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-   -   Mutagenicity of methylphenidate (new research) (http://www.addforums.com/forums/showthread.php?t=29778)

steven d 06-19-06 03:11 PM

Mutagenicity of methylphenidate (new research)
 
CYTOTOXICITY AND MUTAGENICITY IN HUMAN
TK6 LYMPHOBLASTOID CELLS EXPOSED IN VITRO TO
METHYLPHENIDATE

M. M. Carter, V. E. Walker, C. L. McCash and D. M. Walker. Cancer, LRRI,
Albuquerque, NM.

Methylphenidate(Ritalin, MPH) is a psycho-stimulant widely used for the treatment
of attention deficit/hyperactivity disorder (ADHD); however, a recent report
of cytogenetic effects in peripheral blood lymphocytes of children treated with
MPH for 3 months (El-Zein et al., Cancer Letters, in press) has raised concerns that
long-term exposure may pose a potential health risk. To investigate the mutagenic
effects of MPH in human cells in culture, a cloning assay was used to measure
cloning efficiencies (CEs) and mutant frequencies (MFs) in the hypoxanthine-guanine
phosphoribosyltransferase (HPRT) and thymidine kinase (TK) genes in TK6
cells exposed to MPH with/without human hepatic S9. TK6 cells exposed to 500
MPH µg/ml + S9 (n=6) for 3 days impeded cell growth with <2 rounds of replication
(compared with >3 in control cells) but was significantly mutagenic
(MF=8.65±2.12/million cells; control MF=5.39±1.91/million cells; p=0.01). In a
follow-up experiment, TK6 cells were exposed to 0, 250, or 500 µg MPH/ml,
with/without S9, for 4 days to acquire at least 3 rounds of cell replication for
treated cells. MPH treatments with or without S9 were cytotoxic relative to controls
(CE in treated cells were 50-56% of control values). Dose-related increases in
HPRT MFs were found in cells exposed to MPH in the presence of hepatic S9, but
not in its absence. Drug-induced MFs were significantly elevated in the 500 µg
MPH/ml + S9 group (n= 6, MF=13.86±7.12/million cells; p=0.007) but not the
250 µg MPH/ml + S9 group (n=5,MF=7.13±4.89/million cells) compared with
controls (n=7, MF=3.79±3.62/million cells). For both experiments, there was no
significant increase in TK MFs in any MPH treatment group, with/without S9.
These findings demonstrate that human hepatic enzymes have the capacity to convert
MPH to a mutagenic metabolite(s) that can induce mutations in exposed lymphocytes.
Further investigations of drugs used to treat children with ADHD are
needed to characterize the mode of action and potential risks of long-term exposure
to therapeutic agents such as MPH and d-amphetamine (Adderall) in children.

Hyperion 06-19-06 03:44 PM

Oy. If you expose human tissue to just about anything in a test tube, it produces mutagenic effects. Milk, fruit juice, even tap water will screw with dna in a test tube.

Furthermore, this sentence:

Quote:

These findings demonstrate that human hepatic enzymes have the capacity to convert
MPH to a mutagenic metabolite(s) that can induce mutations in exposed lymphocytes.
Does not seem to be supported by the evidence that is mentioned. What metabolites?

Also, note the tiny sample sizes and huge confidence intervals. Seeing these pretty much screws the pooch with regards to validity.

Look, if this was the only data you had to go on, then yeah, I might be worried. However, I am curious why no epidemiological survey has found an increased risk of cancer in methylphenidate patients as compared to the general public. This medication has been used since the 50's, millions of people have taken it, surely an epidemiological survey shouldn't be too difficult. If methylphenidate were carcinogenic, we ought to see an increased risk of cancer in patients taking methylphenidate once environmental and hereditary factors are controlled for. Given the number of patients taking the drug, and the length of time that the drug was on the market, such an effect would be blatantly obvious if it existed.

Finally, I'm also curious as to why they mention the need to look into other ADHD drugs. amphetamine and methylphenidate aren't really all that similar from a structural point of view, even though their method of action is similar. Even if methylphenidate were mutagenic or carcinogenic, it wouldn't really implicate amphetamine at all. Of course, I'm positive that there have already been mutagenicity studies of amphetamines, and as far as I know no mutagenicity or carcinogenicity has been found.

steven d 06-19-06 03:45 PM

I will give you my interpretation of this article:

Based on this research methylphenidate does damage to genes after it has been converted by human enzymes into a mutagenic metabolite. Rats don't have these human enzymes so that explains why rats are immune to the mutagenic effects of methylphenidate.

