What is “abuse potential” and how does it influence the FDA approval process?
With the recent success of clinical trials assessing the efficacy of MDMA-assisted psychotherapy for PTSD and the numerous other studies on the use of psychedelics as therapeutics, focus has begun to shift towards their approval by regulatory agencies. As with any new drug that affects the central nervous system (CNS), both MDMA and psychedelics such as psilocybin will need to be evaluated for their “abuse potential” as a part of their application for approval by the FDA.1 Although the vast majority of Americans likely have an intuitive understanding of what the term abuse potential entails, how it is defined and assessed by medical and legal authorities is quite complex. The subsequent sections of this article will provide an overview of the medical and legal concepts of abuse potential and how it is measured in order to explain the challenges that MDMA and psychedelics such as psilocybin must face before they can be approved for therapeutic use.
Scientists and medical professionals have hotly debated what exactly constitutes drug abuse ever since the use of psychoactive therapeutics became prevalent in western medicine. Currently, there are several definitions of “drug abuse” that predominate depending upon the field (or faction) in question. Legal and regulatory authorities define substance (drug) abuse as “the intentional, non-therapeutic use of a drug product or substance, even once, to achieve a desired psychological or physiological effect.”2 Conversely, many medical professionals have begun to define substance abuse, or more conventionally a substance use disorder, as the use of a drug in a manner that causes significant problems or distress to the user, such as endangering health, missing work, or getting into legal trouble. Under this definition, someone who uses a substance without medical direction in order to treat a legitimate medical need would be considered to be misusing the drug rather than abusing it. Put another way, abuse of a drug is characterized by a desire to produce euphoric or desirable subjective effects, whilst misuse is characterized by a desire to treat a real or perceived medical condition.
Drugs and therapeutics are considered to have abuse potential when there is evidence indicating they produce desirable subjective effects that may be sought for recreational or other nonmedical use. The use of such drugs by patients or nonmedical users has historically been associated with a variety of harms, including the development of addiction (substance use disorder), overdose, and psychosocial consequences, among others. Based on the perceived risks to patients and public health posed by drugs with significant abuse potential, among other sociopolitical factors, the Controlled Substances Act (CSA) was passed in 1971 in order to provide a framework for controlling the use, manufacture, and sale of these drugs.
The CSA created five “schedules” that such drugs could be placed in, with those in Schedule I having a high potential for abuse, a lack of established safety when used under medical supervision, and no accepted therapeutic uses.3 Schedule II – V drugs are those with currently accepted therapeutic applications, with those in Schedule II having the highest potential for abuse and those in schedule V the lowest, respectively.3 Table 1 contains several examples of commonly abused drugs and how they are scheduled under the CSA.Table 1: CSA Schedules of various drug classes. Created by Harrison Elder.
|Mechanism of Action
|Morphine, Heroin, Oxycodone, Fentanyl, Methadone
|Activation of opioid receptors in brain and body
|I (Heroin) - V (Low dose codeine)
|Cocaine, Amphetamine, Methamphetamine, Cathinone
|Release of dopamine, serotonin, and norepinephrine in the brain
|I (Cathinone) - II (Methamphetamine, Cocaine)
|Benzodiazepines (Valium/diazepam), Barbiturates (Seconal/secobarbital), Methylqualones (Quaaludes)
|Increase the activity of inhibitory GABA signals in brain and body
|II (Seconal) - V (Valium)
As of 2017, the FDA has clarified that the abuse potential of new therapeutics must be examined as a component of a drug’s safety evaluation so that the benefit to risk ratio can be accurately assessed prior to approval.2 Generally, this means that the expected benefit to patients and public health offered by a new therapeutic must outweigh the risks posed by any abuse potential it may have. New Drug Applications (NDA) to the FDA can be rejected on the basis of unacceptable risk of abuse potential vs therapeutic benefit. This was recently demonstrated in 2020 when Nektar Therapeutic’s NDA for their opioid analgesic NKTR-181 failed to gain regulatory approval based on concerns over its potential abuse.4
Should the clinical evaluation of MDMA and other psychedelics continue to demonstrate the therapeutic utility of these drugs, they will need to clear the final hurdle of regulatory approval before patients can access them.1 Considering their long history of stigmatization and present status as Schedule I drugs, whatever abuse potential MDMA and psychedelics like psilocybin may have will need to be thoroughly evaluated and found to be acceptable in relation to their therapeutic benefits if they are to be approved.
