"We know that drugs that cause euphoria are potentially abusable, and euphoria requires rapid delivery to the brain. Using sophisticated PET scan imaging, we were able to examine the rate of delivery of both rapid- and delayed-release formulations of methylphenidate and correlate those results with how the drugs felt to study volunteers," says Thomas Spencer, MD, of the MGH Pediatric Psychopharmacology Unit, the paper's lead author. "The ability to show that rate of brain delivery may determine abuse potential is important to our understanding of the safety of different formulations."
Methylphenidate and other stimulant drugs used to treat ADHD act by blocking the dopamine transporter, a molecule on brain cells that takes up the neurotransmitter dopamine, raising its level in the brain. Studies have shown that the brains of ADHD patients have abnormal regulation of dopamine, which plays a key role in the control of movement, behavior and attention. While stimulants are effective for controlling ADHD symptoms, the drugs are also subject to abuse, so the current study was designed to compare the abuse potential of two formulations of methylphenidate.
The researchers compared a traditional, quick-release form of the drug with Concerta, a formulation that is released over 12 hours to produce a gradual increase in blood levels. With Concerta, the drug passes slowly through a hole in capsules that do not dissolve, reducing the possibility that the gradual-release feature might be bypassed. Study participants received the two medications at dosages designed to produce comparable peak levels in the blood and brain.
Twelve adult volunteers, none diagnosed with ADHD or any neurological or psychiatric disorder, were randomly assigned to receive either the immediate-release or delayed-release form of methylphenidate on two separate days. PET scans - which showed whether or not the dopamine transporter molecule was occupied by the medication - were taken the day before drug administration as a baseline, one and three hours after the first drug administration and five and seven hours after a second drug administration on a different day. During the 10 hours after each drug administration, hourly blood samples were taken from the volunteers, who also completed hourly questionnaires regarding whether they were aware of the drug's effects and whether they enjoyed or disliked those effects.
As expected, the delayed-release formulation took longer to produce maximum blood levels and blockade of the dopamine transporter than did the immediate-release drug. While most of those receiving immediate-release methylphenidate reported detecting and enjoying the drug's activity, few of those receiving the delayed-release form were aware of or enjoyed the drug's effects.
"The differing reports on feeling and liking the drug effects occurred despite using larger doses of the delayed-release formulation and the equivalent peak blood and brain levels," says Spencer. "Previous studies have showed that both versions are effective for treating ADHD. Whether delayed- or sustained-release formulations of other potentially abusable ADHD drugs share the same safety characteristics needs be studied, since different forms vary in the levels and timing of drug delivery." Spencer is an associate professor of Psychiatry at Harvard Medical School.
The study was supported by grants from the National Institute of Mental Health and McNeil Consumer & Specialty Pharmaceuticals, which manufactures Concerta. The study's co-authors are Joseph Biederman, MD, Bertha Madras, PhD, and Darin Dougherty, MD, of MGH Psychiatry; Ali Bonab, PhD, Elijahu Livni, PhD, and Alan Fischman, MD, PhD, of MGH Radiology; and Patrick Ciccone, MD, and Dolly Parasrampuria, PhD, of McNeil.
Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of nearly $500 million and major research centers in AIDS, cardiovascular research, cancer, cutaneous biology, medical imaging, neurodegenerative disorders, transplantation biology and photomedicine. In 1994, MGH and Brigham and Women's Hospital joined to form Partners HealthCare System, an integrated health care delivery system comprising the two academic medical centers, specialty and community hospitals, a network of physician groups, and nonacute and home health services.