a study was assessed at overall low risk only when all individual items were at low risk) could have contributed to downgrade the final GRADE ratings."

It thus supports methylphenidate as an effective first-line treatment with a moderate-to-high quality of evidence further supported by the International Consensus Statement on ADHD. Which also concurs nicely with e.g. NICE guidelines, most recent guidelines from the World Health Organisation, among others.

I want to emphasise that we should not generally be peer-reviewing medical articles, but contrasting conclusions instead. Cortese et al. (2018), and the International Consensus Statement on ADHD (2021-2024), attest these conclusions clearly contradicting those of "clinicians should consider whether it is appropriate to prescribe IR methylphenidate, given its limited efficacy and increased risk of harms" and that there exists only "very low level of certainty" about evidence that it is efficacious.

The other meta-analyses cited are not small or irrelevant. Regardless of the main question, Carucci et al., 2021 is a peer-reviewed systematic review that concluded based on comprehensively reviewing existing scientific data that methylphenidate is very effective. Also, please refer to, which are neither small, old or irrelevant:

A meta-analysis of 11 studies found that methylphenidate is effective and concluded that it should be considered as a first-line treatment option in most patients with ADHD (Liu et al., 2018). A meta-analysis found a methylphenidate derivative strongly reduced ADHD symptoms relative to placebo (seven studies, almost 1500 participants), and had three times the clinical response rate (four studies, over 600 participants) (Maneeton et al., 2015). A systematic review and meta-analysis of 13 studies with over 2200 adults found that methylphenidate led to small-to-moderate reductions in ADHD emotional-dysregulation symptoms (Lenzi et al., 2018). A systematic review and meta-analysis of 8 studies and 423 patients found moderate-to-strong improvements in ADHD symptoms with methylphenidate in ADHD patients (Sun et al., 2019). A network meta-analysis found that extended-release methylphenidate is significantly effective for reducing ADHD symptoms; equivalent to atomoxetine (Bushe et al., 2016). A meta-analysis of 7 studies and 1368 patients found that methylphenidate is significantly effective for reducing ADHD symptoms; comparable to atomoxetine (Hazell et al., 2011). A long-term systematic review and meta-analysis of 7 studies found that immediate-release methylphenidate sustains its efficaciousness for ADHD for periods longer than 12 weeks (Maia et al., 2016). Two systematic reviews (of 29 studies and 36 studies respectively) found that methylphenidate was effective; more than non-stimulant medications, but less than lisdexamfetamine, for reducing ADHD symptoms (Joseph A et al., 2014) (Joseph A et al., 2017). A meta- and-network meta-analysis of 73 studies with 15,025 patients concluded: "The stimulants LDX and MPH are still highly recommended because they are highly effective and are tolerated well by patients"(Luan et al., 2017). A meta-analysis of 21 studies concluded that "methylphenidate is an effective treatment for adults with ADHD" based on its alleviation of EF deficits underlying ADHD (Pievsky & McGrath, 2019). A literature review concluded: 'There is substantial body of evidence to suggest that MPH is an effective and safe treatment option for adults with ADHD.' (Jaeschke et al., 2021).

Also keep in mind, when suggesting there is only very low level of certainty, the evidence I cited from relapse prevention studies demonstrating the persistence of clinically meaningful and neuropsychological benefits for people with ADHD with continued long-term methylphenidate treatment (Matthijssen et al., 2019; Rosenau et al., 2021), minimal tolerance (dissipation of effects) in long-term studies (Handleman & Sumiya, 2022) and from extensive long-term studies of many symptomatic functional outcomes.

These were baselessly ignored.

I understand that several Cochrane reviews suggest strong uncertainty, and this should be weighed in. However, it is evident that they are in fact the minority, and contradict the global scientific consensus, and the conclusions of regulators, medical guidelines and agencies worldwide, which are all important references. The Storebø and colleagues' controversial analysis of methylphenidate, made systematic errors and used an idiosyncratic application of the Cochrane risk of bias tool. As a result, if it is to be cited in the article, the rebuttals should be also be cited in addition to the other meta-analyses.