How is abuse potential evaluated and quantified?
Considering the substantial harms associated with drugs that have a high potential for abuse, numerous methods have been developed over the years to characterize and quantify the abuse-related effects of novel compounds. Such methods may involve laboratory studies of a substance’s pharmacology, evaluation of behavioral effects in animals, specialized clinical trials, and epidemiological surveys of usage patterns by the population, among many others.1,5,6 For the purposes of formal evaluation by regulatory authorities, as in the case of an NDA, data obtained from these varied methodologies is typically compiled in what’s known as an 8-Factor analysis to provide a holistic picture of a drug’s possible abuse-related effects.2 The individual sections of an 8-factor analysis are given in Table 2 with each intended to capture evidence from specific clinical, preclinical, and epidemiological domains to quantify both actual and relative (in relation to other scheduled drugs) abuse potential.Table 2: 8-Factor Analysis. Adapted from Henningfield et al., 2022 by Harrison Elder.
|Factor and Title
|Primary Questions Addressed
|Types of Evidence
|I: Actual or relative potential for abuse
|Concerned with the current or potential scope of recreational use and diversion, presence of desirable subjective effects and addictive properties
|-Surveys of naturalistic and recreational use -Human and animal abuse potential studies -Evidence of diversion for nonmedical use
|II: Scientific evidence of pharmacological effect (if known)
|Includes data on the drug’s mechanism of action, receptor targets and effects in humans and animals. Focus on overlap with known drugs of abuse.
|-Neuropharmacology and receptor binding studies of known abuse-related targets
-Observational studies of drug effect
-Human and animal pharmacology studies related to mechanism of action
|III: State of current scientific knowledge regarding the drug or related substances
|How much is known about the drug, how thoroughly has it been studied and what types of evidence exist in the literature? Not necessarily abuse-related evidence.
|-Overall preponderance of nonclinical research in vivo and in vitro
-Modes of use (oral, injection, etc.)
|IV: History and current pattern of abuse
|Does the drug have a history of use by the public? How is/was it used? How has use changed over time?
|-Use trends over time collected via annual surveys and forensic laboratory reporting
-Qualitative reports on use patterns and behaviors
|V: Scope, duration, and significance of abuse
|How widespread is abuse of the drug? How long has it been abused? What harms have been documented as a result of its abuse?
|-FDA Adverse Event Reporting System data
-Clinical case reports on toxicity/overdose
-Adverse events noted in clinical trials
|VI: What, if any, risk is posed to public health
|What is the risk of overdose or other serious health effects? Does use of the drug pose a risk to others (violence, driving)? What public health benefits are there that should be balanced with risks?
|-Documented risk of overdose or other serious health effects
-Poison control center data
-Documentation of intoxicating, disinhibiting or other effects known to affect public health
|VII: Psychological or physiological dependence liability
|Is there evidence that the drug may be mentally or physically addictive (lead to a substance use disorder)? Does the drug cause mental or physical withdrawal symptoms when stopped?
|-Clinical evidence of substance abuse disorders related to use of the drug
-Clinical evidence of physiological dependence and withdrawal (clinical trials)
-Human abuse potential studies
-Animal studies of withdrawal and self-administration
|VIII: Whether the substance is an immediate precursor of another controlled substance
|Can the drug be easily transformed into another drug of abuse/controlled substance?
|-Factual determination of whether or not the compound’s chemical structure allows said transformation
Although the types of studies and evidence required for the assessment of each factor are not specified in the CSA, certain preclinical and clinical models have nevertheless risen to prominence as the commonly accepted methods of evaluating various aspects of abuse potential. To evaluate abuse-related effects of CNS-active drugs, the FDA recommends preclinical studies such as drug self-administration and drug discrimination. Generally, self-administration studies aim to see if an animal, such as a rat or a monkey, will perform an action like a lever press to receive a dose of the drug (self-administer). Drugs such as cocaine or heroin that are self-administered by animals are considered to have abuse potential and usually affect dopamine transmission in some way.
