One of the first steps in prevention of prescription drug abuse is effective scheduling, or categorizing, of candidate medication prior to approval by the FDA. The Controlled Substances Act, or CSA (21 U.S.C. 811(b), 811(c)) describes eight factors that are used in determination of appropriate scheduling of a new molecular entity: (1) its actual or relative potential for abuse (also called its abuse liability); (2) scientific evidence of the drug’s pharmacological effects; (3) the state of current scientific knowledge regarding the drug or other substance; (4) its history and current pattern of abuse; (5) the scope, duration, and significance of abuse; (6) what, if any, risk there is to the public health; (7) its psychic or physiological dependence liability; (8) whether the substance is an immediate precursor of a substance already controlled. The FDA should ensure that abuse liability is examined for new candidate medications that target changes in neurochemistry, for currently prescribed medications that show unexpected abuse potential, and when changes are made to the formulation or route of administration.
In collaboration with the FDA, the Drug Enforcement Agency (DEA) uses this information to schedule a drug into one of five classifications (schedule I–V), with increasing abuse potential and decreasing legal access at lower schedule numbers. For example, most schedule I drugs have high abuse potential and no accepted medical use in the US. (e.g., heroin, lysergic acid diethylamide [LSD]). According to federal law, possession of a schedule I drug is illegal without an appropriate license (e.g., for research purposes). In contrast, schedule V drugs have relatively low abuse potential. Many of them can be purchased without a prescription, and others are readily available through prescription (e.g., many anticonvulsants). Notably, this classification system applies only to drugs that are covered by the CSA. Drugs without abuse potential (e.g., those that do not cross the blood-brain barrier, and many over-the-counter drugs such as aspirin) are approved by the FDA but are not reviewed by the DEA and are unscheduled.
For a candidate medication that an 8-factor analysis has indicated may have abuse liability, the manufacturer must include an abuse potential section containing detailed information on the drug’s chemistry, pharmacology, and effects in humans in the New Drug Application (NDA) that it submits to the FDA. The NDA also must have a subsection on animal behavioral and dependence pharmacology. The purpose of this occasional paper is to describe four specific methods that are most commonly used to satisfy the animal behavioral and dependence pharmacology requirement (FDA, 2010
), including psychomotor activity, self-administration, drug discrimination, and assessment of tolerance and dependence. The following section provides an overview of each procedure, accompanied by presentation of actual data for known drugs of abuse to illustrate results similar to those that might be obtained with drugs having potential abuse liability.