Dear poppabear,
Scientific data on the long-term effects of Ritalin therapy is rather
scarce. The studies that enjoy the most exposure are the positive ones,
which is perhaps a testament to the clout of the pharmaceutical industry
and of its close allies in the psychopharmacological profession. Although
Ritalin was synthesized almost half a century ago, in 1956, there is
still a dearth of longitudinal studies on its therapeutic use.
A research paper published in the Canadian Medical Association Journal
in 2001 concluded that although Ritalin is effective in short-term
usage with mild side effects, its consequences for long-term usage are
unknown and have not been adequately tested. (Bear in mind that the
drug marketed by the Novartis corporation under the brand name Ritalin
is known generically as methylphenidate, or MPH for short.)
We observed that almost all the differences between
methylphenidate and placebo were in favour of a higher percentage
of adverse events while participants were taking methylphenidate
(Table 7). The largest statistically significant divergences
were exclusively in favour of methylphenidate and entailed
parent/self ratings: all related decreased appetite (30.3%, 95%
CI 18.0?42.6), insomnia (17.0%, 95% CI 8.3?25.8) or stomach
ache events (9.0%, 95% CI 1.2?16.9) and serious decreased
appetite events (8.7%, 95% CI 3.6?13.9). Teacher/staff ratings
for serious decreased appetite events (6.1%, 95% CI 0.2?12.0)
also showed a statistically significant difference in favour of
methylphenidate. Children were more likely to experience anxiety
(reported by parent/self) and headache (reported by teacher/staff)
events while on placebo,54 although neither of these results
achieved statistical significance.
[...] we were unable to demonstrate that the methylphenidate
effect is maintained beyond 4 weeks. Few trials (14.5%)
included treatments of this duration; perhaps due to
the dearth of trials and participants, both hyperactivity
index?defined methylphenidate effects for these longer-term,
exclusively parallel design trials (maximum 28 weeks) failed
to achieve statistical significance. The paucity of long-term
trials3,10,20,21,22,40 is problematic, because children
routinely receive methylphenidate in clinical contexts for much
longer than was observed in the present collection of small
trials.7,67 The recently completed MTA trial,68 though lacking
a placebo group, may address some of the concerns identified
in this meta-analysis regarding long-term treatment. It was
methodologically sound and had sufficient power to detect the
superiority of medical management (with 73.4% of participants
maintained on methylphenidate at study end) over a relatively
long-term period (i.e., 14 months) in a comprehensively assessed
patient population.
We also found that whereas adverse event data were underreported
by trialists,69,70,71 both parent/self and teacher/staff data
revealed that serious episodes of decreased appetite were
statistically significantly more common when children were on
methylphenidate rather than placebo (Table 7). Significant
differences in favour of methylphenidate also characterized
other parent/self-observed adverse events (i.e., all related
instances of decreased appetite, insomnia, stomach ache, headache,
dizziness, and serious headache and stomach ache events). Although
requiring cautious interpretation,72 notable parent/self-derived
number-needed-to-harm data highlighted difficulties with decreased
appetite and insomnia and, to a lesser extent, stomach ache,
drowsiness and dizziness. Although methylphenidate-related adverse
events can be dose-dependent and can diminish over time,18,21,22
the dearth of data precluded the evaluation of the impact of
either of these factors on the safety profile. Finally, as with
efficacy data, we do not know whether this short-term safety
profile21 persists in the long term. The longer-term MTA trial
results highlighted similar safety issues, in that 64.1% and 14.3%
of children who received a stimulant exhibited side effects of
any severity or of a moderate-to-severe kind respectively.
Canadian Medical Association Journal: "How efficacious and safe is
short-acting methylphenidate for the treatment of attention-deficit
disorder in children and adolescents? A meta-analysis" by Howard
M. Schachter et al.
http://www.cmaj.ca/cgi/content/full/165/11/1475
A news article, also dating to 2001, reports on this study.
Randomized trials -- where participants are randomly assigned
to receive the drug being tested or a placebo -- are the gold
standard of medical research.
"There aren't long-term studies," Schachter, a research scientist
at the Children's Hospital of Eastern Ontario in Ottawa, said
in an interview.
"And that's of some concern because we don't know whether the
initial positive effects ... might diminish over time. Moreover,
we don't know what happens to the side-effects ... whether those
get worse or maybe they diminish too -- we don't really know."
Canoe: Health: "Little known about safety of long-term Ritalin use,
study warns" by Helen Branswell
http://www.canoe.ca/Health0111/27_ritalin-cp.html
Nonetheless, I have been able to find a number of references to published
clinical studies that show negative long-term and permanent effects of
Ritalin. In some cases, I have located the publication text in part or
in whole. In other cases, I have found only a summary in the popular
news media. I present my findings in chronological order according to
date of publication.
