Assessing the abuse potential of methylphenidate in nonhuman and human subjects: a review

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Abstract

Methylphenidate (MPH) is widely used for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in children, adolescents, and adults. Methylphenidate is clearly effective for the treatment of ADHD, but there is controversy as to whether it has significant abuse potential like other psychostimulants (e.g., d-amphetamine and cocaine). In general, the drug is believed to be abused at rates much lower than those for other stimulants. The present review examines studies that investigated the behavioral pharmacological profile of methylphenidate and discusses how results from these studies address its abuse liability. Using MEDLINE search terms methylphenidate, drug discrimination, reinforcement, self-administration, subjective effects, subject-rated effects, abuse potential, and abuse liability, along with a review of the references from identified articles, 60 studies were located in which the reinforcing, discriminative-stimulus, or subjective effects of methylphenidate were directly assessed in nonhumans or humans. Forty-eight (80.0%) of the studies reviewed indicate that methylphenidate either functions in a manner similar to d-amphetamine or cocaine (e.g., functions as a reinforcer, substitutes fully in drug discrimination experiments), or produces a pattern of subjective effects suggestive of abuse potential. The results are discussed as they pertain to factors that may account for the apparent discrepancy in abuse rates between methylphenidate and other stimulants, including characterization of actual abuse rates, defining abuse and misuse, pharmacokinetic factors, and validity of abuse liability assays.

Introduction

Methylphenidate (MPH, Ritalin) is one of the most commonly prescribed psychoactive drugs in the United States (Cardinale, 1996). Clinically, it is used primarily in the management of Attention Deficit Hyperactivity Disorder (ADHD) and recent prevalence estimates suggest that between 6% and 7% of all school-aged children are prescribed the drug for such behavioral problems (Safer et al., 1996). Methylphenidate's efficacy has been documented for treating a range of behaviors across a variety of settings (Swanson et al., 1993). Despite its documented efficacy, questions have arisen regarding the potential misuse and abuse of this stimulant drug. A number of single-case studies exist in the literature describing intranasal or intravenous use of prescribed methylphenidate Garland, 1998, Jaffe, 1991, Levine et al., 1986, Massello and Carpenter, 1999, Parran and Jasinski, 1991. Furthermore, there is evidence, primarily from nonscientific sources, that methylphenidate misuse and abuse may be widespread among adolescents and college students, with the drug garnering such street names as “Vitamin R,” “Skippy,” and “the smart drug”Drug Enforcement Administration, 2000, Llana and Crismon, 1999, Stepp, 1996, Vogt, 1999.

Methylphenidate is a piperidine derivative structurally related to amphetamine. The neuropharmacologic profile of methylphenidate is similar to that of other commonly used or abused stimulants like cocaine (Hoffman and Lefkowitz, 1996). Methylphenidate, like cocaine, blocks the dopamine transporter (DAT) (Ritz et al., 1987). Methylphenidate and cocaine are very similar in terms of their actions at the DAT Gatley et al., 1999, Volkow et al., 1999a, Volkow et al., 1999b. In baboons, for example, methylphenidate and cocaine produce comparable increases in synaptic dopamine levels (Volkow et al., 1999a). As another example, the in vivo potency of methylphenidate at the DAT is comparable to that of cocaine in human brain (Volkow et al., 1999b). In humans, the regional distribution of [11C] methylphenidate is almost exactly the same as that of [11C] cocaine (Volkow et al., 1995).

Because of its structural and pharmacological similarity to drugs such as cocaine and d-amphetamine, there is reason to suspect that methylphenidate may have significant abuse potential, and as a result, the drug has been regarded in conflicting ways by clinicians, scientists, and policymakers. One study that surveyed children and adolescents who had been prescribed methylphenidate found that nearly one in five had been approached to sell, give away, or trade their medication at least once in the past 5 years (Musser et al., 1998). The Drug Enforcement Administration (DEA) has recently expressed concern that diversion of methylphenidate and subsequent misuse is increasing in prevalence and have suggested that rises in methylphenidate production from 1768 kg in 1990 to 14 957 kg in 1999 have resulted in increased availability of the drug (Drug Enforcement Administration, 2000). Several indices of methylphenidate misuse have also steadily increased in the same time frame, such as the number of reported thefts from licensed handlers of the drug and the number of young people who have reported using it without a prescription Drug Enforcement Administration, 1995, Feussner, 1998. In a recent testimony to the United States Congress, a DEA spokesperson cited information from case files and state investigative services suggesting that the drug has been illegally diverted in several ways, as evidenced by thefts of the drug from pharmacies and schools; ADHD “scams” in which parents obtain multiple prescriptions from different doctors and then use the drug illegally, sell, or trade it; undercover street sales; multistate distribution rings; multidrug distribution rings (along with cocaine and other substances); and smuggling from Mexico (Drug Enforcement Administration, 2000).

