Following is a brief discussion about the safety of drugs used for treatment of ADHD (including DAMP).

There are two types of drugs used to treat ADHD. The first type are called “stimulants”; these are drugs that cause normal healthy adults to become more active. The other type of drugs are called simply “non-stimulants”.

Stimulant drugs—Ritalin
By far the most commonly-used drug for ADHD is a stimulant known as Ritalin (also known as Concerta, Equasym, Metadate, and Methylin; the medical name is “methylphenidate”). Ritalin has been prescribed for hyperactive people for decades, and it is nowadays in use by millions of children. Despite that, there are no good-quality long-term studies on the effects of Ritalin.

Studies on mice have suggested that Ritalin could cause cancer. Such studies were first reported in 1995. In 2005, Randa El-Zein and colleagues at the University of Texas reported on twelve children who had been given Ritalin for three months. All the children showed increased genetic damage, which increases the chance of getting cancer. A subsequent study by other researchers has indicated what some of the underlying mechanism might be (briefly, enzymes in the liver convert Ritalin into a substance that causes genetic damage).

What is not known is how much Ritalin increases the chance of getting cancer. The increase might be so small as to be immaterial. Further research to study this is currently underway.

There are other potential problems besides cancer. In particular, there is evidence that Ritalin can adversely affect the development of the reproductive system of adolescent girls. A study done on adolescent female rats found that Ritalin adversely affected the development of ovarian follicles (the small cavities that grow eggs) as well as the release of luteinizing hormone (which is necessary for triggering ovulation); Ritalin also caused poor vaginal development.

In this rat study, Ritalin was administered directly into the bloodstream. With people, however, Ritalin is almost always administered orally. When administered orally, Ritalin is partially transformed by the liver before entering the main bloodstream. It is not certain that Ritalin taken orally by adolescent girls would have a similar effect to Ritalin administered directly to the bloodstreams of the rats. Clearly, though, this is a risk.

There is an additional problem: various studies on child and adolescent rats show that stimulant drugs cause changes in the rats' brains (and behaviors) that endure through to adulthood, long after drug use has been halted. This is related to an important question: is ADHD a condition that can be diagnosed by measuring some physical, chemical, and biological factors in the brain? No one has yet found such factors. If such factors were found and the drugs induced changes in the brain that countered those factors but did nothing else, then the long-lasting effects of the drugs could potentially be a good thing. At present, however, there is no evidence that such is true. It might well be that the drugs cause enduring harm to the brain. As an example, studies on rats indicate that use of Ritalin during childhood increases the chance of depression during adulthood.

Stimulant drugs—amphetamines
[This section is currently just a few rough notes.]
The primary stimulants other than Ritalin are amphetamines. There are two main amphetamines. One is methamphetamine (popularly known as “meth”, this drug is often abused). The other is dextroamphetamine.
Methamphetamine is not legal for treating ADHD in some countries. As well, several studies have suggested that it can be toxic for neurons in the brain.

Non-stimulant drugs
The only non-stimulant drug approved for treatment of ADHD is known as Strattera (the medical name is “atomoxetine”). Strattera is often used with patients for whom stimulant drugs are ineffective or have obvious adverse side effects. Strattera was approved for use in the U.S.A. in 2002, and approval in several European countries followed. It has now been used by over two million children.

Partly because Strattera has not been in use for long, it has received substantially less scrutiny than Ritalin. Also, there are no long-term studies of its safety (as with Ritalin). The most serious danger that is known is a possible increase in suicidal thoughts. (In the U.S.A., Strattera is labeled with a warning about this, and health care providers everywhere are encouraged to monitor new users closely for warning signs.) There is also evidence that, in rare cases, Strattera can induce psychosis or mania (such as hallucinations, which are particularly problematic for children); what could make this a strong concern is that in roughly half of such cases, the psychosis or mania seems to persist even after Strattera use is halted.

Other non-stimulant drugs, besides Strattera, have been tried. The main such drugs are known as bupropion and tricyclic antidepressants. Those drugs, however, sometimes have severe, occasionally fatal, side effects—hence their non-approval.