A clinical study published in 1994 in the American Journal of
Cardiovascular Pathology found that Ritalin causes permanent damage to
the hearts of mice. For obvious reasons, studies that end in autopsy and
other invasive procedures are not often performed on human subjects. The
applicability to humans of rodent-based trials remains a subject of
dispute. Although I was not able to locate a firsthand copy of this paper,
I did find a page of interesting excerpts.
"A number of adverse reactions have been associated with
MPH therapy, particularly cardiovascular side effect, such as
arrhythmia, tachycardia, and changes in blood pressure [1,2]. MPH
is an amphetamine congener with a molecular structure resembling
that of amphiphilic drugs. Administration of certain amphiphilic
drugs has been shown to induce phospholipidoses by interfering
with phospholipid catabolism in a variety of cell types, resulting
in a lysosomal accumulation of abnormal amounts of membranes.
Ultrastructurally, one striking alteration, among others, is the
presence of lamellar bodies in a variety of tissues exposed to
amphiphillic drugs."
"We have previously observed analogous lamellar membrane
accumulations in myocardial cells of a patient on chronic therapy
with MPH." "In order to determine if a causal relationship exists
between MPH and ultrastructural myocardial changes previously
described in the patient, we administered MPH to two rodent
species.
[...] "Pronounced lesions in our rodents were more evident with
prolonged exposure and appeared to approach a stable level of
[...] "Pronounced lesions in our rodents were more evident with
prolonged exposure and appeared to approach a stable level of
incidence; however, lesions were highly focal and a wide range
of alterations within individual animals was noticed. These
structural abnormalities persisted to a reduced degree, for as
prolonged time after stopping the MPH injections.
"?it could be argued that our results do not directly apply
to the clinical situation, because MPH was administered by
injection. Yet, similar pathological changes were see in the
six mice that received MPH orally. The limited number of animals
receiving MPH by this route dictates a cautious interpretation;
nevertheless, we found no basis to expect a different pathological
profile following oral administration."
"?it is difficult to draw conclusions concerning long-term
accumulation or safe doses. Yet our observations definitively
showed that lesions were present in animals treated with
therapeutic doses and that these lesions persisted. "
"this study, using laboratory animals under a controlled
single drug regimen, corroborates and strengthens the previous
supposition that MPH was a likely causal agent in the formation
of similar ultrastructural alterations observed in a patient on
chronic MPH therapy."
"Our treatment protocol revealed clearly the requirement of
a minimal dose, in order to induce even incipient structural
changes; however, these minimum dosages fell within the range
of therapeutic dosage prescribed for patients with attention
deficit disorders."
The American Journal of Cardiovascular Pathology. "Effects of
Methylphenidate (Ritalin) on Mammalian Myocardial Ultrastructure" by T. A.
Henderson et al.
http://www.adhdfraud.org/commentary/110302-3.htm
Another trial with mice, in 1996, suggested that Ritalin may be
carcinogenic, but the FDA declared the results so tenuous as to be
irrelevant for children currently undergoing ADHD treatment. Although
further trials were promised, I have not found any mention of them. This
study was reported through an AP newswire article that is reproduced on
a third-party website.
Government scientists have uncovered a sign that the widely used
children's drug, Ritalin might cause cancer in mice. But they
said Friday that parents should not stop giving their children
the drug used to treat hyperactivity based on such weak findings.
"We felt physicians and parents should know this and have a right
to know this," explained Dr. Murray Lumpkin, the Food and Drug
Administration's deputy drug director. "But it's not enough of
a signal that we think kids should be taken off the drug."
That leaves children and teen-agers restless, easily distracted
and sometimes aggressive. As many as 2.5 million children are
thought to have ADHD. It is more common in boys than girls and
sometimes persists to adulthood.
Ritalin is the brand name of the brain stimulant
methylphenidate. Some 6 million prescriptions for the generic
and brand-name versions were filled in 1993, the latest data
available.
Ritalin has been sold for 40 years, but it came on the market
before drug makers were required to test for carcinogenicity. The
National Toxicology Program, a branch of the National Institutes
of Health, routinely tests such older drugs for possible risks.
Mice were fed high doses of methylphenidate -- up to 30 times the
typical human dose -- for two years. Four of the male mice who
got the highest doses developed cancerous liver tumors called
hepatoblastomas, when no more than one of the extremely rare
tumors should have formed, the study found.
The mice also had somewhat elevated levels of a noncancerous
liver tumor called hepatocellular adenoma.
