380: A new top drug regulator and the future of psychedelics

What It Covers

Tracy Beth Hoag becomes FDA's new drug center leader after Rick Pazder's departure over concerns about commissioner Marty Makari's influence. David Olson discusses developing neuroplastogens—drugs that provide psychedelic therapeutic benefits without hallucinogenic effects—and Delix Therapeutics' phase one trial results showing rapid antidepressant effects comparable to traditional psychedelics.

Key Questions Answered

• •Neuroplasticity mechanism: Psychedelics activate serotonin receptors to promote rapid structural brain rewiring in the prefrontal cortex, which atrophies in depression and PTSD. This physical repair produces therapeutic effects within 24 hours versus weeks with SSRIs, and benefits persist long after drug clearance. Every effective antidepressant intervention promotes cortical neuron growth, making neuroplasticity central to treating neuropsychiatric conditions.
• •Dose-dependent efficacy: Zalzupendol demonstrates concentration-dependent therapeutic effects—higher doses produce stronger antidepressant responses without causing hallucinations. Over 100 patients have taken the drug with only mild nausea and headaches at very high doses. The compound shows identical EEG biomarkers for neuroplasticity as ketamine and psychedelics, confirming brain engagement despite lacking hallucinogenic properties.
• •Episodic dosing paradigm: Phase one trials tested two regimens—daily dosing for seven days versus two doses on days one and four—both producing identical rapid MADRS score reductions sustained four weeks post-treatment. This episodic approach mirrors electroconvulsive therapy protocols and treats depression as an episodic disease, eliminating need for daily medication and allowing retreatment only when episodes recur.
• •First-line treatment positioning: Non-hallucinogenic neuroplastogens can serve as first-switch treatments after generic SSRIs fail, rather than reserving them for treatment-resistant patients like traditional psychedelics. FDA approval for at-home dosing in phase two trials enables broader patient access without clinic supervision requirements. Patients can determine treatment response within days instead of cycling through months of failed medication trials.
• •Regulatory consolidation concerns: Rick Pazder resigned as FDA drug center leader after one month due to concerns about commissioner Makari handpicking hires, inserting himself into drug review decisions, and promoting a commissioner voucher program for expedited reviews. Tracy Beth Hoag, who challenged COVID policies during the pandemic, replaces him, consolidating power among officials aligned with RFK Jr and Vinay Prasad's vaccine skepticism.