🫠 Psychonaut POV

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Steve Levine was one of the very first clinicians to advocate for ketamine in psychiatry. But these days, he's all in on psilocybin (of the crystalline polymorph variety) as Chief Patient Officer at Compass Pathways, the company closest to FDA approval for a classical psychedelic.

We asked Steve how psilocybin and ketamine differ from a patient perspective, what's left to be done before COMP360 is available to patients, and where he's fighting for access as patient champion at Compass.

This experience is a weekend group psilocybin journey at Sangam Healing Center in Lakewood, Colorado, just outside Denver. The format is simple: Friday evening preparation, a full-day guided journey on Saturday, and a Sunday morning integration session. Groups are capped at 8 with at least one licensed facilitator for every four participants. Sangam's approach is trauma-informed and draws on a mix of breathwork, meditation, somatic practice, and Ayurvedic tradition.

I genuinely like people and find them endlessly fascinating. Life is absurd and hard, and the fact that we all keep doing it anyway, each in our own way, never stops amazing me. So when someone comes to me hurting and looking for help, I feel enormous pressure to do something meaningful for them. But I've often felt dissatisfied with what I've been able to offer people.

The turn came in 2010 when a patient came to me for a second opinion. She'd had good care. She’d tried TMS, ECT, and a long list of off-label strategies. Nothing had stuck. In the course of our conversation, she somewhat guiltily admitted that whenever she got a cold and took cough medicine, she felt better for a little while. She'd noticed it as a pattern. When we narrowed down which medicines and which active ingredients, the common denominator was dextromethorphan. That made me really curious: what's the mechanism, and is there anything else with similar pharmacology that has any evidence in depression? That's what led me to the early research on repurposing ketamine for depression.

Nobody was doing this clinically at the time. I talked to a lot of anesthesiologists just to see if the idea alarmed them. It didn't. They used ketamine every day and considered it one of the safest drugs they had. So I stood up a program.

From there I started experimenting with dextromethorphan-based medicines as a follow-on to ketamine, to help patients hold onto the benefit after treatment ended. The most reliable combination turned out to be dextromethorphan paired with bupropion, and in 2012 I wound up consulting for the founder of what became Axome on exactly that. It's now FDA approved as Auvelity. Then Spravato opened up the broader category of interventional psychiatry, and psychedelics followed from there. It's always been less about the drugs themselves and more about the people who need something better.

The differences come down to rapidity of effect and durability of effect. With our data from February, we showed that if you're going to benefit from COMP360, you'll likely know by the day after your first treatment. But we still need patient-level data to know if that holds across the board. Spravato's primary endpoint was at week four, after eight administrations. At our primary endpoint at week six, we showed the same effect size after a single administration.

The durability gap is even starker, though we'll need further data to confirm. Spravato's approval trials involved eight administrations over four weeks, then weekly or every-other-week maintenance after that. Most patients end up with somewhere between 25 and 50 treatments per year, each a three-hour appointment they need someone to drive them to. Right now our profile looks like one or two initial treatments, and maybe two to four total over the course of a year.

People sometimes frame the length of a psilocybin session as a drawback. I'd push back on that. You're dedicating a full day to your mental health, with a trained team of people whose entire job is to support you through it. Compared to taking a modestly effective pill at home every morning, essentially alone, that full day is a feature, not a bug.

On the regulatory front, the FDA is directionally aligned with us on submitting our application on a rolling basis. We've requested a follow-up meeting to confirm that, and once we do, we'll start submitting. The last gating item will be the 26-week data from our Study 006 Part B, which we expect in early Q3. We've said we expect to complete the full application in Q4, and we plan to be ready to launch by end of year.

If we do get approval, the drug will need to be rescheduled. Right now it's Schedule I, so it first goes to the DEA at the federal level, and they have 90 days to act. Then it needs to be rescheduled state by state. About half of states have trigger laws and follow federal guidance automatically. The other half require legislative or administrative action, and we've already been doing work in those states.

In parallel, we're building out our commercial infrastructure from scratch. We've never had a commercial product before, so that means a sales team, a payer and market access function, and all the support services around a REMS program we expect will look similar to Spravato's.

✍️ Editor’s note: Two days ago, Compass Pathways received one of three FDA Commissioner’s National Priority Vouchers awarded to psychedelic drug developers, following last week’s Executive Order. Steve chose not to update his response.

They'll likely coexist. Think of Epidiolex, GW Pharma's FDA-approved CBD product for pediatric epilepsy. When it launched, there were already state-level CBD programs and artisanal natural products like Charlotte's Web being used by families with kids who had certain types of epilepsy. But as soon as Epidiolex was approved, the first customers were people who transitioned over from those other products. People trust FDA-approved products. They know there are safety, purity, and standardization requirements behind them.

Probably most importantly, FDA approval is in most cases the only path to insurance coverage. That's what makes treatments actually affordable. If you look at Oregon's state psilocybin program, the average income of participants estimated recently was over $150,000. It's mostly not even Oregonians using it. It's people traveling there and paying thousands of dollars out of pocket.

I think state programs will continue to exist for people who want that model and can afford it. But the vast majority of people with a diagnosed condition like treatment-resistant depression, who don't have thousands of dollars of disposable income and don't want to travel to another state for a treatment that's still federally illegal, will likely choose COMP360.

Honestly, I'm not sure I'd call it fighting. I'm always preaching to the choir. Compass is a genuinely patient-centric organization, which is probably part of why there's a Chief Patient Officer in the first place. But what I am focused on is making sure we don't define success too narrowly. My priority is broad and equitable access, not just commercial success.

The sites that currently deliver Spravato are the obvious starting point for COMP360. The physical infrastructure and staffing are the same. We could draft on their success and be very commercially successful without going any further. But the 80/20 rule is in full effect there. The vast majority of prescriptions are written in fewer than 1,000 of those 7,300 sites. Access so unevenly distributed is a failure in my mind.

That's the reason we're building a network of strategic collaborations with certified community behavioral health clinics, hospital systems, and integrated primary care models with largely underserved populations. Each one is a template for a different type of access.

We're also moving our PTSD program rapidly ahead. We've initiated a Phase 2b/3 study that's designed to go straight to approval, with about 300 participants. Thirteen million people have PTSD compared to four million with treatment-resistant depression, and there hasn't been an approval for PTSD this century. The only approved options are a couple of old generic SSRIs that are modestly effective at best. And unlike treatment-resistant depression, which is by definition a third-line indication, PTSD could potentially be first line for COMP360.

The only way to stay honest about our work is to keep one foot in the clinic. I still occasionally put the sweater vest back on and see a small number of patients. We also bring in patient speakers regularly, including people inside Compass who live with treatment-resistant depression. The whole organization needs to understand what's at stake, not just the clinicians.

Read about Compass Pathways’ clinical approach and drug development pipeline.

That’s all for today, Cyclists! Whenever you’re ready, here’s how we can help.

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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.