When the FDA obtained the study, it made Ritalin manufacturer
Ciba Geigy Corp. add the mouse findings to the drug's label and
notify doctors about the potential -- though questionable -- risk.
Greater Rochester ADD Association: One Article, Two Headlines - What
a Difference!?
http://www.netacc.net/~gradda/sp96onea.html
A pair of studies conducted in 1999 emerged with contradictory conclusions
about the long-term substance-abuse consequences of Ritalin therapy. The
negative study found that adults who were treated with Ritalin in
childhood are more likely to become smokers and drug addicts. This
finding and an opposing one are summarized in a Psychiatric Times article.
Nadine Lambert, Ph.D., implicated a causal role for stimulant
medication in a longitudinal study that she presented at the
National Institutes of Health Consensus Development Conference
on ADHD conducted by NIMH and NIDA in Bethesda, Md., in November
1998 (in press). NIMH/NIDA drew the opposite conclusion in a
study published in the August electronic issue of Pediatrics.
In this study, Joseph Biederman, M.D., and colleagues (1999)
found that pharmacotherapy of ADHD reduces the risk for substance
use disorder (SUD) relative to the risk for SUD associated with
unmedicated ADHD.
While Lambert acknowledged convincing evidence of the therapeutic
efficacy of stimulant medications for ADHD symptoms, she noted
that few studies have examined the effects of their long-term
use in treating this disorder. Lambert found in the available
longitudinal research, however, "ADHD and childhood use of CNS
[central nervous system] stimulants have been shown to predispose
children to early tobacco use and to adult use and dependence
on tobacco and substances with stimulating properties."
[...]
The Lambert study (in press) drew longitudinal data from a large
population with age-matched controls. The cohort diagnosed with
ADHD consisted of 492 subjects. The subjects, now adults, had
been followed since childhood diagnosis based on 1974 parent and
teacher ratings on the Children's Attention and Adjustment Survey
of inattention and hyperactive-impulsive symptoms. Applying DSM-IV
diagnostic criteria for ADHD to these original symptom ratings,
132 subjects were deemed to have severe ADHD, 99 moderate ADHD,
61 mild ADHD, and 200 subjects did not satisfy the DSM-IV ADHD
criteria.
Utilizing interview protocols, Lambert elucidated eight domains,
including adult ADHD symptoms and treatment history, lifetime
tobacco use, and current smoking status. In addition, each subject
completed the computer-based Quick Diagnostic Interview Schedule
III-R, with dependence measures of tobacco, cocaine, stimulants,
marijuana and alcohol.
Lambert reported that both severe ADHD symptoms and treatment
with stimulant medications in childhood appeared as risk
factors for earlier onset of regular smoking in childhood and
adolescence. There appeared to be some protective effect of the
stimulant medication, however, wherein the longer the medication
was used, the longer the delay until smoking commenced on a
regular basis.
"This suggests that subjects begin regular smoking when
[stimulant] treatment ends, implicating support for both the
self-medicating and sensitization hypothesis," Lambert indicated.
[...]
Lambert concluded, "Childhood use of CNS stimulant treatment is
significantly and pervasively implicated in the uptake of regular
smoking, in daily smoking in adulthood, in cocaine dependence,
and lifetime use or abuse of cocaine and stimulants. [...]"
Psychiatric Times: "Researchers Differ on ADHD Medication Risks" by
Kenneth J. Bender
http://www.psychiatrictimes.com/p991201b.html
In 2001, a two-page article published in the Journal of the American
Medical Association reported on clinical experiments which concluded
that Ritalin acts on the brains of children undergoing ADHD treatment
on the same neurochemical principles as cocaine, although at a much
slower rate. This circumstance alone is not necessarily negative or
positive, since the therapeutic dosage of Ritalin is too small to
produce a discernible narcotic effect on children. It is nonetheless
an illuminating finding. In addition to a brief summary of the article,
I have found a page from which one may purchase it online for $12.
Advanced imaging research has answered a 40-year-old question
about methylphenidate (Ritalin), which is taken daily by 4
million to 6 million children in the United States: how does
it work? The answer may unsettle many parents, because the drug
acts much like cocaine, albeit cocaine dripped through molasses
(J Neurosci. 2001;21:RC121).
Taken orally in pill form, methylphenidate rarely produces a
high and has not been reported to be addictive. However, injected
as a liquid it sends a jolt that "addicts like very much," said
Nora Volkow, MD, psychiatrist and imaging expert at Brookhaven
National Laboratory, Upton, NY. "They say it's like cocaine."
