FDA general knowledge
The FDA requires this many phases of clinical trials before a drug can be approved.
Three (Phase 1, 2, and 3)
"4th phase" = continuous monitoring (this is when recalls happen)
What does MAPP stand for?
MDMA-Assisted Psychotherapy for PTSD
LSD, psilocybin, and MDMA are all being studied for psychiatric indications, but only 1 of these three is NOT a classic serotonergic psychedelic. Which is it, and what makes it different?
MDMA (an empathogen/entactogen that works primarily via SERT reversal, not a 5-HT2A agonist like LSD and psilocybin)
What is Prof Cazares's dog's name?
Valentina (named after hot sauce)
This is what it means when the FDA grants a drug "Breakthrough Therapy Designation," and what is the point of it?
Faster, more intensive FDA guidance and review (it does NOT mean approval is guaranteed)
MAPP1 was published in what journal in 2021?
Nature (Same as MAPP2 in 2023 which we read for today!)
What is the ONLY FDA-approved psychedelic/drug we studied this semester?
Ketamine
approved for treatment-resistant depression (as esketamine/Spravato) and as an anesthetic!
If Prof. Cazares had to try one psychedelic from this semester's syllabus, which would he choose?
When the FDA rejects a drug application, they send this document explaining why and what is needed to resubmit.
Complete Response Letter (CRL)
What percentage of MDMA participants in the MAPP2 trials correctly guessed they had received the drug (BIG statistic central to the FDA rejection)
94%
MDMA, psilocybin, and ketamine are all being investigated for depression, but each works through a different mechanism. Name the three different receptors they work on.
MDMA = reverses SERT
Psilocybin = 5-HT2A receptor agonist
Ketamine = NDMA blocker
What is Prof. Cazares' spirit animal
Crow
The FDA can approve a drug for a specific "indication," meaning a specific condition. A doctor can then prescribe it for something else entirely without FDA approval. What is this called, and why does it matter for psychedelics?
Off-label prescribing
This matters because, theoretically if MDMA got approved for PTSD, psychiatrists could prescribe it for depression, anxiety, etc.
The MAPP2 placebo arm had a response rate of 48%, dramatically higher than MAPP1's 32%. Explain how a critic could use this as an argument against approval by FDA.
The therapy protocol itself is helping, not necessarily the drug!
The FDA rejected MDMA partly because 94% of participants knew they got the drug, making blinding nearly impossible. You are a scientist: name one specific solution to improve the blinding problem in future psychedelic trials.
Open answer, but maybe:
1. Active placebo (low or varying doses) to mimic physical sensations
2. Third-party blinded external raters rather than self-report
3. Adding objective biomarker endpoints like neuroimaging, get rid of subjective self-report?
4. kinda radical: open-label trials with a different design that do not depend on blinding?
What TWO instruments does Professor Cazares play?
Harmonica and Accordion
Who is the current acting FDA commissioner, and who just resigned?
Kyle Diamantas (current acting) and Dr. Marty Makary (just resigned)
!!DAILY DOUBLE!!
Lykos Therapeutics' NDA was rejected in August 2024. Name at least 3 of the 5 specific reasons the FDA cited in their rejection.
1. Functional unblinding
2. Therapist misconduct/data integrity issues
3. Drug + therapy conflation
4. Generalizability
5. Cardiovascular Safety
!!PLAY DEVIL'S ADVOCATE!! Why would the FDA's rejection of MDMA ultimately make psychedelic medicine stronger?
(Open answer: points go to any answer that mentions improved trial design, active placebos, blinded raters, or any lesson from this class)
One of Prof Cazares' favorite papers this semester identified THIS brain region as the primary target of ketamine's antidepressant effects. Name the region and the lead author.
Lateral Habenula and Chen et al. (2024)