Samuel Wilkinson is a psychiatrist, researcher, and Associate Professor at Yale University, where he serves as the Associate Director of the Yale Depression Research Program. He has been studying, and using, ketamine as a rapid-acting antidepressant since well before the advent of high-street ketamine clinics and mail-order injectables. That dual perspective across clinical research and real-world patient care means Wilkinson offers a grounded view of the (es)ketamine landscape and the associated evidence base.
In this conversation with Psychedelic Alpha’s Josh Hardman, Wilkinson explores what we can (and cannot) conclude from the current literature on IV ketamine versus intranasal esketamine (Spravato), the role of patient preference and expectancy, recent null findings from a buzzy ketamine versus midazolam trial, speculation around opioid-based mechanisms, and other research questions. They also cover some of the logistical and practical challenges limiting broader adoption of rapid-acting psychiatric interventions, as well as Wilkinson’s view of the psychedelics field.
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In this Interview
- Esketamine vs Ketamine
- Psychotherapy
- Redosing: Clinical Reality or Commercial Incentive?
- Patient Convenience
- Practical Barriers to Spravato Uptake
- Ketamine vs Midazolam
- An Opioid-Based Mechanism?
- At-Home Ketamine
- Psychedelics
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Esketamine vs Ketamine
Josh Hardman, Psychedelic Alpha: What do we know, from published studies as well as your clinical experience, about the differences in clinical outcomes for esketamine versus ketamine?
Prof. Samuel Wilkinson: It’s important to understand that virtually all of the esketamine clinical trials were registered with the FDA or some other regulatory authority, meaning they have a different level of complexity and rigour than many of the ketamine studies, which have often been single-site or relatively small academic studies. So, although some researchers have looked at them and tried to compare these two different types of trials, you’re not necessarily comparing apples to apples.
There are a few key studies that have reported clinical health outcomes. These include one from us at Yale, one from Mayo, and another from MGH Harvard, who certainly seem to think something is leaning in the direction of IV ketamine.
But the data still has limitations, with one of the biggest being that it’s not randomised. With all things being equal in the U.S. health system, patients who get ketamine are going to be wealthier than those who do not, and we know that wealth predicts clinical outcomes.
So the data needs to be taken with a grain of salt, which is one of the reasons I’m leading a large multi-site study where patients are randomly assigned in a head-to-head trial comparing IV ketamine, which is probably the most commonly used form of ketamine for depression, and intranasal esketamine. It’s structured as a non-inferiority study, so the research question is basically: Is IV ketamine as good as Spravato for treatment-resistant depression?
Hardman: As it’s open-label, have you seen patients expressing any preferences for one versus the other?
Wilkinson: Some people do have a preference, but it varies. Sometimes they come in and say their doctor has advised that IV ketamine is much better and so they want that one. We have to accommodate their expectations and their preferences as much as we can.
Our clinic is one of the few that has insurance coverage for IV ketamine, and we also have near-universal coverage for esketamine. So if someone comes in with a strong preference for IV ketamine but they don’t have insurance, then we need to have some conversations about practicality and so forth.
Hardman: Are you systematically measuring expectation and preference?
Wilkinson: Yes. We aim to enrol 400 patients, and hope to enrol our last participant in just over two years. So in 2-3 years, we’d hope to have some top-level, preliminary results.
Psychotherapy
Hardman: That’s exciting. As you might have seen, Norwegian regulators have approved national reimbursement for the off-label use of generic ketamine for treatment-resistant depression. Interestingly, the protocol that advocates and healthcare professionals pushed for includes psychotherapy. Do you have any views on whether psychotherapy is essential in ketamine-based therapies?
Wilkinson: Part of it depends on what you mean by ‘ketamine-assisted psychotherapy’. I’ve done three studies now where we combine either ketamine or esketamine with cognitive therapy. I don’t think it makes a lot of sense neurobiologically to do the therapy while people are high, because everything we know about neurobiology suggests that during this time, memory is impaired and slower.
So maybe 3, 4, 5 or 6 hours after the ketamine infusion or esketamine insufflation, when there’s more plasticity and memory seems to be activated or enhanced, it could make sense. In my studies, we have given ketamine and then 8-12, or 24 hours later, the CBT session, which I think is a bit different to what people mean when they say ‘ketamine-assisted psychotherapy’.
Sometimes this is just a practical matter where someone has to be monitoring patients anyway, so they think they may as well be doing psychotherapy while they’re there, but there’s actually not a whole lot of data to show that doing psychotherapy while people are in an altered state adds anything to…
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