Considerations in assessing the abuse potential of psychedelics during drug development.

The recent increase in clinical research on the potential therapeutic uses of classic psychedelics has prompted the need to revisit the assessment of the abuse potential of these drugs. The term "classic psychedelic" is used in this manuscript to describe serotonergic 5-HT2A agonists that alter perception, cognition, and mood (i.e., psychedelic effects) and that are currently controlled in Schedule I of the Controlled Substances Act (CSA). Schedule I drugs are subject to the most restrictive controls under the CSA, as they are considered to have a high abuse potential and no currently accepted medical use in the United States (USA). However, these classic psychedelics were placed in Schedule I at the time the CSA was enacted in 1970, and their abuse potential has not been systematically assessed using modern methodology. This paper provides an overview of scientific evaluation of the abuse potential of classic psychedelics and delineates the data that will be needed in support of a recommendation for the rescheduling, if a drug product containing a classic psychedelic gains FDA approval. This article is part of the Special Issue on 'National Institutes of Health Psilocybin Research Speaker Series'.

Concentration-Response Model of Immediate Release Oxycodone Drug Liking by Different Routes of Abuse.

OBJECTIVE: To understand the correlation between oxycodone concentration and drug liking response for immediate-release formulations as they relate to different doses and different routes of administration following manipulation involved in opioid misuse and nontherapeutic use. METHODS: Concentration-response and noncompartmental analyses of drug liking and plasma oxycodone data from Category 3 human abuse potential studies (n = 15-29 per study) were conducted, using Phoenix 6.0 software. Time to onset of a set threshold of subjective effects (Tonset) and offset of subjective effects (Toffset) were estimated based on a baseline pharmacodynamic response set at 50 on a bipolar Drug Liking visual analog scale of 0-100 and the threshold for drug liking set at ≥65, based on study qualification criteria. Partial Area Under the Concentration (AUCTonset-Toffset) and Effect (AUETonset-Toffset) profiles were calculated and their correlation with individual partial AUE vs partial AUC was assessed. RESULTS: The oxycodone concentration-response (drug liking) was best described by a sigmoidal-effect Emax model (S-shaped). Using a defined threshold, drug liking was closely associated with the rate of rise in concentration and the onset of action for oxycodone administered via oral or intranasal route. Partial AUCTonset-Toffset and AUETonset-Toffset showed a strong linear correlation. CONCLUSIONS: Results indicate that oxycodone concentration-response and duration of drug liking following manipulation via different routes of administration may be an approach for further exploring drug liking effects of opioids.

Association of partial systemic exposure and abuse potential for opioid analgesics with abuse deterrence labeling claims supporting product-specific guidance.

BACKGROUND: Over the past decade, U.S. FDA has approved 10 opioid analgesics in abuse-deterrent formulations (ADFs). ADFs are intended to reduce abuse of a prescription opioid through manipulation of the product to use one or more routes of abuse. Although it is critically needed for evaluation of the abuse deterrent properties of an opioid product, the relationship between systemic exposure and likelihood of abuse of the opioid has not been fully characterized. To fill the current knowledge gap, we have evaluated the association of subjective measures predictive of abuse potential (e.g., scores of "drug liking," "take drug again"), which are referred to as 'pharmacodynamic (PD)' responses for measuring abuse potential, with systemic exposure of the opioid using the data from all the clinical abuse potential trials submitted to FDA in support of the approval of innovator ADFs. METHODS: Extensive pharmacokinetic (PK) and subjective response data from 11 clinical abuse potential trials in recreational opioid users following oral and nasal administration of intact and manipulated oxycodone, hydrocodone and morphine products from the FDA internal database were utilized for the present analysis. This retrospective study used data collected from January 11th, 2010 until March 25th, 2015. The potential relationship between PK metrics, especially those for early exposure measures, and the subjective measures of drug liking and take drug again as PD metrics of abuse potential were explored using linear and logistic regression analyses. Heterogeneity analysis was conducted to assess study-to-study variation and multi-level logistic regression analysis was used to affirm the identified PK-PD relationship based on pooled data. FINDINGS: Following oral and nasal administration of intact and manipulated opioids, the maximum visual analogue scale (VAS) for Drug Liking was generally achieved no later than the time to peak plasma drug concentration. Both heterogeneity analysis and multi-level logistic regression indicated insignificant inter study variability for the evaluated PK-PD relationships. Duration of Drug Liking response (i.e., VAS ≥ 65) lasted for 2 to 4 h after drug administration. The early portion of the systemic area under the plasma concentration-time curve (AUC), e.g., partial AUCs in the first 3 h and 4 h were found to be associated with abuse potential measures including maximum Drug Liking VAS and maximum Taking Drug Again VAS. Neither a formulation factor (e.g., immediate-release vs. extended-release, intact vs. manipulated) nor a route of administration was identified as a significant factor together with early partial AUCs to predict the probability of maximum Drug Liking or maximum Take Drug Again responses being greater than or equal to 65. INTERPRETATION: Our assessment indicates that the measure of early systemic drug exposure of opioids is the best predictor of the abuse potential response in recreational opioid users following oral or nasal administration of a single dose of an intact or manipulated abuse deterrent opioids. Our findings support FDA's recommendation of comparative PK studies with early partial AUCs as a supportive PK metric for the assessment of abuse deterrent properties of generic opioid drug products in the general and product-specific guidance's of ADFs. FUNDING: The study was partially funded by Fiscal Year 2017 Critical Path of the Center for Drug Evaluation and Research at the U.S. Food and Drug Administration.

