Human abuse potential (HAP) clinical studies are important components of the risk assessment for centrally-acting drugs, particularly those with psychoactive effects of interest, such as mood-elevating, stimulant, sedative, or hallucinogenic effects.

Study Objectives

The primary objective of a HAP study is to evaluate the subjective abuse potential of a drug by comparing its effects to placebo and known drugs of abuse, such as opioids, stimulants, or sedatives. These studies help inform drug control decisions (i.e., scheduling) and guide labelling and risk management strategies. Centrally-active drugs that show signals of interest in animals, such as behavioral or reinforcing effects, or that produce adverse events (AEs) of interest in humans, may require a HAP study to be conducted and included as a part of the regulatory submission.

Study Populations

Typically, HAP studies are conducted with individuals who have a history of “recreational” drug use, including non-therapeutic experience with the drug class of interest. These participants are selected based on their substance use history; however, participants with active substance dependence (physical or psychological) are excluded from most HAP studies, as their physiological state that may confound the results and put individuals at risk for relapse. Participants are tested for their ability to distinguish the positive control(s) from placebo in a pre-study Qualification phase (i.e., drug-discrimination test). Dr. Vince Clinical Research maintains an active database of potential participants with appropriate substance use histories and treat participants with care, dignity, and respect.

Study Design

A HAP study design involves a randomized, double-blind, placebo- and active-controlled, crossover approach, with participants receiving different single-dose treatments during multiple study periods, each separated by an appropriate washout interval. Treatments typically include:

• Test drug: The substance under investigation for its abuse potential. Commonly, 3 doses of test drug are evaluated, ranging from therapeutic to supratherapeutic. The highest dose is chosen based on nonclinical, pharmacokinetic, and safety data but is typically in the range of 2 – 3-fold higher than the therapeutic dose, if safe to administer.
• Positive control: An approved drug with established abuse potential (i.e., Schedule II to V). The positive control is selected based on pharmacological similarities to the test drug. These similarities may be determined based on mechanism or action, animal behavioral data, and/or AEs observed in clinical trials (i.e., those indicating mood-elevating, stimulant, sedative, or hallucinogenic effects). Although a single dose of positive control is most commonly used, in some situations, two or three doses may be included. Alternatively, HAP studies with drugs that have mixed effects may include more than one positive control drug from different classes.
• Placebo: A substance with no pharmacological activity used to assess baseline expectations and placebo effects.

After single doses are administered in each treatment period, participants are monitored at multiple timepoints using various outcome measures, including:

• Visual analog scales (VAS) for subjective effects: Participants rate how much they like or dislike the drug, how much they want to use it again, and how much it produces other subjective experiences of interest, such as “good effects”, sedation or stimulation.

In some studies, physiological outcomes (such as pupillometry) or cognitive/psychomotor measures may be included. The selection of specific outcome measures is based on the pharmacology and developmental pathway of the test drug.

Statistical Considerations

The data from HAP studies are analyzed using both qualitative and quantitative methods. Primary analyses are based on a set of hypothesis-testing steps using the primary endpoint (typically “drug liking”), including:

• Positive control(s) vs. placebo – to determine the validity of the study
• Test drug vs. positive control – to determine the abuse potential of the test drug relative to a known drug of abuse
• Test drug vs. placebo – to determine whether the test drug has any abuse potential

Key secondary and other secondary endpoints may be analyzed similarly.

Regulatory Implications

Along with other nonclinical and clinical data collected during drug development, the findings of an HAP study can provide important data for regulators to determine the control status of the drug once available on the market, as well as inform labeling and risk management. By comparing the test drug to placebo, these studies can help inform whether a drug will be controlled under the Controlled Substance Act [1], while the comparisons to positive control(s) may help determine the relative placement of the drug within the schedules (Schedule II to V for approved medications).

 

[1]  “Title 21 United States Code (USC) Controlled Substances Act”. Drug Enforcement Administration: Office of Diversion Control. United States Department of Justice. Retrieved January 31, 2025.