I must also restate something very important: safety and efficacy data have been reviewed extensively by medical regulators (e.g., the US Food and Drug Administration and the European Medicines Agency), the developers of evidence-based national guidelines (e.g., the UK National Institute for Health and Care Excellence, the World Health Organisation and the American Academy of Pediatrics), and government agencies who have endorsed these guidelines (e.g., the Australian National Health and Medical Research Council). These all conclude (i.e., medical guidelines, regulations and agency endorsements globally), based on the scientific evidence, that methylphenidate is safe and effective and should be considered as a first-line treatment for ADHD.

In your response, you criticised the FDA for not reviewing the evidence properly. However, not only is this highly selective, it does not take away from the fact that they conclude it is safe and effective; we are not really here to peer-review them but contrast conclusions as the other user correctly pointed out.

To conclude, it still strongly seems to me that the vast majority of publications support the effectiveness and use of methylphenidate; especially when considering the International Consensus Statement, systematic reviews and meta-analyses of short and long-term effects, and evidence-based guidelines, regulatory and agency conclusions. Димитрий Улянов Иванов (talk) 01:42, 4 May 2024 (UTC)[reply]

@Димитрий Улянов Иванов, I appreciate your long explanation, but Wikipedia editors are not supposed to be doing a Peer review of medical journal articles. Most of us aren't qualified to do so anyway.

What matters here is Wikipedia:Due weight. If most/all the review articles in the last five to ten years say ____, then the Wikipedia article should say ____, too. If 50% of them say ____ and 50% say the opposite, then the Wikipedia article should have a 50–50 split. If most say ____ and a few the opposite, then the Wikipedia article should say ____ and also note that a significant minority disagree.

In other words, the way to get the view you disagree with out of the article (or minimized in the article) is to say "This view is an outlier. Only these two papers say this, but here are 20 more recent ones, in better journals, saying the opposite." WhatamIdoing (talk) 16:14, 3 May 2024 (UTC)[reply]

Thanks for clearing up what would be necessary to do here. The notions that there is very low level of certainty about evidence that methylphenidate is efficacious for reducing ADHD symptoms is based a couple controversial publications. I have replied above citing the majority status of the scientific literature and the global scientific consensus which contradict those results. Димитрий Улянов Иванов (talk) 21:15, 3 May 2024 (UTC)[reply]

Is there a reason there are two images? Could they be combined and the legend amended accordingly? 90.240.165.192 (talk) 09:13, 15 May 2024 (UTC)[reply]

In 2024, the European Society for Child and Adolescent Psychiatry (ESCAP) and the American Academy of Child and Adolescent Psychiatry (AACAP) recalled the decision of an Expert Committee under the World Health Organisation (WHO) to recommend against the use of methylphenidate as an essential treatment due to strong doubts about its efficacy relative to placebo. They endorsed the inclusion of methylphenidate in the WHO Essential Medicines List due to its proven track record of short and long-term safety, effectiveness and necessity as an essential treatment for ADHD.^[1][2]

ACCAP recognises that methylphenidate is among the most safe and efficacious drugs in all of paediatrics. Both ESCAP & ACCAP denounce the meta-analysis of RCTs by Storebø and colleagues due to its use of idiosyncratic methods to assess the quality of the evidence and factual errors, a crucial point I and others have established in this talk page.

These recent endorsements, in combination with 51 other professional medical organisations in 2021, and the International Consensus Statement on ADHD, I hope will add to the evidence-base for maintaining the article in its current state; encourage consensus; and prevent any future reliance on such evidently flawed meta-analyses and contradictory WHO interpretation. Димитрий Улянов Иванов (talk) 23:41, 1 June 2024 (UTC)[reply]