The Four Factors of Rejection

Making Sense of the Senseless

In 1914, the assassination of Franz Ferdinand, the Archduke of Austria-Hungary, set off World War I. 

But to say this was the “cause” of World War I would be a gross mischaracterization.

Leading up to this event, Europe was undergoing a period of increasing militarization, imperialism, and nationalism that made for a volatile environment.

The assassination was the proverbial spark in a tinderbox.

Similarly, the proximate cause for the FDA’s rejection of MDMA-Assisted Therapy may be one (or several) factors that emerged from an increasingly tense, complex, and uncertain drug development process. 

Unlike the assassination of Archduke Ferdinand, we may never know the proximate cause for the FDA’s rejection of MDMA-Assisted Therapy, since the details of their rationale are (presumably) contained in the Complete Response Letter (CRL), which is not usually made publicly available.

However, we can examine the factors that contributed to the information landscape that led to the FDA decision. 

Four Factors of Rejection set the stage for the rejection of MDMA-Assisted Therapy. 

1. Methodological Limitations: How do you study a treatment you can’t blind for a condition you can’t measure?

2. Industry (In)experience: Outsiders playing an insider’s game

3. Ossified Institutions: An inadequate regulatory apparatus ill-equipped to assess novel therapeutic modalities

4. Circular Firing Squad: Ideological differences within the “psychedelic community” led to an effective opposition campaign against Lykos

Let’s explore each.

Methodological Limitations: How do you study a drug you can’t blind for a condition you can’t measure?

Psychedelics, MDMA, and related compounds pose a unique—but not wholly novel—challenge to the dominant method of clinical scientific research.

In studies of HIV antivirals, for example, neither the study participants nor the study staff know if they are taking the study drug or placebo. This is known as double blinding.

In contrast, consider a randomized trial of psychedelic compounds: both study participants and study staff know pretty quickly who got the study drug and who got a placebo. 

This is referred to as functional unblinding. It is called “functional” because the study design attempted to blind both participants and study staff, but the obvious subjective state changes render it moot.

Secondly, in the example of our hypothetical HIV treatment study, the goal of the study is to evaluate some objective biomarker, like viral load or T-cells, which are obtained from blood samples run through documented, validated, and replicable objective measurement processes like polymerase chain reaction (PCR) and complete blood count (CBC). 

In the case of a trial for PTSD, the primary outcome measure is the CAPS-5 (Clinician-Administered PTSD Scale for DSM-5), which is a structured clinical interview designed to assess PTSD according to the criteria outlined in the DSM.

It is an attempt to make the subjective objective.

This combination of factors makes it particularly important to have clear, agreed-upon guidelines from the FDA…that won’t change. 

Industry (In)experience: Outsiders playing an insider’s game

The drug development gauntlet is the ultimate insider’s game.

And by insiders, I mean organizations flush with money, relationships, and expertise.

It is well known that the average duration of a drug development project is 10-12 years and costs hundreds of millions, if not billions, of dollars.

But the so-called “hidden costs” are in the form of expertise. The expertise required to develop new drugs is both technical and social.

On the technical side, the process of drug development is replete with guidelines, rules, and procedures that are difficult for upstart, bootstrapped, or inexperienced groups to carry out.

Social expertise highlights the issue of the “revolving door” in regulatory agencies. This phenomenon involves individuals frequently transitioning between government regulatory roles and positions in the industries they oversee, raising concerns about potential conflicts of interest and undue industry influence.

Scott Gottlieb is perhaps the most high-profile example of the revolving door phenomenon. Gottlieb was the commissioner of the FDA from 2017 to 2019 before joining the board of Pfizer in June 2019. 

Throughout most of its time as study sponsor, MAPS/Lykos navigated the drug development gauntlet without a Gottlieb-like guide, and even more “outsider-ly” was their explicit agenda to “change the system.”

The goal has always been not only to bring MDMA-Assisted Therapy to market as a prescription drug but to bring forth a post-prohibitionist world and “spiritualize humanity.”

When competing goals conflict, it creates an environment in which one must subjugate the other. To the extent that adherence to the mission led to data mishandling, as alleged, we may never know.

What we do know is that Lykos, as of yesterday, has brought in a pharma exec with the requisite expertise as Rick Doblin left the board of directors, potentially marking a pivot to a narrower, more pragmatic goal of achieving FDA approval.

To further solidify this point, Endpts just published an interview with Lykos CEO Amy Emerson, where she noted:

“It was re­al­ly im­por­tant that the com­pa­ny evolved from Rick. He moved out of the com­pa­ny a num­ber of years ago and on­to just the board. Rick is still much more in­volved in MAPS. But there’s been a lot of con­fla­tion of what the two com­pa­nies are.

