Although her primary research interests involved neuroimaging studies of patients with alcohol or substance abuse problems, Nora Volkow, MD, found herself increasingly intrigued by methylphenidate, the stimulant widely prescribed for treating attention-deficit/hyperactivity disorder (ADHD). From a pharmacological standpoint, methylphenidate is the drug that most resembles cocaine. Yet, despite the fact that methylphenidate is frequently abused, users do not become severely addicted or exhibit the desperate binges that can sometimes lead cocaine users to take the drug every half hour for days at a time.
An explanation for these intriguing observations has emerged from an innovative series of studies that Dr. Volkow has conducted during the past decade. These studies not only suggest why methylphenidate is relatively nonaddictive but have also helped shed light on why the drug improves symptoms of ADHD. Dr. Volkow, who is Associate Director of the Laboratory for Life Sciences at Brookhaven National Laboratory in Upton, New York, reviewed these studies at the annual meeting of the American Academy of Child and Adolescent Psychiatry, as part of a symposium examining the mechanisms of stimulants in the treatment of ADHD.
SAME TARGET, DIFFERENT EFFECTS
Studies by Dr. Volkow and colleagues using positron emission tomography (PET) have shown that the distribution of cocaine and methylphenidate in the brain after administration is almost identical: Not only do the two drugs accumulate in the same regions, but they bind to the same molecule, the dopamine transporter. For example, in one of Dr. Volkow’s studies, human volunteers with a history of cocaine abuse were given methylphenidate and, shortly thereafter, a dose of 11C-labelled cocaine. PET was unable to detect any radio-labeled cocaine in the brain, indicating that the drug’s binding sites were occupied by methylphenidate. Similarly, administration of cocaine blocked the binding of a subsequent dose of radio-labeled methylphenidate.
The dopamine transporter, of course, is the molecule that binds to dopamine in the extracellular space and recycles the neurotransmitter by returning it to the neuronal terminal. But when the transporter is blocked, as it is by cocaine and methylphenidate, dopamine accumulates in the extracellular space, producing strong signals in the brain’s reward centers (notably the striatum). The finding that cocaine and methylphenidate bind to the same target, reported by Dr. Volkow and colleagues in 1995, was particularly surprising given the difference in the addictive potential of the two medications. “I was very perplexed, and I didn’t know what to make of this,” Dr. Volkow admitted.
Because a drug’s effects are influenced not just by its molecular target but also by how long it takes to reach that target, Dr. Volkow hypothesized that differences in pharmacokinetics were responsible for the divergent effects of cocaine and methylphenidate. “The temporal course—the dynamic interaction of the drug with the brain—has profound effects automating the responses to the drug,” she noted. For example, intravenous injection (which gets a drug into the brain quickly) is more reinforcing than administering the same medication orally; in fact, injected caffeine produces a “high” very similar to that of cocaine.
IN QUICKLY, OUT SLOWLY
Using PET, Dr. Volkow confirmed that cocaine does get into the brain quickly—in about five minutes—and that it is cleared rapidly as well; the drug “has basically disappeared from the brain at 40 minutes,” she said. But to her surprise, uptake of intravenously administered methylphenidate proved to be nearly as fast: large amounts are already present in the brain within eight to 10 minutes. However, the psychostimulant is cleared much more slowly than cocaine is, so that substantial levels are still present 90 minutes after administration.
Methylphenidate’s relatively slow clearance presented something of a conundrum, Dr. Volkow noted, because one could speculate that if blockade of the dopamine transporter is central to a drug’s effects, then methylphenidate “should be more reinforcing than cocaine, because it stays there longer.” To investigate the issue further, she and her colleagues collected self-reports of subjects’ perceptions during the PET sessions. The findings revealed that the time course of a patient’s high following cocaine administration largely mirrors the drug’s pharmacokinetic properties, peaking about four to five minutes after administration and returning nearly to baseline after 20 minutes.
Somewhat surprisingly, the study participants reported a similar pattern with methylphenidate, with the high peaking, again, around five minutes after administration and largely dissipating after 20 minutes. The PET scans, however, confirmed that the drug continued to block the dopamine transporter, indicating that the presence or length of dopamine transporter blockade is not the essential variable for reinforcement. Instead, Dr. Volkow said, what seems to matter is the rate at which blockade occurs. Thus, it is the rush of dopamine blockade following injection of cocaine or methylphenidate that produces the high, whereas the subsequent period of continued binding and clearance (whether slow, as with methylphenidate, or fast, as with cocaine) has little impact on the perception of pleasure.
However, methylphenidate’s slow clearance may protect against abuse of the drug. Because cocaine is rapidly removed from the brain, dopamine transporters are soon free to bind to another dose of cocaine, allowing users to experience another high in as little as 20 to 30 minutes; this sets up the potential for binges lasting hours or even days. But because methylphenidate continues to block dopamine transporters after the high dissipates, potential abusers who take another dose 60 or even 90 minutes later do not experience the desired effect. “Slow clearance interferes with repeated, frequent administration,” Dr. Volkow stated.
DOES POTENCY MATTER?
Another factor that may come into play is a drug’s potency—in this case, the level of dopamine transporter occupancy required to produce a high. Although Dr. Volkow’s search of the animal literature revealed hundreds of papers examining cocaine’s ability to block the dopamine transporter, none of the studies had determined the occupancy rate necessary to produce a high; moreover, the speculative estimates offered by some authors varied 20-fold. The methylphenidate literature on the topic was similarly unenlightening.
