Human abuse potential (HAP) studies play a crucial role in evaluating the safety and risks of new medications with psychoactive properties. These studies help determine the likelihood that a drug might be abused recreationally, which is an important component for regulatory approval of central nervous system (CNS)-active drugs. To assess these risks, HAP studies primarily rely on subjective outcome measures; while objective measures (like physiological responses) may be included in some studies, there are currently no objective measures that can assess the abuse potential of a drug.

What Are Subjective Measures?

Subjective measures are tools used to assess how a person feels or experiences the effects of a drug, using self-report scales or questionnaires. Assessments rely on the participant’s own observations and experiences during the study, making them inherently different from physical outcomes. Because subjective measures can be more variable than physiologic outcomes, HAP studies are typically designed as randomized crossover studies, where the test drug is compared to positive control and placebo using a within-participant design.

1. Drug Liking VAS, “At this Moment”: This bipolar measure assesses the appeal of a drug from the perspective of a potential user at the time that the question is asked, or “at the moment.” As such, this outcome is usually administered multiple times throughout a treatment period, and the peak effect or “E_max” is typically the primary endpoint in a HAP study.
2. End-of-Day/Next-Day VAS: These bipolar measures include the Take Drug Again VAS and Overall Drug Liking VAS. These measures determine how much the participant liked the drug overall (taking into account both positive and negative effects across the entire experience) and how likely they would be to take the drug again. These measures are often included in HAP studies as key secondary endpoints.
3. Other “At this Moment” Subjective VASs: These measure asks participants to rate other subjective effects that may be of interest to individuals who recreationally abuse drugs, such as feeling “high,” good effects, sedative, or stimulant effects. The “any drug effects” VAS assesses how strong the drugs effects are overall, while “bad effects” are evaluated to determine if there might be any potential averse effects that could counterbalance the positive effects. As with the Drug Liking VAS, these measures are administered multiple times during the study, with E_max as the endpoint of interest.
4. Drug Similarity VAS: This measure is usually included in HAP studies of new molecular entities to determine if participants might rate the test drug as having effects similar to existing drugs of abuse, such as opioids, stimulants (cocaine, amphetamines), sedatives, or hallucinogens. These results can help provide valuable qualitative information on whether a drug is likely to be abused once available in the community.

Tablet-Based Assessments

DVCR leverages the Cambridge Cognition’s Clinical Trials Information System for Abuse Liability (CTIS-AL) to capture subjective data, which allows for:

• Computerized, paperless administration and data collection
• Configurable questionnaires and VASs
• Immediate data storage and real-time data access
• Electronic management of volunteer visit schedules
• Dedicated operational and scientific support

This tablet-based system is easy to use and more engaging to participants than paper-based systems, and scoring is automated and less prone to error.

Staff and Participant Training

Because subjective measures are based on individual experiences, responses can be subject to greater variability. In addition, these measures are administered when participants are under the influence of psychoactive drugs. Therefore, clear, memorable instructions, as well as repeated training and practice, are critical for ensuring the success of a HAP study. Participants receive extensive training on the importance of the assessments, but are not coached into giving any specific responses, which could bias the outcomes of the study. Highly trained staff are required to strike this balance.

To ensure that the best quality subjective data are produced, DVCR has a full-time Ratings Manager responsible for protocol review, staff oversight, and participant training. DVCR has invested heavily in materials, systems, and personnel to ensure that these complex studies are executed carefully.

Conclusion

Subjective outcome measures provide a deep qualitative and quantitative understanding of how participants might react to a drug, forming the backbone of HAP studies. By accurately assessing these subjective effects with reliable systems and employing highly trained participants and personnel, HAP studies can help to ensure the safety of new medications before they hit the market.