With any treatment, there are benefits and risks. Assuming that the treatment for ADHD should include drugs (something that is disputed), the benefits and risks of each potential drug need to be assessed.

The benefits of stimulants and Strattera have been established in short-term studies only. There is a problem with this, because people might become used to the drugs after some months, so that the drugs stop having any beneficial effects. There are no long-term studies any ADHD drug that prove otherwise. For example, in 2006, researchers at Oregon Health & Science University conducted a comprehensive review of the scientific publications on ADHD drugs; the review concluded that “Good quality evidence on the use of drugs to affect outcomes relating to global academic performance, consequences of risky behaviors, social achievements, etc. is lacking”.

There are also no long-term studies on the safety of the drugs. For example, a 2005 study by the U.S. Department of Health and Human Services concluded that “long-term studies on the [harmful] effects of therapy with [Ritalin] are … lacking”. As another example, a 2004 review by Todd Kociancic and colleagues at Case Western Reserve University stated that “the lack of data concerning long-term safety of psychostimulants may be alarming”, although also noting that strong data do not exist to point to long-term harm—i.e. we know little.

A lack of long-term studies on safety is actually a problem with pharmaceuticals generally (not just for ADHD drugs). Indeed, a 2006 commentary in the New England Journal of Medicine stated that “Our reliance on regulation alone to demonstrate the long-term safety of drugs has been an unequivocal failure”. And a 2006 proposal by some current and former members of the FDA Drug Safety and Risk Management Advisory Committee included the recommendation that “medicines for chronic conditions should be evaluated in large, long-term trials”. I believe that this recommendation should be obvious.

Despite the lack of long-term studies, the safety of ADHD drugs is obviously called into question by the research discussed above. The overall conclusion is a serious concern: millions of children have undertaken long-term usage of drugs for which there are important questions about safety and no demonstrated long-term benefits.

Adriani W., Leo D., Greco D., Rea M., di Porzio U., Laviola G., Perrone-Capano C. (2006), “Methylphenidate administration to adolescent rats determines plastic changes on reward-related behavior and striatal gene expression”, Neuropsychopharmacology, 31: 1946–1956. doi: 10.1038/sj.npp.1300962. [Ritalin given to adolescent rats causes changes in the rats' brains and behaviors that endure through to adulthood.]

Aldhous P. (31 March 2006), “Prescribing of hyperactivity drugs is out of control”, New Scientist, 2545: 8. [This article tells that four million American children are taking Ritalin, and also discusses some of the drug's side effects.]

Carter M.M., Walker V.E., McCash C.L., Walker D.M. (2006), “Cytotoxicity and mutagenicity in human TK6 lymphoblastoid cells exposed in vitro to methylphenidate”, The Toxicologist, 90: 26. [This describes the study that examined cancer and the role of liver enzymes on Ritalin; abstract only.]

CDER [FDA Center for Drug Evaluation and Research] (29 September 2005), Public Health Advisory for Atomoxetine. [This press release warns about increased risk of suicidal thoughts due to Strattera.]

CDER [FDA Center for Drug Evaluation and Research] (03 March 2006), Psychiatric Adverse Events in Clinical Trials of Drugs for ADHD. [This report is a companion to the next CDER report; it includes discussion of psychosis and mania probably induced by Strattera (and possibly Ritalin).]

CDER [FDA Center for Drug Evaluation and Research] (03 March 2006), Psychiatric Adverse Events Associated with Drug Treatment of ADHD. [This report is a companion to the previous CDER report; it includes discussion of psychosis and mania probably induced by Strattera (and possibly Ritalin).]

Chase T.D., Carrey N., Brown R.E., Wilkinson M. (2005), “Methylphenidate differentially regulates c-fos and fosB expression in the developing rat striatum”, Developmental Brain Research, 157: 181–191. doi: 10.1016/j.devbrainres.2005.04.003. [A study on rats that indicated that the effects of Ritalin on children's brains were long-lasting.]

Chatterjee-Chakrabarty S., Miller B.T., Collins T.J., Nagamani M. (2005), “Adverse effects of methylphenidate on the reproductive axis of adolescent female rats”, Fertility and Sterility, 84: 1131–1138. doi: doi:10.1016/j.fertnstert.2005.03.071. [This details the study of the reproductive system of female adolescent rats, discussed herein.]

