Taking the drug out of the trip: 5 Questions for Stanford anesthesiologist and neuroscientist Boris Heifets

Heifets discusses what his work might suggest about how psychedelics work, and what role placebo and expectation play in outcomes of psychedelic studies.

Boris Heifets got into drugs the usual way: youthful experimentation. As a college student at Yale, he wanted to study them, so he traveled to UC San Francisco; at the time, the university was the only institution that was giving humans MDMA in research studies. While there,he met psychedelic luminaries like the researcher John Mendelson and chemist Sasha Shulgin. Around the same time, he also met Rick Doblin at a MAPS conference, and helped on an early draft of the investigational new drug application for MAPS’ MDMA studies — but his mentors told him that psychedelics weren’t a viable career path, as there was no funding for research. Instead, Heifets got an MD and PhD, studying anesthesiology and neuroscience at New York’s Albert Einstein College of Medicine. He continued his training at Sloan Kettering and Stanford but he knew he’d come back to psychedelic drugs someday. When he started working in Rob Malenka’s lab at Stanford, which studies synaptic plasticity and how drugs affect memory and learning, he finally had his chance and began publishing papers on MDMA.

Heifets remained at Stanford, where he is now an assistant professor of anesthesiology, and his lab is studying MDMA, ketamine, and psilocybin. In 2023, Heifets and his collaborators published a buzzy study investigating whether ketamine given to people with depression under anesthesia affected their depression symptoms. The Microdose spoke with Heifets about what his work might suggest about how psychedelics work, and what role placebo and expectation play in outcomes of psychedelic studies.

Tell me a bit about how you set up this ketamine while under anesthesia study, and what you found.

We know that after surgery, people with depression can feel worse. We had a lot of questions going into this study, but one of the main ones was: Can we make it better? As we designed this trial, we also realized that this was also an extremely convenient population to ask the question: Can you take the trip out of the drug? The lack of good placebo controls has been a sore spot for psychedelics, and in our study, people under anesthesia clearly will not know whether they got ketamine or a placebo — and we wanted to know whether ketamine would have any therapeutic benefit to the people who received it.

What we got at the end of it was 40 participants, many with treatment-resistant depression, showing around 30% remission for depression symptoms in the days after receiving ketamine. These were great outcomes. I was just so struck by some of the participants’ stories; their joy was infectious. Some said it was life-changing, that they feel better than they had in years, that they wanted to get back in touch with friends they’d lost touch with. I didn’t know whether or not they got the drug but all I could think was, “I want to bottle this up and give it to everyone else in this hospital.” I assumed that those people must have been in the ketamine group.

But then when it came time to unblind the study, my guesses were basically 50-50. I looked back at what some of these participants wrote about their experience and it was clear that something really happened for them, even if they were given a placebo. There was just no denying the difference they felt in their lives.

What does this tell us about the power of expectation, or of placebo?

Placebo is usually a term we use to subtly impugn the credibility of patients. Like, if you got a placebo and you got better, there wasn't really anything wrong with you to begin with. I think that’s the wrong message and we need to rethink how to present it. Saying placebos shouldn’t work is like saying that psychotherapy doesn't do anything, or that having a religious revelation doesn't do anything. We know intuitively that’s wrong. Placebo is a real thing with a biological mechanism. And if we accept that there's a biological mechanism, then why shouldn't we expect that you can act through that mechanism to achieve therapeutic change? Maybe psychedelics act on that very mechanism, that mechanism of expectancy and hope. If there were a drug that could improve your likelihood of feeling hope again, that’s a real drug! What if we thought about psychedelics that way?

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So what if we did think about psychedelics that way — how might that change our approach to understanding them?

I think psychedelics are essentially a standardized way to generate a powerful experience. What we know about placebos and effective transformative experiences is that there is almost always something at the center of it all. There's a structure, you can call it a ritual. There is a central event. That central event can be holotropic breathwork, jumping out of a plane. It could be a car crash, or a heart attack. I was spared by an angel, and I'm going to change my life, or it could be a source of trauma for years to come. A lot of it's in the framing.

