5th March 2024

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Exploring Psychedelics With Boris Heifets

Dr. Boris Heifets is an assistant professor in the Department of Anesthesiology, Perioperative and Pain Medicine and the Department of Psychiatry and Behavioral Sciences at the Stanford School of Medicine. Dr. Heifets’ research aims to understand how drugs like ketamine, MDMA and psilocybin rapidly treat psychiatric disease and how they might be incorporated into clinical care and perioperative medicine.

Technology Networks invited Dr. Heifets to an Ask Me Anything session to answer your questions about psychedelics. These are just some of the questions that we asked Boris, click below to watch the full AMA.

Lucy Lawrence (LL): How do psychedelics work?

Boris Heifets (BH): The answer is that we don’t know! There are a couple of different motivations behind that question. One is “how do they make people feel better?” And the other is “how do they do what they do? What is a trip?” The way that medical science approaches these questions doesn’t give a lot of satisfying answers. We know a lot about which receptors these drugs bind to (Figure 1), we know what people report a trip to feel like, but very little beyond that.

The neuronal effects of psychedelics on the brain. Credit: Analytical Cannabis, adapted from Psychedelics and the Brain.

Figure 1: The neuronal effects of psychedelics on the brain. Credit: Analytical Cannabis, adapted from Psychedelics and the Brain.

There are a lot of ideas about how psychedelics work. Professor Robin Carhart-Harris (Founder of the Centre for Psychedelic Research at Imperial College London) has one idea about it called the “entropic brain”. If we consider it as a metaphor, the idea can be compared to metalwork. When you work metal, you heat it up, change the shape of the metal while it’s hot, and then cool it down again. Every time you heat it up, you can move things around, and then each time you cool it, it gets harder and stronger. It’s not an exact metaphor, but it does go some way to explaining what psychedelics feel like.

One thing we’re particularly interested in is how psychedelics change people. How do they change people’s lives, their mental outlook and their resilience? We’ve broken it down into three basic possibilities for what is driving these changes. Let’s start with the easiest one, the drug.

We think that these drugs, for whatever reason, hit an evolutionary switch in your brain to make new connections that can lead to better mental health resilience.  

The second is the experience. There are so many different drugs that all have similar effects, including psilocybin, LSD, DMT, ketamine and ibogaine. They all use different receptors and have different chemical structures, yet they can all profoundly alter the consciousness, and then restructure how you see the world and how you interact with it.  That suggests that it’s not really about the drug, it’s about the experience.  

Thirdly, we have to consider all the other aspects, like the preparation, the cultural context and then the crystallization of all the experiences in the aftermath, all of which play a big role in how you change your behavior.

LL: What is the key study that would advance psychedelics research, but hasn’t yet been conducted?

BH: I’ve only come to appreciate this after doing it for a while, but there is no perfect study. One of the biggest controversies in psychedelics right now is that none of our trials are blinded. The sceptics say that because the participants know if they were given MDMA or psilocybin, they’re just going to tell you what you want to hear. People hold that up as a reason why we will never be like oncology or cardiology research where you have wonderful clinical trials because we can’t do a proper clinical trial. 

We took this to heart, and said “How do we do a blinded study on psychedelics?” The answer was to perform the study on patients who were anesthetized. We recruited participants who were depressed and were already going to be undergoing surgery for other reasons. All the participants were therefore fully blinded. We saw a 50% response rate, even in those with treatment-resistant depression. 30% of the group went into full remission. This was expected, it’s what we’ve been seeing for 15 years in ketamine studies. However, the placebo group also showed improved symptoms. This doesn’t mean that the ketamine didn’t work, but it does mean that we tried to solve one methodological issue and discovered that there is an enormous non-specific effect. We think you can attribute a lot of this to the non-drug, non-experiential factors – just the fact that they’re involved in a trial where they think they might get better triggers a lot of hope, for example.

The problem is that these factors are very hard to pin down. We addressed the issue of blinding, but we didn’t solve any of the other issues associated with psychedelic trials, like how to control for expectations, is it the drug or is it the experience? Ultimately, I think the next avenue needs to be “How do you induce the psychedelic state – i.e., free association imaginal thinking – without the drugs?” That way we can discover if the experience alone is enough to drive these changes.

 

LL: How do you avoid your patients having bad reactions or bad trips?

BH: This is an excellent question. There’s some controversy around this too, but then everything is controversial in psychedelics! Everyone has opinions and no one has the answer. Avoiding bad trips is one of the primary motivators for what we’ll call the modern renaissance of psychedelics.

The “dark ages” of psychedelics began around 1974 when the United States passed laws making it impossible to do research with psychedelics. At that point, the cultural context mostly associated psychedelics with hippy culture and the anti-war movement, but there was also some knowledge of the therapeutic potential in the medical field. There were also a lot of stories about people developing long-term psychosis from trips. Then, there was a 3035-year-long ellipsis with no research at all, and now we’re finally starting again. One of the first papers that helped jump-start psychedelic research again was from Dr. Matthew Johnson in 2008, exploring how to safely test psychedelics and hallucinogens. It was aimed squarely at all the cultural baggage that comes with psychedelics. It showed that the considerations for studies would be impeccable if, for example, you screen for psychosis risk factors, control the setting and, most importantly, guide the trip so that participants don’t have any long-term issues.