Cohen D., Leo J. (2004), “An update on ADHD neuroimaging research”, Journal of Mind and Behavior, 25: 161–166. [This refutes claims that neuroimaging studies have found correlates with ADHD.]

El-Zein R.A., Abdel-Rahman S.Z., Hay M.J., Lopez M.S., Bondy M.L., Morris D.L., Legator M.S. (2005), “Cytogenetic effects in children treated with methylphenidate”, Cancer Letters, 230: 284–291. doi: 10.1016/j.canlet.2005.01.003. [This details the study of twelve children with Ritalin, discussed herein.]

El-Zein R.A., Hay M.J., Lopez M.S., Bondy M.L., Morris D.L., Legator M.S., Abdel-Rahman S.Z. (2006), “Response to comments”, Cancer Letters, 231: 146–148. doi: 10.1016/j.canlet.2005.10.007. [A response to comments on the authors' 2005 research paper; this includes a brief discussion of the much-earlier studies on mice and rats, which are treated further in the NTP-CERHR monograph.]

Eli Lilly (18 May 2004), “Non-Stimulant Strattera More Widely Available for Attention-Deficit/Hyperactivity Disorder Patients in Europe”, PR Newswire. [This press release gives the dates for Stattera's regulatory approval in the U.S.A. and several European countries.]

Furberg C.D., Levin A.A., Gross P.A., Shapiro R.S., Strom B.L. (2006), “The FDA and drug safety: a proposal for sweeping changes”, Archives of Internal Medicine, 166: 1938–1942. [This is the article by current or former members of the FDA Drug Safety and Risk Management Advisory Committee, quoted above.]

Himpel S., Banaschewski T., Heise C.-D., Rothenberger A. (2005), “The safety of non-stimulant agents for the treatment of attention-deficit hyperactivity disorder”, Expert Opinion on Drug Safety, 4: 311–321. doi: 10.1517/14740338.4.2.311. [This includes discussion of bupropion and tricyclic antidepressants.]

Kociancic T., Reed M.D., Findling R.L. (2004), “Evaluation of risks associated with short- and long-term psychostimulant therapy for treatment of ADHD in children”, Expert Opinion on Drug Safety, 3: 93–100. doi: 10.1517/14740338.3.2.93.

Mague S.D., Andersen S.L., Carlezon W.A. Jr. (2005), “Early developmental exposure to methylphenidate reduces cocaine-induced potentiation of brain stimulation reward in rats”, Biological Psychiatry, 57: 120–125. doi: 10.1016/j.biopsych.2004.10.037. [This study, on rats, indicates that Ritalin use during childhood increases the chance of depression in adulthood.]

McDonagh M.S., Peterson K. (2006), Drug Class Review on Pharmacologic Treatment for ADHD (Oregon Health & Science University). [A thorough review of the scientific literature on drugs for ADHD; available from here.]

Moll G.H., Hause S., Rüther E., Rothenberger A., Huether G. (2001), “Early methylphenidate administration to young rats causes a persistent reduction in the density of striatal dopamine transporters”, Journal of Child and Adolescent Psychopharmacology, 11: 15–24. doi: 10.1089/104454601750143366. [This study, on rats, indicates that when Ritalin is given to juveniles, it induces changes in the brain that endure through to adulthood.]

NTP-CERHR [National Toxicology Program – Center for the Evaluation of Risks to Human Reproduction] (2005), The Potential Human Reproductive and Developmental Effects of Methylphenidate, NIH Publication No. 05-4473. [This monograph was written by an expert panel that was convened under the auspices of the U.S. Department of Health and Human Services.]

Virani A. (November 2005), “Spotlight on atomoxetine”, Canadian Child and Adolescent Psychiatry Review, 14: 96–98. [A discussion of the data on Strattera and suicide.]

Wood A.J.J. (2006), “A proposal for radical changes in the drug-approval process”, New England Journal of Medicine, 355: 618–623. [This is the commentary quoted above.]

Douglas J. Keenan