MAPS has a dif­fer­ent mis­sion than Lykos, and Lykos needs to fo­cus nar­row­ly on clin­i­cal, reg­u­la­to­ry work for mido­mafe­t­a­mine as a pre­scrip­tion med­i­cine. That is a much more nar­row fo­cus than what Rick works on at MAPS. And we have to make that more clear. He hasn’t had day-to-day re­spon­si­bil­i­ty in Lykos for years.”

Ossiffied Institutions: An inadequate regulatory apparatus ill-equipped to assess novel therapeutic modalities

Two weeks ago, former head of the National Institute for Mental Health, Tom Insel, MD, published an article in STAT News titled “Adding psychotherapy to drug therapy works, but the FDA may not be able to handle it,” where he opined in the aftermath of the Adcom meeting (emphasis added):

While this application has attracted attention mainly because of the possibility of approving a psychedelic drug as a medical treatment, I believe the key innovation here was the proposal to combine medication and psychotherapy as a bundled intervention. This combination was not convenient for the FDA or its advisory committee, but wasn’t it really a proposal for a best practice that needs to scale across mental health care? I believe this new drug application could serve as a wake-up call for new regulatory processes that would view psychological treatments as key facilitators rather than as confounders of behavioral change.”

In the week since the rejection, the prevailing sentiment I hear is that therapy is a liability.

Yet, here we have a former head of a federal agency highlighting the inadequacies of the current regulatory system to evaluate innovative treatments effectively.

Elsewhere in the same article, Insel notes:

“One lesson from the ‘no’ vote on MDMA-assisted psychotherapy for PTSD is that the U.S. regulatory system is not optimized for mental health care.”

George Mason economist Alex Tabarrok is probably best known for researching the FDA decision-making process.

Tabarrok puts it this way:

“The FDA is conservative because when it approves a bad drug, its error is visible, but when it fails to approve good drugs, the dead are buried in an invisible graveyard.”

In other words, people get fired for approving bad drugs, but they don’t get fired for rejecting good drugs.

MDMA-Assisted Therapy is a good drug—ney, an incredible drug—that died at the hands of bureaucratic cowardice.

A Circular Firing Squad: aka the “Psychedelic Community”

Finally, the most overlooked in mainstream media coverage are the contributing dynamics of the so-called “psychedelic community”—the amorphous blob of people, groups, and organizations that are deeply invested—financially, socially, spiritually, ideologically—in the “psychedelic renaissance.”

The narrative surrounding psychedelics is complex and often contentious, especially within the “psychedelic community” itself. MAPS and its for-profit spinout Lykos, leading the charge for MDMA-assisted therapy approval, became a lightning rod for controversy.

While some saw MAPS as ushering in a new era of psychedelic-based therapies, others feared “medicalization” and viewed the organization with deep suspicion. Concerns about patient safety and alleged ethical breaches fueled opposition, even among those generally supportive of psychedelic medicine.

This internal conflict culminated in a powerful narrative of misconduct presented during the FDA Advisory Committee meeting, undermining the objectivity of the process. Despite support from veterans and members of Congress, the damage was done, and the negative narrative left an indelible mark on the proceedings.

While the validity of these accusations remains unclear, the rift within the psychedelic community undoubtedly played a role in the FDA’s decision.

It underscores the critical need for unity and collaboration as the field progresses. 

Only by working together can we ensure the safe, effective, and accessible integration of psychedelics into mainstream healthcare.

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The rejection of MDMA-Assisted Therapy by the FDA is emblematic of a complex and multifaceted challenge.

Like the geopolitical tensions that precipitated World War I, the factors leading to this rejection are rooted in an intricate web of methodological limitations, industry dynamics, institutional inertia, and internal discord within the psychedelic community.

These factors contributed to a climate of uncertainty and contention, making the path to approval fraught with obstacles.

As we move forward, it is imperative that stakeholders across the spectrum—researchers, regulators, advocates, and industry leaders—come together with a shared vision to address these challenges.

Only through collaboration and a commitment to rigorous, transparent, and innovative approaches can we hope to realize the potential of MDMA-Assisted Therapy and similar modalities in the future.

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Psychedelic Entrepreneurship: Navigating the Emerging Market

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Panelists:

• Daniel Love, Co-Founder, Beckley Waves

• Amy Kruse, Chief Investment Officer and Advisor, Satori Capital

• Manish Agrawal, Founder & CEO, Sunstone Therapies

• Sherry Rais, Co-Founder & CEO, Enthea