Ritalin: The Case History of a Drug One of the most noticeable and prevalent disorders occurring in children is attention deficit hyperactivity disorder (ADHD). It is commonly diagnosed when the child begins to attend school or kindergarten, and occurs in 3 to 5% of the population. A chronic condition, it normally carries over into adolescence and perhaps into maturity as well. ADHD children can be hyperactive, inattentive, distractible, aggressive and impulsive, and as a result tend to do poorly in school and present behavioral problems both in academic, social and familial settings. ADHD adolescents, in addition to the above-mentioned difficulties, may be disposed toward delinquency and involvement in car accidents and substance abuse. Co-occurring disorders such as conduct disorder, anxiety and depression tend to exacerbate both the symptoms and the difficulty of treating ADHD. (Hyman, 2000)

Unfortunately there is no single diagnostic test to establish ADHD, and the etiology of the syndrome is not understood. Only when the behavioral symptoms are of an established and on-going nature should the possibility of ADHD be entertained. Minor neurological signs and abnormalities in the EEG may indicate on a medical basis that ADHD is present, as may learning disabilities identified by the educational system. Typically, a diagnosis of ADHD should be derived from medical, psychological, educational and family input and consultation. (Novartis Pharmaceutical Corporation, 2001)

For many children with ADHD, the drug Ritalin hydrochloride (methylphenidate hydrochloride USP), administered as part of an overall treatment program including psychological, educational and social measures, has proved to be highly effective in controlling the symptoms of the disorder. More than 160 clinical trials, involving more than 5000 children over a period of 30 years, have consistently shown that Ritalin was effective in improving the situation of over 80% of those treated. (Hyman, 2000) It does not, however, cure ADHD, and because of ADHD's chronic nature, the patient is faced with a long-term, ongoing program of treatment in order to mitigate the symptoms alone. Although the effects of taking Ritalin for periods longer than fourteen months have not received adequate study, doctors have concluded that there are no long-term detrimental consequences in adults to the childhood use of Ritalin when properly diagnosed and administered. (Hyman, 2000)

However, there are also strong objections to the use of Ritalin from certain groups. Their objections include the possibility of Ritalin being used by children or adults for whom it was not prescribed, as a recreational drug; the possibility of overdosing children into a zombie-like state of obedience; the possibility of arriving at a false diagnosis; and the danger of Ritalin's side effects.

Ritalin is a mild central nervous system stimulant, which appears to activate the brain stem arousal system and cortex. It is administered orally in tablets of 5, 10 and 20 mg, or as sustained-release tablets of 20 mg. The sustained-release tablets allow similar extensiveness in the amount absorbed, but at a slower, more constant rate, than does the regular tablet. (Novartis Pharmaceuticals Corporation, 2001)

Ritalin, according to Novartis, the manufacturer, is not indicated for children under the age of six. Also, it should not be prescribed for those with primary psychiatric disorders, including psychosis, or those whose environmental factors are primary to the ADHD symptoms. Its use should be supported socially, educationally and psychosocially. It is contraindicated for those suffering from severe anxiety, tension and agitation, glaucoma, Tourette's syndrome, tics, or hypersensitivity to Ritalin itself. It should be prescribed with caution for those patients who exhibit hypertension and/or high blood pressure. Patients taking other medications, prescribed or otherwise, should be carefully assessed by their physician before starting them on Ritalin. (Novartis Pharmaceuticals Corporation, 2001)

In spite of these admonitions, certain side effects are sometimes experienced, the most usual being nervousness and insomnia. These problems can be mitigated either by reducing the dosage, using less in the evening before bedtime; in some cases, they disappear as the body accustoms itself to the drug. Some children experience loss of appetite, which also may improve after a while, or which can be accommodated by giving snacks or cutting back the medication prior to mealtime. Other possible side effects are abdominal pain, weight loss and tachycardia. (Novartis Pharmaceuticals Corporation, 2001) Some patients experience "rebound," an exacerbated state of depression or irritability as the drug begins to wear off. Smaller, more frequent doses can alleviate rebound. Caffeine intake may cause depression, irritability and the jitters, and may have to be reduced. (Watkins and Brynes, 2001)

More serious side effects can include hypersensitive skin conditions, anorexia, persistent nausea, dizziness, blood pressure and pulse changes, angina, cardiac...

