Role of Human Laboratory Studies in the Development of Medications for Alcohol and Substance Use Disorders

Acknowledgments

Dr. Leggio’s work is supported by National Institutes of Health (NIH) intramural funding ZIA-AA000218 ( Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology ), and jointly supported by the Division of Intramural Clinical and Biological Research of the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the Intramural Research Program of the National Institute on Drug Abuse (NIDA).

The authors would like to thank Vignesh Sankar, BSc, from the NIAAA/NIDA Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology for bibliographic assistance.

The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Introduction

The development of medications that are useful for the treatment of alcohol or substance use disorders requires the clinical and preclinical testing of existing and novel compounds in various experimental models useful for evaluating the mechanism, safety, and possible efficacy of the putative treatment. Medication development research has sought to evaluate both existing medications already on the market for other indications as well as new, novel compounds never yet tested in humans. Regardless of the stage of development for any particular medication, experimental human studies in controlled environments (i.e., “human laboratory” studies) will be required at some step of the process for at least one of three possible reasons.

- 1.
  Phase I Safety Testing of Novel Compounds : For novel compounds not yet approved by the US Food and Drug Administration (FDA), Phase I clinical trials will be required to evaluate the safety and abuse liability of the new medications. Basic safety testing in healthy subjects is normally required for first-in-human studies but basic Phase I safety testing approaches will be required in the drug-using target population as well before the FDA will allow Phase II and III treatment trials to proceed.
- 2.
  Phase I, II Safety Testing in the Target Population : If the medication is already approved by the FDA for another indication, development of that medication for addiction treatment still will require safety testing in drug-using or addicted populations. Safety evaluation includes both the biomedical safety of treatment in a drug-using population as well as an assessment of the abuse liability of the medication in a population likely to misuse substances. In addition, the FDA likely will require these studies to address the safety of the drug interaction between the treatment medication and the drug of abuse.
- 3.
  Evaluation of Pharmacokinetic and Pharmacodynamic Mechanisms : Although Phase III treatment trials will be required to demonstrate efficacy, human laboratory studies also can be helpful to evaluate the clinical pharmacology (both kinetics and dynamics) of a medication. These studies can evaluate the possible behavioral or neurochemical mechanism(s) of action or use human laboratory models to estimate the possible efficacy of new medications.

For many human laboratory studies, subjects are research volunteers not engaged in treatment. However, individuals who are “in treatment” also may be tested under controlled human laboratory conditions. The purpose of this review is to identify and highlight the role of and contributions made by human laboratory studies in the development of new medication treatments for addictions.

Pioneering studies conducted in the 1950s, 1960s, and 1970s at the Addiction Research Center of the Public Health Service Hospital in Lexington, Kentucky, developed the basic experimental approaches useful for understanding the clinical pharmacology of alcohol and drug dependence, and their treatment. In many cases, early development studies may require the administration of alcohol or drugs to human subjects who have the alcohol or drug use disorder. The National Advisory Council on Drug Abuse and the National Advisory Council on Alcohol Abuse and Alcoholism have both recommended guidelines for the ethical and safe study of, respectively, drugs and alcohol, given to human subjects ( http://www.drugabuse.gov/Funding/HSGuide.html , https://www.niaaa.nih.gov/research/guidelines-and-resources/administering-alcohol-human-studies ). Broadly speaking, pharmacological approaches to the study of the behavioral effects of drug abuse and its treatment are characterized under the umbrella of abuse liability assessment. Abuse liability assessment involves estimation of the likelihood that a substance will be used or self-administered and/or the liability or harmfulness of that use. Thus, abuse liability assessment approaches to human laboratory studies encompass all aspects necessary to evaluate both the safety (i.e., abuse liability of the treatment agent and the harmfulness of the drug interaction) and possible efficacy (i.e., does it reduce the likelihood of using the drug of abuse) of medications useful for treating alcohol and drug dependence.

Role of the Human Laboratory in Evaluating the Abuse Liability of New Medications

When medications are developed for human use, the FDA or Drug Enforcement Administration may require an assessment of the abuse potential of the new agent and this generally will require human laboratory studies. Typically, abuse liability assessment will be required when the medication under development shares pharmacological characteristics or planned indications with other drugs of known abuse potential. Broadly speaking, the abuse liability of a potential medication can be characterized in the human laboratory using one or more of three different behavioral approaches as described below.