So, IMO, this could be the end of all safe methylphenidate usage (for children anyway).

steven d 06-19-06 03:55 PM

Quote:

Oy. If you expose human tissue to just about anything in a test tube, it produces mutagenic effects. Milk, fruit juice, even tap water will screw with dna in a test tube.
I'm not going to argue about this because I am looking for solutions, not trying to argue with you if ritalin is dangerous or not. I didn't said that ritalin was dangerous, just sharing this research.

Quote:

Look, if this was the only data you had to go on, then yeah, I might be worried. However, I am curious why no epidemiological survey has found an increased risk of cancer in methylphenidate patients as compared to the general public. This medication has been used since the 50's, millions of people have taken it, surely an epidemiological survey shouldn't be too difficult. If methylphenidate were carcinogenic, we ought to see an increased risk of cancer in patients taking methylphenidate once environmental and hereditary factors are controlled for. Given the number of patients taking the drug, and the length of time that the drug was on the market, such an effect would be blatantly obvious if it existed.
It takes 2-10 years for leukemia to develop from exposure and most cancers develop 20-30 years after chemical exposure. I'm not sure, you should read Ruddon, Cancer biology. There it is explained.

No epidemiological survey has showed it because there are no epidemiologic survey conducted on the long term, I think. If you believe you found one then please share.

Hyperion 06-19-06 03:56 PM

Hmmm, but that doesn't explain why we don't see this damage at the 250ug level.

Also, if this metabolite exists, it would be interesting to see it. Wouldn't it make more sense to first find the metabolite, then figure out how much of the metabolite will be present in vivo after taking an average dose, and then testing to see if those levels are mutagenic?

Finally, it still doesn't answer the question of the lack of epidemiological evidence linking methylphenidate to cancer.

I think that you are jumping to conclusions.

steven d 06-19-06 03:59 PM

Quote:

Finally, I'm also curious as to why they mention the need to look into other ADHD drugs. amphetamine and methylphenidate aren't really all that similar from a structural point of view, even though their method of action is similar. Even if methylphenidate were mutagenic or carcinogenic, it wouldn't really implicate amphetamine at all. Of course, I'm positive that there have already been mutagenicity studies of amphetamines, and as far as I know no mutagenicity or carcinogenicity has been found.
Yes, methamphetamine is genotoxic.

Li JH, Hu HC, Chen WB, Lin SK,
Genetic toxicity of methamphetamine in vitro and in human abusers.

Yes, life is hard for ADD'ers. But you have to move on.

steven d 06-19-06 04:02 PM

Quote:

Hmmm, but that doesn't explain why we don't see this damage at the 250ug level.
I believe there is, but it isn't significant.

Quote:

Also, if this metabolite exists, it would be interesting to see it. Wouldn't it make more sense to first find the metabolite, then figure out how much of the metabolite will be present in vivo after taking an average dose, and then testing to see if those levels are mutagenic?
Sounds difficult. Donno, I'm not a toxicologist. Maybe you should ask the authors.

steven d 06-19-06 04:11 PM

The methylphenidate use really started between 1990 and 2000. In that period there was a great upsurge. So the consequences should be noticed between now and the future. So if this study proves true you see the negative health effects in the near future.

You can prevent cancer. Ever heard about Quercetin?

Hyperion 06-19-06 04:35 PM

I did a scholar.google.com search for "methylphenidate AND Cancer" (but without the quotation marks, obviously).

The vast majority of the hits were for the use of methylphenidate in treating depression and fatigue in cancer patients, or using it to potentiate the action of painkillers. I did find one study showing that it caused a decrease in the incidence of mammary gland tumors in rats:

http://www.ncbi.nlm.nih.gov/entrez/q...&dopt=Citation

I finally added the term "epidemiological" to the search, in an effort to find such a study, and found a paper from California's dept of Health, in which they examined several possible carcinogens. Methylphenidate was examined and then dismissed as a possible cause of cancer. In this paper, they examined a long-term epidemiological survey which concluded:

Quote:

In a screening study of participants in a health plan in Oakland, California, taking a wide range of prescription drugs
between 1969 and 1973 and followed up through 1984 (11-15 years later), 529 study subjects had received
methylphenidate HCl (Selby et al., 1989). No increased risk of cancer at any site was associated with
methylphenidate HCl exposure. Fifteen cases of cancer were observed (32.7 cases expected), resulting in a
standardized mortality ratio of 0.46 (negative association with p<0.002). Results were not adjusted for confounding
due to smoking or alcohol consumption because of limited data available for the cohort. Occurrence of cancer in the
general population was drawn from the California Resource for Cancer Epidemiology, the San Francisco Bay Area
tumor registry, and the hospital’s discharge abstracts.
http://www.oehha.ca.gov/prop65/pdf/Fb3sums.pdf

So we can take the word of two in vitro studies involving a handful of cases, or we can look at a long-term in vivo epidemiological study with 500 cases.