A regulatory perspective on the evaluation of hallucinogen drugs for human use.

In recent years, there is renewed interest in the study of various hallucinogens for their potential therapeutic effects. In the United States of America (USA), the abuse potential assessment of a drug is carried out as part of the general safety and efficacy evaluation of a drug. Additionally, the abuse potential assessment is taken under consideration in determining if a drug needs to be subject to controls to minimize the abuse of the drug once on the market. This assessment is conducted for all new drugs with central nervous system (CNS) activity, that are chemically or pharmacologically similar to other drugs with known abuse potential, or drugs that produce psychoactive effects predictive of abuse, such as euphoria and hallucinations. This paper describes the regulatory framework for evaluating the abuse potential of new drugs, with emphasis on hallucinogens. The paper discusses the role of the United States Food and Drug Administration (FDA) in the evaluation of the abuse potential of drugs and its role in drug control, and provides an overview of the controlled status of hallucinogens and the requirements to conduct research with Schedule I substances in the USA. This article is part of the Special Issue entitled 'Psychedelics: New Doors, Altered Perceptions'.

Risk based in vitro performance assessment of extended release abuse deterrent formulations.

High strength extended release opioid products, which are indispensable tools in the management of pain, are associated with serious risks of unintentional and potentially fatal overdose, as well as of misuse and abuse that might lead to addiction. The issue of drug abuse becomes increasingly prominent when the dosage forms can be readily manipulated to release a high amount of opioid or to extract the drug in certain products or solvents. One approach to deter opioid drug abuse is by providing novel abuse deterrent formulations (ADF), with properties that may be viewed as barriers to abuse of the product. However, unlike regular extended release formulations, assessment of ADF technologies are challenging, in part due to the great variety of formulation designs available to achieve deterrence of abuse by oral, parenteral, nasal and respiratory routes. With limited prior history or literature information, and lack of compendial standards, evaluation and regulatory approval of these novel drug products become increasingly difficult. The present article describes a risk-based standardized in-vitro approach that can be utilized in general evaluation of abuse deterrent features for all ADF products.

A regulatory perspective on the abuse potential evaluation of novel stimulant drugs in the United States.

In the United States of America (USA), the abuse potential assessment of a drug is performed as part of the safety evaluation of a drug under development, and to evaluate if the drug needs to be subject to controls that would minimize the abuse of the drug once on the market. The assessment of the abuse potential of new drugs consists of a scientific and medical evaluation of all data related to abuse of the drug. This paper describes the regulatory framework for evaluating the abuse potential of new drugs, in general, including novel stimulants. The role of the United States Food and Drug Administration (FDA) in the evaluation of the abuse potential of drugs, and its role in drug control are also discussed. A definition of abuse potential, an overview of the currently accepted approaches to evaluating the abuse potential of a drug, as well as a description of the criteria that applies when recommending a specific level of control (i.e., a Schedule) for a drug under the Controlled Substances Act (CSA). This article is part of the Special Issue entitled 'CNS Stimulants'.

Nonpeptidic delta (delta) opioid agonists and antagonists of the diarylmethylpiperazine class: what have we learned?

The discovery of the selective delta (delta) opioid agonists SNC 80 and BW373U86, which possess a diarylmethylpiperazine structure unique among opioids, represented a major advance in the field of delta-opioid ligands. Extensive research has recently been performed to uncover the structure-activity relationships (SAR) of this class of ligands, thereby providing valuable tools for the pharmacological characterization of the delta opioid receptor. This review focuses on the SAR of this unique series of ligands, and provides an overview of the various chemical routes that have been developed and optimized through the years to allow the syntheses of these ligands on a multigram scale. The search for selective delta opioid agonists and antagonists, as well as for those with mixed opioid agonist properties with potential therapeutic value, continues. Several questions regarding the interaction at the molecular level of diphenylmethylpiperazine derivatives and related analogs with opioid receptors and in particular with the delta opioid system still remain unanswered. Indeed, the development and pharmacological characterization of novel nonpeptidic delta opioid ligands remains an active area of research, as it may provide a better understanding of the role of this receptor in multiple disease states and disorders.