Redefining the Recreational Drug User Population in Human Abuse Potential Studies

Human abuse potential (HAP) studies are essential to the development of central nervous system–active drugs and to evaluate the relative abuse potential of new drugs. Subjects in these studies are generally recreational (nontherapeutic) drug users who are not physically dependent on substances (excluding nicotine or caffeine).1-4 The Diagnostic and Statistical Manual of Mental Disorders (DSM) has been used in HAP studies to exclude subjects with substance dependence as recommended by regulatory authorities.4 In the fourth edition of the DSM (DSM-IV), issued in 1994 (and earlier versions), and the Text Revision in 2000, substance dependence and abuse were classified as 2 separate disorders, each based on distinct diagnostic criteria.5 In 2013, the fifth edition (DSM-5) was issued, and the 2 sets of criteria to establish dependence or abuse were merged, with some modification, into 1 set of criteria to establish a diagnosis of substance use disorder (SUD).6 Thus, dependence is no longer a diagnosis in the DSM-5 and no longer available to use as exclusionary criteria in HAP studies. These differences in diagnostic criteria between the DSM-IV and DSM-5 have been effectively described7; however, the implications of the DSM-5 in HAP studies have not been as widely discussed, and this dialogue is needed. Table 1 presents a summary of the diagnostic criteria in the DSM-IV and DSM-5. In the DSM-IV criteria, individuals who meet at least 3 of 7 criteria are classified as dependent substance users, whereas at least 1 of 4 criteria for abuse is required for a diagnosis. In the DSM-5 criteria, all 7 criteria for dependence and 3 of 4 criteria for abuse from the DSM-IV have been merged into 1 set of criteria for SUD. Other changes include removing the DSM-IV criterion “repeated legal problems” for abuse and adding 1 new criterion, “craving.” At least 2 of 11 criteria are required for a SUD diagnosis. In addition, SUD is further classified using a severity scale based on the positive responses (total number) as follows: mild SUD, 2 to 3; moderate SUD, 4 to 5; and severe, at least 6. The rationale for these changes is based on a concept that abuse and dependence are unidimensional rather than a hierarchy of dependence over abuse. At the time the DSM-IV was issued, abuse was assumed to be prodromal to substance dependence, and all cases of dependence were assumed to meet the criteria for abuse.7 However, nearly half the diagnoses of abuse were based on only 1 criterion (hazardous use). A unidimensional approach of combining the criteria of abuse and dependence was also adopted to eliminate the possibility of no diagnosis, commonly referred to as “diagnostic orphans,” which occurred with 1 or 2 positive responses to the criteria for dependence. The hierarchical approach resulted in a diagnosis of abuse that was considered milder than the diagnosis for dependence; however, given that 3 of 4 abuse criteria from the DSM-IV are included in the SUD diagnostic criteria, abuse criteria now have equal weight in the DSM-5. In terms of HAP studies, the approach used to identify an appropriate subject is no longer evident given the unidimensional criteria used to diagnose SUD in the DSM-5. Based on our experience in conducting HAP studies, the criteria in the DSM-IV are the most appropriate criteria currently available to identify nondependent recreational drug users. The nondependent recreational user is the target population typically enrolled in clinical trials designed to investigate the abuse potential of a drug. The Food and Drug Administration (FDA) considers that a drug has abuse potential if the drug is used for nontherapeutic reasons (eg, recreationally for the positive psychoactive effects the drug produces). Based on recommendations from the FDA for clinical conduct of HAP studies, experienced recreational drug users with a current diagnosis of substance dependence should not participate in these studies.4 Potential subjects are typically assessed by DSM-IV substance dependence clinical interviews as exclusionary criteria during the screening phase of a HAP study. Thus, abolishing the diagnosis of dependence from the DSM has regulatory implications for identifying the appropriate population to enroll in HAP studies. With some drugs (ie, opioids), where antagonists are available, an objective diagnosis of physical dependence is possible to confirm eligibility. However, for other classes of drugs, an objective pharmacological test is not available to confirm physical dependence, hence reinforcing the need for reliable diagnostic tools for use in HAP studies. It is important in HAP studies to enroll experienced recreational drug users who can tolerate minimally effective to supratherapeutic doses of a drug and are able to discriminate the effects of a drug compared with placebo.4 If subjects are excluded based on a SUD diagnosis (ie, at least 2 positive responses and meet the criteria for mild, moderate, or severe SUD), then the subject population enrolled may be less likely to have a positive experience when administered a supratherapeutic dose of a drug that is not well tolerated. The outcome may be that a larger number of subjects will be screened for qualification into the treatment phase because subjects with only 1 positive response are less likely to reliably experience the positive effects required to pass qualification criteria. If the severity scale (ie, mild, moderate, severe) in the diagnosis of SUD is considered, then which severity should be exclusionary in HAP studies? Another consideration regarding the severity scale is the variation in the behavioral characteristics of study populations that may be introduced given the extended range of criteria in the DSM-5 compared with the DSM-IV. For example, a pool of subjects with mild SUD (2 to 3 criteria) may combine subjects who meet 2 to 3 criteria previously associated only with abuse with subjects who meet 2 to 3 criteria previously associated only with dependence. In another scenario, enrolling subjects with moderate SUD (4 to 5 criteria) may include subjects who meet at least 3 criteria previously associated with dependence and therefore would have been excluded from HAP studies based on the DSM-IV. These issues highlight important challenges imposed by the DSM-5 to redefine the nondependent recreational drug user in HAP studies. Despite the release of the DSM-5 in May 2013, to our knowledge, no clinical HAP studies have been conducted using DSM-5. This is likely due, in part, to some of the challenges highlighted above in redefining the recreational drug user population. Who is the recreational drug user based on SUD diagnostic criteria in the DSM-5? Is a diagnosis of moderate SUD valid exclusionary criteria in a HAP study? Is mild SUD? Or perhaps all classifications of SUD (ie, mild, moderate, severe) should be exclusionary? Until a valid set of criteria for recreational drug users is defined, the ability to evaluate the relative abuse potential of a drug (ie, relative to a drug with an established abuse profile) will be impeded if HAP studies are conducted in varying subject populations or inadvertently include subjects who are physically dependent on a drug of abuse. The inability to interpret clinical data across HAP studies will affect the development of HAP study designs that rely on the established abuse profiles and appropriate selection of positive controls. A consensus of valid criteria is needed to redefine the nondependent recreational drug user. In step with this effort, a working task force comprised of psychiatrists, addiction specialists, clinical neuropsychologists, and pharmacologists has been created to address the issues raised by the introduction of the DSM-5. The working group is tasked with redefining the recreational drug user population and developing valid criteria that would be most suitable for HAP studies, while protecting individuals with SUD. Given the importance of HAP studies in drug development, comparative analysis of empirical data across studies is encouraged to redefine the nondependent recreational drug user. In the interim, we caution against adopting DSM-5 criteria as exclusionary criteria for SUD in HAP studies until a consensus is reached in the industry and regulatory authorities. Talar Hopyan, Pierre Geoffroy, Yuko Hirata, and Beatrice Setnik are employees of INC Research, Inc. Marta Sokolowska is an employee at Grünenthal USA, Inc.

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