The study cited was:

Selby JV, Friedman GD, Fireman BH (1989). Screening prescription drugs for possible carcinogenicity: Eleven to
fifteen years of follow-up. Cancer Res 49:5736-5747.

I can be found here"

http://cancerres.aacrjournals.org/cg...act/49/20/5736



Hmmmm.

Hyperion 06-19-06 04:43 PM

The study of human methamphetamine users is confounded y the fact that illicitly produced methamphetamine often contains large amounts of impurities from poorly done synthesis which are known carcinogens.

Also, I'm not sure what

Quote:

Yes, life is hard for ADD'ers. But you have to move on.
Is supposed to mean. Are you suggesting that people with ADD should stop using medications regardless of whether there is a link to cancer?

Imnapl 06-19-06 04:49 PM

Quote:

Originally Posted by steven d
Yes, life is hard for ADD'ers. But you have to move on.

As in suck it up, Buttercup? :eek:

Scattered 06-19-06 04:56 PM

Life without medication can indeed be a lot harder on an ADDer -- double the risk of drug abuse, increase in the number of traffic accidents, 3 x the prevalence of depression and anxiety compared to the general public, etc, so it makes sense to carefully evaluate the research before making blanket statements sure to inspire fear:
Quote:

So, IMO, this could be the end of all safe methylphenidate usage (for children anyway).
You admitted that you're not a toxocologist but yet your statement was absolute and went beyond what the authors of the study assert.

Scattered

steven d 06-19-06 05:52 PM

Quote:

You admitted that you're not a toxocologist but yet your statement was absolute and went beyond what the authors of the study assert.
It's an opinion. You don't want to endanger children by exposing them to a (possible) mutagen.

Quote:

Is supposed to mean. Are you suggesting that people with ADD should stop using medications regardless of whether there is a link to cancer?
No, never mind. You don't have to stop the meds even if there is a link. But you should do some chemoprevention I think. Discuss it with your doctor.

Quote:

Selby JV, Friedman GD, Fireman BH (1989). Screening prescription drugs for possible carcinogenicity: Eleven to
fifteen years of follow-up. Cancer Res 49:5736-5747.
Let's hope this is enough safety.

Hyperion 06-19-06 06:32 PM

Oh, here's the MSDS (Material Safety Data Sheet) for methylphenidate:

http://bulkpharm.mallinckrodt.com/_a...msds/MTHPN.htm

Quote:

11. Toxicological Information

Oral rat LD50: 350 mg/kg; oral mouse LD50: 60 mg/kg; Investigated as a tumorigen.
--------\Cancer Lists\------------------------------------------------------
---NTP Carcinogen---
Ingredient Known Anticipated IARC Category
------------------------------------ ----- ----------- -------------
Methylphenidate hydrochloride No No None
(298-59-9)
And here are the MSDS for amphetamine (separated into amphetamine sulfate and amphetamine aspartate, oth of which are found in Adderall):

http://bulkpharm.mallinckrodt.com/_a...msds/APTAE.htm
http://bulkpharm.mallinckrodt.com/_a...msds/APTSE.htm

note that while they warn against using it during pregnancy due to possile risks to the fetus, amphetamines are also listed as eing non-carcinogenic:

Quote:

11. Toxicological Information
Reproductive Toxicity:
The theraputic use of amphetamines during pregnancy may be associated with an increased risk of congenital malformations in the fetus. Reproductive studies in animals have suggested both an embryotoxic and a teratogenic potential when amphetamines were administered in high multiples of the human dose.
--------\Cancer Lists\------------------------------------------------------
---NTP Carcinogen---
Ingredient Known Anticipated IARC Category
------------------------------------ ----- ----------- -------------
Amphetamine Aspartate No No None

Hyperion 06-19-06 06:39 PM

Arrrrg, the charts didn't line up right. Regardless, if you look on the pages, the charts have "no" listed under "known" and "anticipated," as well as "none" under the International Agency for Research on Cancer (part of the World Health Organization) category.

Just in case anyone is curious about the IARC's list of possible carcinogens:

http://users.westnet.gr/~aesclep/carcinog.htm


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