Dr. Volkow and colleagues proceeded to explore this issue by using a radioactive compound that binds to the dopamine receptor. By varying the dose of the compound—as well as subsequent doses of cocaine or methylphenidate—one can calculate how many dopamine transporters are occupied by either drug and whether occupancy rates predict the presence and intensity of a high. The findings revealed that, with intravenous cocaine, an occupancy rate of at least 50% is necessary to produce a high; this level of blockade corresponds to a dose of about 0.13 mg/kg. (Abusers tend to use 0.3 to 0.6 mg/kg, a dose easily sufficient to produce a high.) Subjects with the highest transporter occupancy had the most intense highs.
Repeating the experiment with methylphenidate yielded a somewhat different picture, however. A 50% occupancy rate could be achieved with a dose of about 0.07 mg/kg, “so, if anything, methylphenidate is slightly more effective than cocaine at blocking these transporters,” Dr. Volkow noted. Yet the correlation between occupancy and the experience of a high, though still statistically significant, was not as strong as that for cocaine; in fact, one subject who achieved 80% blockade reported having no high at all. Thus, with methylphenidate, a blockade of at least 50% to 60%, though required for a high, is not necessarily sufficient.
The existence of such outliers, Dr. Volkow said, further suggests that the intensity of a high is influenced more by the amount of extracellular dopamine present than by the transporter occupancy rate per se. Though the concentration of extracellular dopamine is obviously influenced by the degree of dopamine transporter blockade, release of new dopamine is important as well. Thus, individual physiology comes into play. At certain levels of transporter blockade, individuals with low dopamine tone may fail to experience a high, whereas others whose dopaminergic neurons are more active may feel the desired effect.
This idea was supported by a PET study in which Dr. Volkow and colleagues gave subjects radio-labeled raclopride, another ligand that binds to dopamine receptors. When study participants were given methylphenidate injections, extracellular dopamine accumulated (because dopamine transporters were blocked) and became bound to dopamine receptors, preventing raclopride from binding. The difference in raclopride binding between patients given methylphenidate and those who were drug-free or who received low doses provided a rough measure of how the drug affects extracellular dopamine levels.
The researchers found that the level of extracellular dopamine was a “much better predictor of the intensity of the high” than was the degree of dopamine blockade. Indeed, a methylphenidate dose of 0.5 mg/kg—not an inconsequential amount—failed both to produce a high and to change extracellular dopamine levels in some participants. Overall, changes in extracellular dopamine levels accounted for 61% of the variance in the intensity of the high that patients experienced, whereas dopamine transporter occupancy accounted for only 22% of the variance.
WHY METHYLPHENIDATE WORKS
Although most of the above studies used methylphenidate injections, the principles elucidated apply as well to the oral form of the medication that is used clinically. It turns out that the oral form, like its intravenously administered counterpart, is effective at blocking the dopamine transporter: Commonly used doses such as 0.5 mg/kg block approximately half of dopamine transporter molecules (nearly the same level of blockade one sees with injected cocaine).
Yet, in a study that Dr. Volkow conducted with normal volunteers, only one patient reported feeling high when receiving oral methylphenidate. The explanation, she said, again comes down to pharmacokinetics: “When you give oral methylphenidate, it takes ‘forever’ to reach peak concentrations in the brain”—more precisely, about one to two hours. Because the rate of uptake, rather than of dopamine transporter occupancy, is the key factor for the perception of a high, the oral form is not reinforcing. (Of course, abusers sometimes crush the tablets and snort the powder, which would accelerate uptake.)
Although one might assume from the research described above that methylphenidate improves function by increasing a patient’s level of extracellular dopamine, until recently the evidence supporting this hypothesis was scant—and came exclusively from studies involving very high doses of injected medication. But in a report published last year in the
Journal of Neuroscience,
Dr. Volkow and colleagues reported perhaps the best evidence to date that therapeutic doses of oral methylphenidate do indeed increase extracellular dopamine. The study, conducted in 11 healthy adults, revealed that methylphenidate (mean dose, 0.8 mg/kg) decreased striatal dopamine D2
receptor availability by 20%, a sign of increased dopamine. The extra dopamine may be particularly crucial to patients with ADHD: recent studies by two laboratories have found that adult patients with ADHD have a greater dopamine transporter density than do healthy controls. Because elevated transporter density should reduce levels of extracellular dopamine, the result is a weakening of relevant signals; as Dr. Volkow noted, the neurotransmitter wouldn’t have enough time to exert its effects, which include increasing the signal-to-noise ratio for target neurons. By making more extracellular dopamine available, methylphenidate in effect amplifies these weak signals, improving the signal-to-noise ratio.
All of this translates to the desired therapeutic effect because the dopamine system isn’t simply a reward circuit (as it is often portrayed to be). It’s also possible, Dr. Volkow said, to conceptualize dopamine as something that “makes a stimulus more attractive, more salient.” Thus, a previously “boring” homework assignment seems more appealing—and gets finished.
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Volkow ND, Wang GJ, Fischman MW, et al. Relationship between subjective effects of cocaine and dopamine transporter occupancy.
Volkow ND, Wang GJ, Fowler JS, et al. Relationship between psychostimulant-induced “high” and dopamine transporter occupancy.
Proc Natl Acad Sci U S A.
Volkow ND, Wang GJ, Fowler JS, et al. Dopamine transporter occupancies in the human brain induced by therapeutic doses of oral methylphenidate.
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Volkow ND, Wang GJ, Fowler JS, et al. Reinforcing effects of psychostimulants in humans are associated with increases in brain dopamine and occupancy of D2
J Pharmacol Exp Ther.
Volkow ND, Wang GJ, Fowler JS, et al. Therapeutic doses of oral methylphenidate significantly increase extracellular dopamine in the human brain.
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