It is not clear if the following occurred because of taking Ritalin, but they have been known to occur in Ritalin patients: abnormal liver function, cerebral arteritis and/or occlusion; leukopenia and/or anemia; and scalp hair loss. (Novartis Pharmaceuticals Corporation, 2001)
Acute overdoses of Ritalin have produced vomiting, tremors, confusion, euphoria, convulsions, sweating, headache, irregular heartbeat, and dryness of the mucous membranes. (Novartis Pharmaceuticals Corporation, 2001)

Overdosing, in the sense of prescribing slightly more than the patient needs to control the symptoms of ADHD, can lead to compulsions and to a zombie-like demeanor. A study was conducted for the American Medical Association to address the concerns of those fearing the prevalence of wholesale prescription of Ritalin to dope difficult children into submission. It found that while some children may be misdiagnosed or prescribed Ritalin although alternative therapies exist, in general there was little evidence of over-prescription or overdiagnosis. (Goldman, Genel, Bezman, Slanetz, 1998)

Prolonged use has been shown to inhibit growth in prepubertal children while the drug was being taken, but the patient appeared to "catch up" when the Ritalin use stopped. (Klein and Mannuzza, 1988) It did not appear to have this, even temporary, effect in a study of 31 adolescent boys. (Vincent, Varley and Leger, 1990)

The Drug Enforcement Agency of the U.S. Department of Justice urges "greater caution and more restrictive use of" methylphenidate, citing the illicit use of the drug. According to their statistics, a 1994 survey of high school seniors (Monitoring the Future) showed that more students were taking the drug illegally than were taking it via a legitimate prescription. They also claim that Ritalin ranks in the top ten pharmaceuticals stolen and sold illegally, and that it is a prime target of organized traffickers for theft and sale. When used for recreational purposes, the drug is usually crushed and snorted or injected like cocaine or crystal meth, with the anticipated result being euphoria and a rush, and the unintentional result being addiction and in some cases death. The DEA appears to believe that, in addition to this illicit use, Ritalin is over-prescribed, citing the belief that the U.S. produces and uses five times as much as the rest of the world put together, and that the production quota has increased almost six-fold from 1990 to 1995. (DEA Press Release, 1995)

Both the DEA and agencies such as the Attention Deficit Help Center believe that, whether prescribed or used illegally, the use of methylphenidate is conducive to increased tolerance and dependence/addiction. (Attention Deficit Disorder Help Center information)

Although the exact mechanism of methylphenidate's efficacy is not understood, it is believed that it increases the synaptic concentration of dopamine by blocking the dopamine transporters. Administered in carefully calibrated dosages, referenced to the patient's weight, it starts to act within an hour, and is likely to occupy more than half of the dopamine transporters. (Volkow et al., 1998)

The process, chemically speaking, involves methylphenidate's binding to a site on the dopamine receptor, thus inhibiting dopamine re-uptake and enhancing synthetic dopamine. The psychostimulation which results regulates the attention of the subject and allows him or her greater impulse control.

Louis Pasteur was the first to observe that roughly fifty percent of organic compounds, and notably racemic acid, can contain mirror-image forms which demonstrate handedness, that is, they rotate light either to the left or to the right. When this occurs, a chiral center (sometimes called a stereocenter) is created. In stereochemical terms, the two mirror images, the left- and right-handed compounds, are referred to as enantiomers, or optically active compounds. A mixture of the two enantiomers is called a racemate or racemic mixture. Molecules lacking handedness are achiral, and those possessing handedness are chiral. (Greener, 2001)

Racemic methylphenidate was first developed in 1994 by Panizzon, and marketed as a mixture of two racemates, 80% erythro and 20% threo. The desired effect (the central stimulant activity) proceeded, however, only from the threo racemate. Thus, Novartis, the manufacturer who had secured the patent on the Ritalin form of methylphenidate, has since 1950 been engaged in on-going research to enrich the enantiomeric purity of threo-methylphenidate hydrochloride. If this could be achieved, it would segregate the pharmacological activity of Ritalin from the undesirable side effects. From a manufacturing perspective, this process also must be cost-effective in terms of yield, process time and other factors. (Prashad, 2001)

Initial attempts centered around classical resolution approaches, which if practicable would have the positive economic effect of recycling the undesired enantiomer through racemization. However, because of…