Now, with that said, even in a nice, beautifully lit, well-appointed therapists’ couch at Johns Hopkins with two caring therapists, you still cannot fully constrain the chaos of a galactic dose of psilocybin.

It’s still an overpowering experience, it can lead to a lot of anxiety, it can lead you to remember things that maybe you didn’t want to remember or make you come to uncomfortable conclusions. The question is – and this is where the controversy comes in – is that a bad trip? Or is that something to work through? The current thinking is that this is a challenging emotional experience, but that’s what the therapists are there for. Their role is to help you get catharsis and resolution.

However, it is absolutely possible to have an adverse psychological reaction to a powerful psychoactive drug, and there are harms that can be done. The worst-case scenario is a long-term psychotic reaction. As a consequence, we’re very conservative at the moment. We don’t include anyone in our studies with histories of psychotic disorders, like schizophrenia for example.

LL: What kind of side effects of psychedelic therapy can patients expect to see? Would you expect to see differences in their urine, stool or blood samples after therapy?

BH: Not that we can find. Or at least, nothing obvious. Let’s take this question in a bit of a different direction though: are there long-term changes, for example, in inflammatory markers? If we think about a trial where we treat chronic pain with psilocybin, there’s a lot of evidence to suggest that depression, pain and all of the symptoms of chronic pain are associated with inflammation changes.

In these trials, people say they’re better and they act better, and they’re doing things that would be associated with a reduction in pain, but can we actually match that up with a biomarker? As of yet, we haven’t been able to identify a clear marker that represents a physical change in addition to the psychological changes. 

 

LL: Are there any exciting projects that you’re currently involved in and can talk about?

BH: The most exciting thing I’ve seen is linked to non-ordinary states of consciousness and whether these effects are due to the drug or the state of mind. We have intentionally induced anesthesia in three patients to allow extended dream state periods. Usually if you have an intense emotion or emotional activation while you’re dreaming, then it will rocket you into consciousness. However, under anesthesia the dream state can be held for longer. All three patients had symptoms of post-traumatic stress disorder and acute stress disorder but were able to basically work through their trauma in the space of 15 minutes in this anesthesia-associated dream state. If you compare that to what’s been shown with MDMA-assisted psychotherapy and the idea of re-exposure using psychedelics to bring forth traumatic memories in a processable way the link is obvious.

This dream state isn’t induced with psychedelics, it’s induced with propofol, but it appears to be similar to the psychedelic state. It’s imaginal, it’s visionary and allows you to work through things. The exciting next step is to move it out of the operating room, and work on inducing it in a controlled way. It would be a psychedelic trial, without any psychedelic drugs. I think it will teach us a lot about inner healing and how people heal when they’re able to process traumatic memories and move on. I think we’ll see that this process is not unique to psychedelics, and that is exciting.

 

LL: How would you like to see the future of psychedelic-assisted therapy develop?

BH: The optimist in me would like to see some societal acceptance, that this is a reasonable thing to try, because whatever else you’ve tried hasn’t worked particularly well. Even if psilocybin is restricted again, so much work has already been done that something is going to come through from that. It is very likely that, rather than dismantling our current mental health system, we’ll see a hybrid system. Perhaps we’ll design a drug that’s like MDMA or psilocybin, but it comes on faster and doesn’t last as long. Then you could sniff some salts or take a nasal spray before you go into a therapist’s office, so that you’re in a moldable state, and in a place where you can work through things. There will probably still be a psychoactive trip aspect to it, but just not as strong, making it more accessible.

Psychedelic therapy brings up a new way of thinking about healthcare that prioritizes human interaction. Psychedelics are a catalyst for growth, they don’t cause growth in and of themselves. I’m not hopeful that we’re going to recreate SSRIs and just make a pill that you take every day that grows synapses but doesn’t do much psychoactively.

My hope for the future is that we can enshrine the importance of human connection, therapy and social support in concert with psychoactive substances.

Dr. Boris Heifets was speaking to Lucy Lawrence, Senior Digital Content Producer for Technology Networks.

About the interviewee

Dr. Boris Heifets seeks to apply fundamental insights from neuroscience to the field of anesthesiology and perioperative medicine. Presently serving as an assistant professor in the Department of Anesthesiology & Perioperative Medicine at the Stanford School of Medicine, he earned his undergraduate degree in neuroscience from Yale University, obtained an MD/PhD from the Albert Einstein College of Medicine, and completed both anesthesiology residency and a neuroanesthesiology fellowship at Stanford Hospital. Heifets’ research, spanning basic and clinical domains, is focused on unraveling the mechanisms of action underlying emerging rapid-acting treatments for psychiatric diseases such as ketamine, MDMA, and psilocybin. 

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