Challenges in translational research: MDMA in the laboratory versus therapeutic settings

This commentary (2021) examines the challenges of translating insights about MDMA (and other mind-altering drugs) from the laboratory to the therapeutic setting. The authors identify differences in expectancies, social and physical context, participant characteristics, pharmacological factors, outcome measures, and patient diagnostics, and explore ways to abridge their methodological divide.

Abstract

“Despite substantial progress in the use of mind-altering drugs to treat psychiatric disorders, the psychological processes through which these drugs change mood or behavior are poorly understood. Controlled laboratory studies with well-defined psychological constructs are valuable to understand how these drugs manifest their therapeutic benefit. However, there are substantial methodological differences between clinical studies investigating therapeutic outcome and laboratory studies investigating the processes that might underlie the therapeutic effects. Here, we examine some of these differences using the example of 3,4-methylenedioxymethamphetamine (MDMA). We review differences in expectancies, social and physical context, participant characteristics, pharmacological factors, and outcome measures in studies with participants who do or do not have psychiatric diagnoses. We describe the challenges and opportunities in translating findings from laboratory studies to the clinic and identify ways to bridge the gap between these approaches.“

Authors: Harriet de Wit, Anya K. Bershad & Charles Grob

Summary

Introduction

Modern psychiatry relies heavily on medications to treat patients with symptoms of mental disorders, yet the neural and psychological processes through which these medications produce their therapeutic effects are poorly understood.

In clinical settings, it is difficult to study the psychological processes underlying therapeutic benefits. In controlled laboratory settings, researchers can manage some of these factors, and can assess the drugs’ effects using sensitive, objective behavioral tasks.

Controlled studies are a good way to understand psychological processes underlying psychiatric medications, without the confounding influences encountered in the therapeutic setting. However, significant challenges remain in translating findings from controlled laboratory studies to the clinical setting.

The psychological processes through which mind-altering drugs change mood or behavior are poorly understood, and there are substantial methodological differences between clinical studies investigating therapeutic outcome and laboratory studies investigating the processes that might underlie the therapeutic effects.

MDMA is studied differently in the human laboratory than it is used in the clinic. This paper examines some of the challenges in bridging the gap in knowledge obtained from controlled studies to what is observed in the clinic.

We first examine how expectancies and contexts influence how a drug is used in laboratory studies and in patients, and then compare laboratory and treatment studies in terms of participant characteristics and outcome measures.

Expectancies and instructions

Clinical studies with MDMA differ in important ways from laboratory studies, but many aspects of expectancies will be similar, once the drug is approved. In clinical settings, patients are told what drug they will receive and what effects they might experience. They enter the experience with a clear intention for a positive therapeutic outcome. In contrast to treatment settings, laboratory studies typically administer drugs under double-blind conditions, with no directive instructions about either therapeutic or other effects that might be experienced. This limits the generalizability of results from one setting to another.

Several psychological processes have been identified as contributing to the therapeutic effects of MDMA, even when the drug is administered under blinded conditions. These processes include reduction of neural responses to social threat, increase of social feelings, and dampening identification of negative emotions in others.

Researchers are investigating the role expectancies play in the therapeutic outcome of drugs used to treat a condition. One way to study expectancies is to manipulate components of expectancies that are present in therapeutic studies.

Physical and social context of drug administration

The experience of taking a psychoactive drug in a therapeutic setting is very different from the experience of taking the same drug in a laboratory. This is not a new idea. There are numerous differences in the physical and social contexts in which MDMA is used for therapy and basic research studies, and little is known about how these contexts influence responses to the drug.

Physical setting: Stimulation and comfort of the environment

MDMA is often taken in dance clubs or raves, but controlled laboratory studies are typically quiet and sterile. Therapeutic settings may include soothing music and subdued décor to help patients “relive” past experiences.

In a clinical setting, MDMA is administered in an environment that is carefully constructed and designed to be comfortable. The environment is decorated with pleasant furnishings, and calming music is played through headphones.

Social setting: Interpersonal support and characteristics of others present

Laboratory studies with MDMA differ markedly in the social settings in which the drug is experienced. These studies are typically conducted in comfortable but solitary conditions, whereas clinical studies with MDMA are conducted in the presence of clinicians who create a supportive, therapeutic atmosphere.

Social settings influence responses to drugs, especially psychedelic drugs. Studies have found that environments with more freedom and interpersonal support lessen psychotic symptom severity, compared to environments with a more sterile and at times overtly hostile approach by hospital staff.

A laboratory-based double-blind study directly compared subjective responses to MDMA in a social and nonsocial context, and found that the strongest subjective and physiological responses were observed when individuals were tested with another drug-treated participant.

Patient/subject characteristics and previous experiences

Clinical studies with MDMA typically involve individuals who are seeking treatment for distressful symptoms, whereas controlled laboratory studies typically involve healthy young adults who are screened to exclude those with serious psychiatric symptoms. MDMA may have different effects in individuals with serious psychiatric symptoms compared to healthy adults, either because of differences in underlying neuropathology or because of differences in how the drug’s effects are perceived.

Laboratory studies obtain a broader range of demographic characteristics with a different focus than clinical studies, making it difficult to compare findings from studies with symptomatic volunteers to findings from healthy volunteers.

Pharmacological considerations

Pharmacological considerations vary in clinical and laboratory studies with MDMA. Participants who are patients have often received other medications that may influence their response to MDMA, and little is known about interactions of MDMA with other medications, taken either concurrently or recently. In treatment studies, participants typically receive two or three doses separated by several weeks, whereas laboratory-based studies of MDMA examine the effects of the drug only in the 4-6 h immediately following the dose.

Outcome measures

In laboratory studies with MDMA, self-report measures of mood and emotional states are collected, as well as standardized, objective behavioral tasks. Physiologic outcome measures are also collected, such as heart rate, blood pressure, salivary cortisol, or brain imaging.

In clinical settings, outcome measures typically include symptom questionnaires. However, there is room for greater harmonization of measures across contexts, such as identifying outcome measures that would be appropriate for both laboratory-based and clinical studies.

Conclusions

MDMA clinical studies differ from basic laboratory studies with the drug in numerous ways. It will be valuable to harmonize these two types of studies to better understand MDMA’s therapeutic benefits.