To Characterize Adverse or Harmful Effects

Characterizing the effects of a new drug on various dimensions of physiological function and performance or other behavioral impairment can be valuable to understand how the drug might alter or impair important biobehavioral functions. For example, drugs could be examined for how they alter cognitive, psychomotor, or other behavioral performance or physiological functioning. Characterization of drug effects on each of these dimensions provides valuable information to assess the potential liability or harm that can occur with drug use. In the context of drug abuse, it also is important to know about the safety of the drug interaction should the new medication be combined with the drug of abuse. For this reason, many studies have been devoted to assessing the potential interactions between the new medication and alcohol—the most common drug for which potentially dangerous interactions might occur. The safety of drug interactions also is very important for FDA approval of potential treatments for alcohol or drug addiction because it is very likely that drug-dependent populations undergoing treatment with a medication will at some point at least sample their primary drug of dependence. Furthermore, the characterization of the drug interaction in the experimental laboratory may provide insight into the mechanism and possible effectiveness of that medication.

To Characterize Its Comparative Pharmacological Profile

The most common approach to abuse liability assessment is the pharmacological bioassay, which is a standard evaluation of the clinical and pharmacological profile of the new drug in comparison with another known drug from the same or similar pharmacological class. Necessarily, pharmacological profiling means evaluating the pharmacodynamic effects of the drug on a variety of dimensions, which could include assessment of performance or physiological effects, but for abuse liability also includes assessment of subjective effects or euphoria. An adequate evaluation of pharmacological profile requires the testing of a range of doses to construct a dose-response curve because the testing of a single dose fails to provide information on the dose-responsiveness of observed effects and is fraught with the potential for false-negative findings. Comparison of the new drug with a standard drug of known abuse potential is an essential element in the pharmacological comparison approach for at least three reasons. First, use of the standard drug establishes the positive control level of response to drugs of abuse under the standard conditions employed by the experiment. This is particularly important given that false-positive or false-negative results may occur due to variations in the assessments, population, or other study conditions. Second, relative potency or relative effect-size comparisons between the novel drug and the standard drug of abuse provide the basis for the most meaningful interpretation of data. Thus, the new drug may differ in the dose-response slope, the maximum effect size, or the relative potency on different dimensions of effect. Each of these variables has a different implication for abuse liability. Third, for clinical advantage estimation purposes, the FDA and medical prescribers would like to know about the differential efficacy contrast of the new drug in comparison with a known drug, which may be a standard drug of abuse or a scheduled prescription medication that has known abuse potential.

To Evaluate Reinforcing Effects or Potential for Self-Administration

Numerous animal models of addiction studied across a wide variety of drugs and species have shown that drug taking is a drug-reinforced behavior controlled by operant contingencies and schedules of reinforcement. The same also has been shown in humans, where several human laboratory models of drug reinforcement and self-administration have been established. Ultimately, the behavior we are interested in understanding, predicting, and treating, is the likelihood that a drug/substance will be used or consumed in a pattern consistent with abuse or dependence. A yes/no decision whether or not the drug is self-administered by the subject population may not be sufficient here because the environment and the availability of alternatives influence choice behavior. For example, the likelihood that a sedative or stimulant drug will be self-administered is influenced by how stimulating the experimental environment is. This phenomenon likely explains how even the sedating atypical antipsychotic quetiapine, with little intrinsic abuse liability, may become a highly preferred drug of abuse in a prison or psychiatric hospital environment where access to other drugs is limited. Therefore, an all-or-none conclusion of whether or not a drug is self-administered under one set of conditions does not indicate much about its potential for self-administration under a different set of circumstances. Thus, studies of the potential for reinforcement or self-administration are limited by the range of conditions (dose, circumstance, population, etc.) under which they are tested.

Issues in Human Laboratory Studies of Abuse Liability

There are several issues that need to be considered by any human laboratory study of abuse liability. The information below summarizes the issues that generally exist in the field and potentially limit any conclusions coming from human laboratory studies of medication effects on drugs of abuse.

