In FDA parlance, an ‘adverse event’ (AE) is defined as ‘any undesirable experience associated with the use of a medical product in a patient.’ But whether or not the distinctive effects of MDMA, which might be considered as positive by those who choose to ingest it, should be recorded as adverse events appears to have been a subject of debate within Lykos.

In the eyes of the agency, these ‘positive’ effects may drive drug-seeking behaviour outside of the confines of medical practice. (And, given the limited number of exposures to MDMA among participants in Lykos’ safety dataset, this might be of particular interest to the agency… as is the durability of treatment response.)

But Lykos did not consider these effects, such as euphoria or enhanced mood, to be “untoward”, according to FDA’s AdComm briefing document (pp10), and as such its Phase 3 program had “no direct assessment of the prosocial or other subjective effects related to potential for nonmedical use of MDMA” (pp98, Sponsor Briefing Document).

In its NDA, Lykos told the agency that it had not collected adverse events that may be “considered to be neutral, positive, or favorable by the participant and the therapist and study physician”. The agency noted in its AdComm Briefing document that this is “not consistent with FDA advice provided to the Applicant in 2017” (pp56).

The FDA’s psychedelics-focused draft guidance notes that sponsors should evaluate psychedelic responses “through the inclusion of validated subjective scales and through monitoring abuse-related AEs”. But this was published in June 2023, far too late to have been useful to Lykos’ clinical development program.

However, a look at FDA’s Abuse Potential guidance, published in January 2017 (nearly two years prior to MAPP1’s start date), provides further information, particularly section V.B. which notes that the “presence of a euphoria-like response is a key observation in the clinical assessment of whether a test drug has abuse potential.”