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Alison McInness believed in ketamine therapy before it was cool. Shoot, she believed before her hospital did (though that didn’t stop her from going rogue). Now, she says it’s time for rules and structure, so more people can access this life-saving treatment.

We spoke to Dr. Alison about launching one of the nation’s first ketamine therapy programs, leveraging data and machine learning to improve outcomes, and setting treatment standards to end ‘wild west’ era of ketamine therapy.

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Can you share how your perspective on psychedelic medicine has evolved over your career?

I got started when I was at Kaiser Permanente Northern California, coming from a background in academia at Mount Sinai School of Medicine. At that time, Sanjay Mathew and Dennis Charney were pioneering intravenous ketamine therapy for depression. It was still very new.

Initially, I was just amazed by how phenomenal it was. You'd see people who'd cycled through maybe their tenth antidepressant getting better from depression in hours. One woman told me, “My problems are all still there, but now they're like sea creatures swimming past my legs and they don't hinder me.” We’d regularly get these very poetic and beautiful testimonials from people who'd felt so stuck.

But over time, after seeing lots of patients, my perspective on its effectiveness has become more modest. While ketamine can be incredibly transformative, I don't think you see sustained benefits unless lasting changes are made in lifestyle. I began thinking about it more as something you do with therapy, not just as a treatment alone. You need to use the treatment, and the synaptic plasticity it engenders, to prime behavioral change and actually implement the insights.

I now have a more measured outlook on the goals for ketamine therapy. It's still incredibly useful and fast-acting, but it needs to be part of a broader program.

You founded Kaiser Permanente's ketamine infusion therapy program. What were the biggest challenges in implementing something so novel within a large health system?

The biggest challenge was risk management. On the physician side, we were so excited to get this going, but from risk management's perspective, we were making ourselves a big target. The health system could get sued if a person snuck out and drove home, or even had an accident the next day after a ketamine session. The off-label nature of the treatment opened us up to a lot of liability, and there were still many unknowns about lingering effects.

What ultimately convinced people was that the treatment was phenomenally successful with really ill patients. By the time risk management caught up to what we were doing, we had patients saying ketamine had saved their lives. Once we got it going, there was really no taking it away. We successfully managed the risks with a very stringent protocol for patient selection, ketamine administration, and follow-up.

One of the most pressing uses turned out to be for patients with acute suicidal ideation. It's hard to argue for taking away something that works so fast in those cases, especially since there’s no comparable alternative. Esketamine also reduces suicidal ideation, but its effects are slower.

How do you think your background in psychiatric genetics informs your approach? Are we getting closer to personalized psychedelic medicine?

I do see a future for precision psychedelic medicine. At Osmind, we're working on looking at clinical predictors of response to esketamine and ketamine. While we're not looking at genetic predictors yet, that could come. For now, we're using machine learning to analyze line items from mood surveys in combination with various clinical and demographic factors.

Others have already seen some interesting patterns. Brittany O'Brien's work has shown that people with high levels of adverse childhood events have a very particular response trajectory. We're also looking at comorbidities, medication history, and other pretreatment clinical factors that might influence response. These variables are expected to have small effects, so very large sample sizes are needed to detect signals. You need machine learning to handle so much complexity.

I think we'll make progress through incremental improvements, not in giant leaps. We'll gradually get better at predicting who will respond to what treatment, and when we add all the different areas of investigation together, hopefully we'll come up with something meaningful.

Osmind is building one of the world’s largest collections of real-world data for ketamine intravenous therapy (KIT). What’s your plan for all this data?

To be clear, while I think we have more real-world data for KIT than anyone, Roger McIntyre's team in Canada has also published an impressive amount of real-world evidence. Recently, Osmind supported the National Network of Depression Centers by co-authoring a letter advocating for insurance coverage based on real-world evidence. We hope it moves the needle because currently, only a very small segment of society has access to the treatment.

We're looking at response prediction, remission prediction, and adherence prediction. We're also exploring indications other than depression. For example, right now we're doing a deep dive on PTSD because of the recent setback with MDMA approval. I'm presenting a poster at the annual American College of Neuropsychopharmacology meeting showing some striking results: 65% of people respond after four infusions. That's pretty extraordinary, even with the open-label caveat.

There's also so much we need to understand about optimization. What's the best dose? The average in our data after induction is 1mg/kg, way higher than the 0.5mg/kg standard. Are these relatively high doses necessary? Are they safe? What if you get your bigger gains with early infusions and diminishing returns as you increase the dose? These are the kinds of questions we can start to answer with this dataset.

What do you see as the most pressing issues facing the field, especially ketamine prescribers and therapists, today?

We need to regulate ourselves. This whole ‘wild west' situation with different practitioners, different protocols, and inadequate addressing of abuse potential can’t continue. We need to manage ketamine therapy systematically. That's why I'm co-chairing the standards committee at the American Society of Ketamine Physicians, Psychotherapists, and Practitioners (ASKP3) along with Dr. Sam Ko, CEO & CMO of Reset Ketamine. We're working to establish the first U.S. consensus guidelines.

We've created a voluntary pledge where providers agree to seven key practice points—things like proper informed consent, not selling packages of infusions, and protecting patient welfare. Then next year, we’ll be rolling out comprehensive guidelines that we've developed with a committee, looking at all the different protocols out there and the supporting literature.

If we don't show evidence that we're willing to self-regulate, the ‘wild west' analogy will stick and we'll never get insurance coverage. Real-world effectiveness studies in over 6,000 patients show basically 50% response and 25% remission. Now, these estimates are an upper bound because real-world data are never complete. They don’t include people who drop out of treatment, likely because they didn't respond as well. But even with this caveat, those results are very impressive. We need these standards in place to move forward.

Want more from Alison?

Learn more about ketamine therapy standards and ethics at ASKP3. If you’re a practitioner, schedule a demo with Osmind to optimize your workflow.

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DISCLAIMER: This newsletter is for educational and informational purposes only and is not intended as a substitute for professional medical advice. The use, possession, and distribution of psychedelic drugs are illegal in most countries and may result in criminal prosecution.