Role of Subjective Effects

Since the earliest studies at the addiction research unit at the United States Public Health Service Hospital at Lexington, Kentucky, it has been observed that drugs of abuse as diverse as alcohol, barbiturates, opiates, and psychomotor stimulants all share a profile of psychoactive effects characterized as euphoria. It is generally accepted that euphoria is at least a partial explanation of why these drugs are abused. Because of the subjective and unobservable nature of this psychoactivity, self-report questionnaires are used to assess these subjective effects. One of the early questionnaires developed to measure the subjective effects of drugs of abuse was the Addiction Research Center Inventory, a multiitem questionnaire completed by human subjects during drug intoxication. Factor analysis was used to empirically derive subscales of items responsive to characteristic drugs of abuse including amphetamine, benzedrine, morphine, pentobarbital, alcohol, chlorpromazine, and lysergic acid diethylamide. Subsequently the morphine-benzedrine groups were combined to represent an opiate or stimulant-type of “euphoria” scale, the pentobarbital-chlorpromazine-alcohol group a distinctly “sedative” scale, and the lysergic acid diethylamide scale as a “dysphoria” or unpleasantness scale. It is important to recognize that these scales actually were derived to measure subjective mood changes induced by pharmacologically distinct drugs of intoxication and not euphoria per se. The Profile of Mood States is a multi-item questionnaire derived in the measurement of mood in normal healthy college students. Nonetheless, it has been used commonly to measure changes in depression-dejection, tension-anxiety, vigor, arousal, and other mood states by various populations under the influence of drugs. Generalized mood measures are valuable to assess the pharmacological profile of a drug and are sometimes presumed to predict abuse potential under the assumption that positive mood states could reflect an increased potential while negative mood states could reflect a decreased potential. In alcoholism research, the biphasic alcohol effects scale was derived to measure the positive and disinhibiting arousal that may occur during the ascending limb of the blood-alcohol curve and the sedative-inhibition that occurs on the descending limb of the curve. Actually there are many other factor-analyzed and single-item rating scales that have been used to evaluate the subjective effects of psychoactive drugs, and enumerating them is beyond the scope of this review.

The psychoactive effects of psychotropic drugs are studied in animals using discriminative stimulus procedures, where subjects are trained to discriminate the differences between drugs. Discriminative stimulus procedures also have been developed to train human subjects to discriminate the interoceptive stimulus effects of drugs. Although subjective rating scales take advantage of the verbal capacity of human subjects to quantitatively report the qualitative characteristics of their subjective experience, the discriminative stimulus approach uses a qualitative analysis of same/different comparisons between drugs. There is reasonable correspondence between conclusions drawn from subjective effects and those from discriminative stimulus studies in humans. Because of differential reinforcement of behavior during discriminative training, it is likely possible to gain a tighter level of discriminative control with this paradigm than with standard subjective questionnaires. However, the specificity and sensitivity of this procedure very much depend on the discrimination training conditions and are achieved only through lengthy training procedures. Nonetheless, the ability to compare the human study results with the preclinical data using discriminative stimulus analyses is a distinct advantage of this procedure. Although there is a good correspondence between “positive” subjective effects and the likelihood of drug self-administration, it is certainly not true that either positive or negative subjective effects alone explain the cause or the reason that drugs are or are not self-administered. ^, ^, ^.

Role of Subjective Euphoria

The cardinal subjective effect commonly assumed to be important to abuse potential is the experience of psychoactive drug effects that are pleasant, preferred, or “euphoric.” A number of reviews of human abuse liability have discussed issues of drug-induced subjective euphoria and its measurement. ^a

a References 61, 64, 65, 83, 226, 229, 240.

Actually, most drug users do not refer to “euphoria” but rather describe the drug intoxication as a “high.” Although cocaine intoxication has been described as “intensely stimulating and pleasurable,” or “orgasmic,” it is clear that not all drugs of abuse produce such intense pleasurable sensations. For many drugs, including alcohol, the intoxication is more often described as a “buzz,” or “drunk,” or “high” that has “good” features and that people report “liking.” Consequently, most studies employ individual-item rating scales for subjects to rate the extent of “high” and “good” subjective effects and the extent to which subjects “like” the effect. There is no standard euphoria scale used by a majority of studies.

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