Drug discrimination studies do not rely on the rewarding effects of a drug, but instead determine if a test drug is similar to another known drug of abuse. In these studies, an animal will be trained to recognize the subjective effects of a specific drug, such as LSD, and then be given a test drug to see if the animal recognizes the effects as being the same or different.7 Results from these types of tests can then be compared with those of common drugs of abuse, such as those given in Table 1, to determine whether the drug shows signs of classical abuse-related effects.
Despite the fact that preclinical studies in animals provide a significant portion of evidence needed for an abuse potential evaluation, evidence from human clinical studies are still considered to be a crucial aspect of the overall assessment. Commonly referred to as Human Abuse Potential (HAP) studies, these specialized clinical evaluations typically involve a small number of participants who may be experienced with recreational drug use. Participants in HAP studies are usually given a therapeutic or even larger dose of the drug being evaluated and then monitored over the course of several hours while they answer questions related to the subjective effects they feel. Results from these types of studies often include measures of “drug liking”, “good drug effect”, “would take again” and may include more specific measures targeted towards the class of drug being evaluated (i.e. stimulant, sedative, or opioid-like effects).
However, due to the decades of preclinical research and population surveillance efforts that have extensively documented the behavioral pharmacology and naturalistic use of MDMA and classical psychedelics by the public, there is likely little need to conduct further dedicated studies on the abuse potential of these drugs.6,8 Nevertheless, it is likely that any specific drug product seeking approval will need to systematically collect adverse events from clinical studies that are suggestive of abuse potential, dependence or diversion in order to support approval and rescheduling efforts.1
Abuse potential of MDMA and psilocybin
The valid concerns regarding abuse potential and the complexities of quantifying it raises the question of how drugs like MDMA and certain psychedelics compare to more notorious drugs. Unlike many new drugs seeking approval, MDMA and the psychedelic psilocybin have documented histories of recreational use by the public and currently reside in Schedule I alongside the likes of heroin and analogues of fentanyl. As such, the contents of their respective 8-factor analyses will be used by the Controlled Substances Staff (CSS) at the FDA to make rescheduling recommendations, should they be approved. Considering both drugs’ relatively long history of use, ample evidence has already been collected to create a clear picture of their relative abuse potential.
The first of these two drugs likely to apply for approval is MDMA, the prototypical entactogen and a structural relative of both amphetamine and mescaline. Since the mid 1980s, MDMA has been studied for its abuse-related effects with early studies demonstrating significant self-administration in monkeys at levels lower than either cocaine or methamphetamine, both Schedule II psychostimulants.9,10 Further experiments utilizing drug discrimination procedures have demonstrated partial substitution of MDMA for either LSD or D-amphetamine depending upon the isomer tested.11
In addition to the large body of work conducted in animals, recent clinical studies of MDMA’s abuse-related effects reported that a single dose of MDMA produced higher drug-liking scores than amphetamine but lower scores than LSD.12 Furthermore, epidemiological data collected from the US population since the 1980s shows that the extent of MDMA use is relatively small. Specifically, patterns of MDMA use reported by national surveys are unlike those seen with commonly used Schedule II stimulants or opioids with frequent or daily use of MDMA being rare.13 Taken together these studies, along with numerous others, indicate that MDMA produces some abuse-related effects but likely has a lower potential for abuse, addiction, and dependence relative to comparable drugs in Schedules II and III.
The organization currently in charge of MDMA’s clinical development program, the Multidisciplinary Association for Psychedelic Studies (MAPS), has previously compiled much of the evidence described here as a preliminary 8-factor analysis in preparation of a possible NDA submission for MDMA.14 Should an NDA be submitted for MDMA containing their assessment and a recommendation for rescheduling into Schedule III or lower, the FDA’s CSS will evaluate the application and provide a recommendation to the DEA based on their findings. With a drug as potentially controversial as MDMA, it is likely that additional measures for ensuring proper use and control of the drug may be required for a period of time following approval and marketing.
In such cases, the FDA can request that a Risk Evaluation & Mitigation Strategies (REMS) plan be developed and implemented in order to ensure safe use and prevent diversion.15 If a REMS were to be required for MDMA approval, it may consist of additional safety protocols including: administration of the drug exclusively at specialized clinics, storage requirements for drug supplies, and restrictions on prescriptions or dispensing, among other measures. Overall, based on the existing evidence and the progress made by MAPS on clinical development it seems likely that MDMA would be rescheduled to Schedule II or III following a successful NDA submission; bringing it out of the shadows and into the clinic.