Journal of the American Medical Association: Medical News and
Perspectives: "Pay Attention: Ritalin Acts Much Like Cocaine" by Brian
Vastag: Summary
http://jama.ama-assn.org/cgi/content/extract/286/8/905
Journal of the American Medical Association: Medical News and
Perspectives: "Pay Attention: Ritalin Acts Much Like Cocaine" by Brian
Vastag: Sign-In Page
http://jama.ama-assn.org/cgi/content/full/286/8/905
A 2001 talk given by the anti-Ritalin activist Fred A. Baughman Jr. before
the Parliamentary Assembly of the Council of Europe makes a number of
interesting, if partisan, points that draw on his interpretation of
some clinical findings. A full transcript of the talk, together with an
extensive appendix, is available online.
The title of the Swanson and Castellanos, [18] Consensus
Conference presentation was ?Biological Bases of Attention
Deficit Hyperactivity Disorder,? as if there was a biological
basis or bases. Reviewing the brain scanning literature, they
reported that the brains of ADHD subjects were, on average, 10%
smaller than those of normal controls. What they neglected
to say, until Baughman [26] challenged Swanson (presenting),
from a floor microphone, was that virtually all ADHD subjects,
in the 12 years of brain scanning research reviewed, 1986-1998,
had been on long-term methylphenidate/amphetamine therapy, and,
that this?their medication--was the only physical difference
between the ADHD subjects and normal controls, and the probable
cause of their brain atrophy.
ADHDfraud: "The Case Against Diagnosis and Treatment of ADHD and Related
Disorders and Their Treatment With Stimulants" by Fred A. Baughman Jr.
http://www.adhdfraud.org/commentary/102604-h.htm
In 2001, there were numerous articles in the popular press reporting on
a clinical study, conducted at the University of Buffalo, that suggests
Ritalin abuse may have long-term effects similar to those of cocaine
and speed. These results were presented at the annual conference of the
Society for Neuroscience and subsequently published in the conference
proceedings, which are unavailable online. We must note, despite the
alarming headlines of the news articles, that the clinical study concerns
high doses of Ritalin.
Scientists at the University at Buffalo have shown that the
drug methylphenidate, the generic form of Ritalin, which
physicians have considered to have only short-term effects,
appears to initiate changes in brain function that remain after
the therapeutic effects have dissipated.
The changes appear to be similar to those that occur with
other stimulant drugs such as amphetamine and cocaine, said
Joan Baizer, Ph.D., UB professor of physiology and biophysics
and senior author of the study. Results of the research were
presented here today (Nov. 11, 2001) at the annual meeting of
the Society for Neuroscience.
"Clinicians consider Ritalin to be short-acting," said
Baizer. "When the active dose has worked its way through the
system, they consider it 'all gone.' Our research with gene
expression in an animal model suggests that it has the potential
for causing long-lasting changes in brain cell structure and
function." Ritalin is the drug of choice for the treatment of
attention deficit disorder in children.
Baizer stated, however, that while the neuronal changes are
similar to those seen with cocaine and other psychoactive drugs,
it does not seem that methylphenidate in very low doses, as used
therapeutically, produces much potential for drug abuse.
"Children have been given Ritalin daily for many years, and it
is extremely effective and beneficial, but it's not quite as
simple as a short-acting drug," Baizer said. "We need to look
at it more closely." Baizer added: "Ritalin does appear to be
safe when used properly, but it is still important to ask what
it is doing in the brain."
biopsychiatry.com: "Ritalin May Cause Long-Lasting Changes In Brain-Cell
Function, University At Buffalo Researchers Find"
http://www.biopsychiatry.com/methylphenidate/ritalin.html
The stimulant Ritalin, a drug used to help children with attention
deficit hyperactivity disorder, may cause long-term changes in
the brain, researchers reported yesterday.
The changes look similar to those seen with other stimulants
such as amphetamine and cocaine, at least in rats, the team at
the University of Buffalo found.
Washington Post: "Ritalin May Cause Brain Change in Children"
http://www.washingtonpost.com/ac2/wp-dyn?pagename=article&contentId=A12922-2001Nov11¬Found=true
New evidence about the effects of Ritalin, a drug used to treat
children with ADD and ADHD, has prompted renewed calls for
research into its long-term effects.
[...]
"These data do suggest that there are effects of Ritalin on cell
function that outlast the short term and we should sort that out,"
Dr Baizer said.
ADHD researcher Dr Alasdair Vance of Melbourne's Alfred Hospital
said the study demonstrated the importance of studying the
long-term effects of Ritalin.
"These drugs may have considerable benefits for children and
families at large, but the key issue is that our understanding
of these medications ? and therefore their appropriate and
optimal use ? must be made a priority," he said.
