Paving the Way: Husseini Manji on Spravato’s Lessons for Psychedelic Drug Development

Dr. Husseini Manji’s affiliations are quite the laundry list: a professor of psychiatry at the University of Oxford with adjunct and visiting positions at Yale and Duke, as well as serving as co-chair of the UK government’s mental health mission. But it’s his earlier work as a pioneer in the development of rapid-acting antidepressants that concerns this interview, with Manji’s role in esketamine’s rise to prominence our primary focus.

Speaking with Psychedelic Alpha’s Josh Hardman, Manji traces that drug’s journey from bench to blockbuster: from a plasticity theory borne out of rodent models, through to in-human studies at the National Institutes of Health, and then his move to Johnson & Johnson, where he led its development into a marketed product, Spravato. He discusses how he won over naysayers regarding an in-clinic, episodic model, and the slow launch that he credits with the drug’s staying power. He also touches on what Spravato’s clinical development, roll-out experience and commercial footprint might mean for psychedelic drug developers, how payors could view the next wave of interventional treatments, and his thoughts on the hype around psychedelics today.

This interview took place in May 2026. It has been edited for length and clarity.

From the monoamine hypothesis to plasticity pathways

For the longest time, I felt there was something wrong with the idea that traditional antidepressants increase intrasynaptic serotonin within hours, and yet it takes six weeks for them to work.

Josh Hardman, Psychedelic Alpha: Can you share how this line of inquiry get started?

Husseini Manji: I've been involved in molecular and cellular research all my life, with the goal of coming up with better treatments. For the longest time, I felt there was something wrong with the idea that traditional antidepressants increase intrasynaptic serotonin within hours, and yet it takes six weeks for them to work. So we did a lot of rodent studies to try to understand what might be going on, and long story short, a lot of the data suggested that plasticity pathways were the key. We weren't just talking about too much or too little serotonin or dopamine. While I was at the NIH, we did a lot of work showing that NMDA- and AMPA-receptor-mediated plasticity might be particularly relevant.

That led to the obvious question: what if you directly targeted AMPA- or NMDA-receptor-mediated plasticity? Would you get antidepressants that worked faster; that even worked in people for whom traditional antidepressants hadn't worked? My thinking was that if you've got an impairment in those plasticity pathways...