The data collection methods and reporting standards of the DEA have been criticized, however, and some have argued that the problem of methylphenidate misuse is not as alarming when base rates for prescriptions are considered. A number of empirical studies have also cast doubt on the notion that methylphenidate possesses significant abuse potential compared to other stimulants. For example, one study reported that despite comparable regional distribution patterns in the brain, intravenously administered methylphenidate was pharmacologically distinct from cocaine, particularly in the rate at which the drugs were cleared from the brain (Volkow et al., 1995). These authors concluded that this difference may account for the more prevalent abuse of cocaine as compared to methylphenidate (National Institute on Drug Abuse, Community Epidemiology Work Group (CEWG) 1995). Others have described reports of methylphenidate abuse in the literature as “anecdotal and uncommon” and have highlighted the discrepancy between the abuse potential and production of methylphenidate and the actual pattern and prevalence of its abuse (Cooper, 1998 p. 206).

Based on some of this controversy and the recent attention that methylphenidate has received, the purpose of the present paper is to evaluate the behavioral pharmacological profile of methylphenidate in both nonhumans and humans with an emphasis on those dependent measures that have traditionally been used to assess a drug's relative abuse potential: (1) the reinforcing effects, (2) the discriminative-stimulus effects, and (3) the subjective effects in humans. By reviewing this literature, the question of whether or not methylphenidate has the potential to be abused can be explicitly addressed. The behavioral pharmacological profile of a drug considered by itself, however, is not entirely predictive of drug misuse or abuse. Indeed, there are many factors beyond behavioral pharmacological properties that influence the likelihood that a substance will be abused, including biological and social determinants (Altmann et al., 1996). With such factors in mind, a comprehensive summary of the abuse potential of methylphenidate will allow for a critical analysis of the characteristics that contribute to its comparative abuse patterns with other similar drugs, especially cocaine and d-amphetamine.

We will first consider the relevance of the behavioral pharmacological profile of a drug in both nonhumans and humans as it pertains to the drug's abuse potential. Then, we will review research examining the reinforcing, discriminative-stimulus, and subjective effects of methylphenidate. Finally, we will discuss factors that may account for the relative abuse patterns of methylphenidate and other stimulants and suggest potentially important areas for future empirical work.

Section snippets

Assessing the abuse potential of drugs

An important component in the development, marketing, and ongoing clinical assessment of any psychoactive drug is a thorough evaluation of its potential for abuse and dependence. Decisions regarding the eventual approval of a drug and the manner in which it is controlled and prescribed are guided, to a large extent, by research targeting a drug's potential for abuse. The history of such abuse potential testing has been concisely reviewed elsewhere (Jaffe and Jaffe, 1989). The methods by which a

Selection of studies for review

To select studies for review, we first performed a MEDLINE search using the following key terms, all in combination with the term “methylphenidate” and the Boolean operator “AND”: self-administration, reinforcing effects, reinforcement, discriminative-stimulus effects, drug discrimination, subjective effects, subject-rated effects, abuse liability, and abuse potential. This initial search yielded 127 studies. At this point, studies from each search were examined for their relevance to assessing

Nonhuman studies

Eleven studies that examined the reinforcing effects of methylphenidate were conducted with nonhuman species (Table 1). In seven of these, methylphenidate self-administration was examined using traditional procedures, wherein an indwelling catheter was used to deliver contingent administration of methylphenidate following some learned response Aigner and Balster, 1979, Bergman et al., 1989, Collins et al., 1984, Nielsen et al., 1983, Risner and Jones, 1975, Risner and Jones, 1976, Wilson et

Nonhuman studies

Seventeen of the twenty studies that assessed the discriminative-stimulus effects of methylphenidate were conducted with nonhuman species (Table 2). In 10 of these, either cocaine or d-amphetamine was used as the training drug and methylphenidate was examined as a substitution drug Colpaert et al., 1979, de la Garza and Johanson, 1987, Emmett-Oglesby et al., 1983, Evans and Johanson, 1987, Huang and Ho, 1974, Kleven et al., 1999, McKenna and Ho, 1980, Rosen et al., 1985, Silverman and Ho, 1980,

Subjective effects of methylphenidate

A total of 25 studies were identified that have investigated the subjective effects of methylphenidate in human participants (see Table 3). Of the seven studies reporting comparative data on methylphenidate and d-amphetamine, all reported that methylphenidate alone significantly increased subjective effects on POMS scales (e.g., Chait, 1994, Smith and Davis, 1977), ARCI subscales (e.g., Chait, 1994, Heishman and Henningfield, 1991, Martin et al., 1971, Rush and Baker, in press, Rush et al., 1998

Implications and directions for future research

Clearly, methylphenidate has a behavioral pharmacological profile similar to other abused stimulants. Overall, 48 out of 60 (80.0%) of the studies reviewed indicate that methylphenidate functions behaviorally in a manner similar to d-amphetamine or cocaine (i.e., produces comparable reinforcing, discriminative-stimulus, or subjective effects). These findings are neither novel nor surprising based on the neuropharmacological profile of the drug. Research, however, has failed to adequately

Summary and conclusions

The present review highlights the similarities between methylphenidate and the commonly abused stimulants, cocaine and d-amphetamine. Although the behavioral pharmacological profile of these drugs is very similar, the actual rates of abuse are believed to be much lower for methylphenidate. However, what little data exist on the actual prevalence rates of methylphenidate and other stimulant abuse suggest that this issue may be in question (e.g., Indiana Resource Prevention Center, 1999). We have

Acknowledgements

Work on this manuscript was supported in part by a grant from the National Institute on Drug Abuse (DA10325) to C.R.R.

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