A key hurdle in psychedelic trials is that patients often know if they received the active drug. The industry is addressing this "functional unblinding" by aiming for therapeutic effects so large in Phase 3 that they significantly outweigh any potential placebo bias, making the unblinding issue less critical for approval.

The drama surrounding Sarepta's gene therapy, where a top regulator was ousted after political pushback and later reinstated, shows the FDA is now more amenable to outside influence. This case study indicates that presidential and activist pressure can directly impact regulatory enforcement and personnel decisions, moving beyond purely scientific considerations.

Voyager CEO Al Sandrock supports the FDA's use of accelerated approval for severe diseases but argues it must be coupled with industry accountability. He praises Amelix for voluntarily pulling its ALS drug after a failed confirmatory trial, framing such responsible actions as essential for maintaining the FDA's willingness to be flexible with approvals based on surrogate endpoints.

While political drama at the top of the FDA captures headlines, the agency's rank-and-file reviewers are largely maintaining operational continuity. Many drug programs are still receiving necessary feedback within expected timeframes, suggesting the core machinery of the FDA is resilient.

Unicure's setback with its Huntington's gene therapy demonstrates a new political risk at the FDA. A prior agreement on a trial's design can be overturned by new leadership, especially if the data is not overwhelmingly definitive. This makes past regulatory alignment a less reliable indicator of future approval.

Internal power shifts at the FDA, such as Vinay Prasad's rising influence, create a chilling effect on review teams. Even without direct orders, reviewers feel less emboldened to be flexible when leadership's public stance favors greater rigor. This 'tone from leadership' can shift regulatory outcomes more than explicit policy changes.

Psychedelics can serve as a high-stakes litmus test for a founder's conviction. An investor might see a founder who hasn't used them as a risk, as a trip could cause a career pivot. Conversely, a founder who continues their B2B SaaS venture post-trip is proven to be a "true believer."

Psychedelics may treat trauma by reducing activity in the brain's outer cortex (responsible for language, planning). This shifts consciousness to deeper regions like the insular cortex, allowing for profound insights and self-compassion without the usual cognitive filters of guilt and blame.

For the next wave of psychedelic therapies, the pivotal regulatory question is treatment durability. The FDA's view on "as-needed" (PRN) dosing versus the fixed-interval schedule of approved drugs like Spravato will determine the commercial viability and clinical pathway for companies like Compass Pathways.