"I am concerned about the long-term use of these drugs, given
their exponential increase in use in the community on a very
insubstantial scientific base."
Australian Broadcasting Corporation: Health & Medical: "New calls for
long-term Ritalin study"
http://www.abc.net.au/science/news/health/HealthRepublish_414363.htm
In 2004, a laboratory study performed at Harvard Medical School found
that Ritalin has pseudo-narcotic effects on laboratory animals and
may contribute to depression later in life. Freely available online
are a press release on this study and an abstract of the journal paper
containing the results. The paper is available in its entirety for a
$15 fee. Furthermore, a news article published in 2004 includes useful
commentary on the study.
McLean Hospital researchers have demonstrated that early
exposure to Ritalin could reduce sensitivity to cocaine reward,
a potentially beneficial effect, but could also increase
depressive-like symptoms in adult rats. The study, led by McLean
Hospital's William Carlezon, PhD, and Susan Andersen, PhD, found
that adult rats given Ritalin as juveniles behaved differently
than their placebo-treated counterparts in a host of tests that
reflect mood and attention. Published in the Dec.15 issue of
Biological Psychiatry (abstract), the study follows up previous
work by the researchers showing that young rats given Ritalin
were less likely to find cocaine pleasurable as adults.
For the new study, Carlezon and Andersen raised two sets
of rats: one was given Ritalin during the rat equivalent
of pre-adolescence, while the other was given saline. At
adulthood, all of the rats were examined in a model of "learned
helplessness," which tested how quickly they gave up on behavioral
tasks under stress.
"Rats exposed to Ritalin as juveniles showed large increases
in learned-helplessness behavior during adulthood, suggesting a
tendency toward depression," said Carlezon, director of McLean
Hospital's Behavioral Genetics Laboratory. "These rats also showed
abnormally high levels of activity in familiar environments,
which might reflect basic alterations in the way rats pay
attention to their surroundings."
Harvard University: McLean Hospital: "Ritalin Use in Childhood May
Increase Depression, Decrease Cocaine Sensitivity in Adults"
http://www.mclean.harvard.edu/PublicAffairs/ritmod20031208.html
In place-conditioning tests, early exposure to MPH or cocaine
each made moderate doses of cocaine aversive and high doses
less rewarding. Early MPH exposure also caused depressive-like
effects in the forced swim test, and it attenuated habituation
to the activity chambers.
Conclusions: Early exposure to MPH causes behavioral changes
in rats that endure into adulthood. Some changes (reduced
sensitivity to cocaine reward) may be beneficial, whereas others
(increases in depressive-like signs, reduced habituation) may
be detrimental. The effects of MPH on cocaine-related behaviors
may be a general consequence of early stimulant exposure.
ScienceDirect: "Enduring behavioral effects of early exposure to
methylphenidate in rats" by William A. Carlezon, Jr. et al.: Abstract
http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T4S-4B6472F-B&_user=10&_coverDate=12%2F15%2F2003&_rdoc=5&_fmt=summary&_orig=browse&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=bd70a4aa8a7091ed9b43cc7e5692f609
In the work funded by the NIH, Dr. Carlezon and his chief
collaborator, Dr. Susan Andersen, examined the effects of
exposing rats to Ritalin during early development on behaviors
later in life. They exposed normal rats to twice-daily doses
of Ritalin during a period that is equivalent to approximately
4-12 years of age in humans. Examining the behavior during
adulthood, Carlezon and Andersen conducted several types of
tests that all showed that the animals had a reduced ability
to experience pleasure and reward, particularly when it was
measured by sensitivity to cocaine. In addition, they found that
the animals exposed to Ritalin during pre-adolescence were more
prone to express despair-like behaviors in stressful situations
(such as swim tests) as adults. Overall, the animals showed more
evidence of dysfunctional brain reward systems and depressive-like
behaviors in adulthood.
These findings are critical because they suggest that Ritalin
can have long-term consequences on normal-functioning brains.
EurekAlert: "New study shows early ritalin may cause long-term effects
on the brain"
http://www.eurekalert.org/pub_releases/2004-12/g-nss121004.php
To recapitulate, hard data on the long-term negative effects of
childhood Ritalin therapy are not readily available due to the lack
of pertinent studies. However, initial findings drawn from clinical
trials suggest that Ritalin may cause structural damage to the heart,
a higher risk of cancer, increased susceptibility to drug addiction,
and adult depression. This is in addition to the reported short-term
side effects of insomnia, nausea, dyspepsia, headache, and anxiety.
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leapinglizard |