But currently, people are inappropriately fixated on the molecular details of psychedelics rather than their potential to generate these experiences. I think it’s easy to take the wrong message from the molecular perspective: that psychedelics are special because they bind to a receptor, and if only we can re-engineer the ligate-receptor interaction so it doesn’t trigger all this unnecessary hoopla, just the necessary underlying biology, then we’ve got the ace. But to me, that would just be engineering the therapeutic property out of psychedelics. I don’t think there’s anything terribly specific about how psychedelics work, and I’d wager there isn’t a big difference between the therapeutic potential of ayahuasca, psilocybin, and ibogaine. You just need to have a big experience. But that doesn't fit the types of interventions we’re used to in medicine, and it’s a difficult hypothesis to test, and to find a control group for.

How else are you looking at the role of expectation in psychedelic treatments?

One idea is not fully disclosing the study design to participants. Currently, I’m collaborating with Josh Woolley at UCSF and Michael Silver at UC Berkeley on a clinical trial using psilocybin to treat chronic pain using an authorized incomplete disclosure design. We’re telling them upfront that expectation plays a big role in these studies and we don’t want them to have too many specific expectations about drugs, and what it means if they don’t get the drugs they expect. I won’t reveal the full design here, either, but participants are told that everyone gets a dose of psilocybin — between 1 and 30mg — and they may also get 0, 1, or 2 other drugs. Those drugs are lorazepam, a benzodiazepine; Ambien, used to treat insomnia; and modafinil, a stimulant.

You mentioned earlier that the big, ritualistic experiences psychedelics provide might be part of its power in helping people. That seems hard to study — are you working on a way to understand that?

As we were doing the ketamine study, we noticed in the operating room that patients dream. This is well known among anesthesiologists, and mostly, you don’t want patients to report back that they dreamed during surgery, because it might suggest they were awake. But anesthesiology has evolved in the last 20 years and now the drugs we use, like propafol, are known to induce dream-like states. One of my colleagues, Harrison Chow, said, “I think we can treat PTSD this way.” And I said, “I think you’re full of shit, but let’s see” — I was interested because what he described sounded like the same situation as when people take MDMA: they have these experiences as they’re dreaming and it helps with their trauma. So we started looking for signs people may have been dreaming from their EEG data, and we caught a few cases. There was one woman who was attacked at close range with a knife and then two weeks later came to Stanford to have her hand repaired; she had nightmares, inconsolable, very much someone you’d expect to progress to PTSD. And Harrison saw her, did his magic, we saw on the EEG that she was dreaming; and when she woke up, she had tears of relief. She had the same nightmare she’d had every night except instead of ending at the attack, rocketing her into consciousness, she just kept dreaming. She dreamt of going to the ER, going to the operating room, running errands, then being home and being healed. She resolved the trauma and we followed her for two years now and she’s able to calmly talk about it now.

So we’ve done it a thousand times now, inducing these dream-like states after surgery, toward the end of anesthesia. Generally patients love it; they dream about all kinds of things. We’ve just happened to find a couple patients with PTSD, both who lost adult children to suicide. Listening to the dreams they had coming out of anesthesia was incredible. One had a dream reimagining the birth of her son, which was initially traumatic but was now cathartic and beautiful. She used to have nightmares of trying to save her son but two years later, they’re gone. It still gives me chills; it was such a powerful experience.

It’s hard to look at this and not see parallels to what’s happening with psychedelics. But there’s no psychedelic involved — just opioids and propofol, and other standard anesthetic agents. There seems to be a similarity in certain EEG characteristics for both psychedelics and dream states; potentially, this is more about brain state than it is about the drug used to achieve that state.

This interview has been edited and condensed for clarity and length.