Mechanism of Action in ADHD

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Most researchers believe that low levels of the neurotransmitter dopamine play an active role in ADHD symptoms. Most medications that are utilized with ADHD (e.g., stimulants and antidepressants) are designed to correct this dopamine deficit and address associated symptoms, such as depression, anxiety, aggression and addiction. Both stimulant and non-stimulant medications are prescribed to control the symptoms of ADHD. However, stimulants are prescribed more often than other types of medications.



Stimulants are central nervous system medications that affect dopamine levels by blocking reuptake (i.e., the reabsorption of dopamine by neurons, cells in the brain and central nervous system). These medications may also block some of the metabolic enzymes that absorb loose dopamine. One of the most desirable qualities of stimulants is that they work quickly. Beneficial effects begin within 20 minutes of dosing and last up to 3 to 4 hours (except when they are made in extended release forms, see below).

It may seem contradictory to give a hyperactive individual stimulant medication. As described previously, ADHD is actually a result of lower levels of brain functioning. This finding explains why introducing stimulants to over-active or impulsive individuals helps them better manage their ADHD related symptoms- it raises their brain functioning activity level to within a normal range. In addition, stimulants also activate brain inhibitory and self-organizing mechanisms, which helps focus attention and manage impulses, thus allowing the person to have greater control over his or her own behavior.

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Stimulants are considered Class II medications, which means that they have a potential for abuse, and that their use is monitored by the Drug Enforcement Agency. Physicians who prescribe these medications must follow special procedures (e.g., prescriptions must be written rather than phoned in, and only a one month supply can be distributed at a time).

Research has shown that 70%-95% of individuals who take stimulants have positive results. Frequently prescribed stimulants include:

  • Methylphenidates (e.g., Ritalin, Concerta, Metadate, Focalin) - This family of stimulants is used to treat both ADHD and narcolepsy.
  • Dextroamphetamines (e.g., Dexedrine, Vyvanse)
  • Amphetamines (e.g., Adderall). Adderall was approved by the FDA in the 1960's for the treatment of obesity and ADHD.
  • Pemoline (Cylert) - This medication has been used to treat ADHD, dementia, depression, anxiety and even schizophrenia. It is no longer frequently used because of the potential for serious side effects (see below).

Ritalin is the most common medication prescribed for ADHD. The initial prescribed dosage is 5 mg of the short-acting variety for young children and 10 mg for older children, adolescents and adults. Most people take a morning and a lunch dose. Some individuals also require a mid-afternoon dose in order to complete homework or other necessary tasks. Patients (and parents) are encouraged to track their medication response and report back to the prescribing doctor. The doctor will gradually increase the dosage if the patient is not experiencing the desired effect (and minimal side effects are present). Children should not increase the dosage without consulting with their doctor. The patient, parents and doctor will continue to evaluate the effectiveness of the medication, continuing to increase the dose as necessary. The maximum recommended dosage of Ritalin is 60 mg per day, which should be tried prior to switching to a different medication.

If Ritalin is effective, the doctor may recommend switching to the slow release form in order to avoid the need for more than one dose per day. Ritalin SR is available in 20 mg tablets and is designed to last for a full 8 hour day. It should be tried only when a patient has responded well to two 10 mg doses in the morning and at noon. However, there are some problems with this form: the effectiveness period is delayed for an hour and a half, and may not actually last the full 8 hrs, fading instead at a little over 5 hours. In addition, a 20 mg dose of Ritalin SR may not be as effective as two 10 mg doses. Finding the most effective dose may require patience and flexibility as different strategies are tested.

If one medication is not effective for ADHD, there is a 25% chance that another stimulant medication will be. Unfortunately, there is currently no screening test that can allow doctors to determine which medication will work best with a particular individual. Medications must be tried, evaluated, and discarded as needed until an effective medication dosage with manageable side effects is found.

If Ritalin does not prove effective, Dexedrine is the most likely next medication of choice. Dexedrine is prescribed for about 12% of people with ADHD who are treated with medication. In addition to impacting the release and reuptake of dopamine, Dexedrine also decreases the reuptake of norepinephrine (another neurotransmitter that affects ability to pay attention and focus), increasing overall norepinephrine levels. This medication produces a decreased sense of fatigue, an increase in motor activity and mental alertness, mild euphoria and generally a better outlook on life. In addition, the drug causes increased heart rate, blood vessel constriction and bronchial dilation.

The primary concern regarding its use is related to its potential as a street drug. It is twice as powerful as Ritalin and is highly desirable in the drug world. A 5 mg dose generally lasts 5 to 6 hours. The use of Dexedrine adds flexibility in that there are 3 strengths of slow release tablets. Although these are more reliable than slow release Ritalin, they are harder to obtain because they are more closely watched by the DEA.

The medication named Obetrol became known as Adderall in 1994. Adderall consists of a mixture of amphetamines that result in a longer active period (twice as long as Dexedrine). Both objective (performance on school work) and subjective (teacher ratings) measures indicate that Adderall has a positive effect on ADHD symptoms. The side effects of Adderall are similar to Dexedrine. A large advantage is that this medication usually requires only one dosage per day. The recommended dose for children is 5 to 60 mg.

Pemoline (Cylert) was first developed in 1956 in Germany. Subsequently, the United States Food and Drug Administration (FDA) concluded that the overall risk of developing liver damage from using Pemoline outweighed the potential benefits. As a result, in May 2005, Abbott ceased sales and marketing of their brand of Pemoline (Cylert) in the U.S. In October 2005, all companies that produced generic versions of Pemoline also agreed to stop sales and marketing of this medication.

In 1999, new medication delivery systems were invented that eliminate the need for multiple doses across the day or for taking medication at school. These new systems include pellets of medication coated with various time-release substances to permit medications to dissolve hourly across an 8-12 hour period (e.g., Medadate CD, Adderall XR, Focalin XR) and an osmotic pump placed just under the skin that introduces medication directly into the blood stream in order to extend the effective period across an 8-12 hour period after ingestion (Concerta). Both forms eliminate dosage fluctuations, allowing a once-daily option. There is a great deal of excitement regarding these new options. However, their true viability and effectiveness will only be established after more research is complete.

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