March 8, 2023
Alison McInnes, MD, MS
The "placebo effect" gets a bad rap. The human mind is a powerful thing, capable of incredible feats of healing and transformation. Nowhere is this more evident than in the world of psychedelic research. Dr. Boris Heifets has spent years studying the neurobiological underpinnings of these compounds, but he knows that their true power lies in something much deeper.
Dr. Boris Heifets is an Assistant Professor of anesthesiology, perioperative, and pain medicine at the Stanford University School of Medicine. He became interested in the potential of psychedelic medicine in the 1990s while doing field research at Burning Man.
He saw firsthand the power of these compounds, such as LSD and MDMA, to positively change people's lives and thought it was absurd to lump them together with drugs like cocaine and heroin as they were inthe "just say no" era. However, as he matured and gained clinical experience, he realized that abuse potential must be reckoned with when scaling these treatments to so many folks in need.
Boris studied the neurobiology of drug abuse early in his career in Eric Nestler’s lab, then joined UCSF in 1999.
“It was the only place in the country at the time that was giving humans MDMA. And that to me was just fascinating.
So back then volunteers would come into a room in the back of the drug dependence research center on the third floor of Langley Porter. And we’d hook 'em up to an IV, give 'em some MDMA, and watch movies with them. That was the protocol, and we would collect everything their body made over the next 48 hours.”
After USCF Boris took a position at Stanford and started working with Dr. Rob Malenka on a project to see if the prosocial effects of MDMA could be separated from its effects on abuse liability in mouse models.
Boris’ team found that the pro-social effects of MDMA could in fact be reproduced in mice by releasing serotonin locally into the nucleus accumbens (NAc), a key reward hub in the brain, resulting in activation of the serotonin 1b (5HT1b) receptor and without triggering abuse liability.
Instead, dopamine release in the NAc led to abuse liability, according to their study published in Science.
Moreover, the same group showed that activation of the 5HT1b receptor also reversed social behavior deficits in mouse models of autism. Excitingly, Stanford investigators are now running a clinical trial of a 5HT1b receptor agonist for autism under the auspices of MapLight.
Psychedelic medicine is exciting but all the hype makes it hard to evaluate the results of clinical trials. Expectations are so high, and the blind (whether or not the patient and the clinician know they are getting a placebo or active drug) is often ineffective.
Boris hopes to deconstruct the contributions of set, setting, and drug at least in part by studying the effects of ketamine and psilocybin on depressed persons undergoing anesthesia for routine surgery. It's as close to the perfect blind as one can get for the patient and the rater.
Boris thinks a lot about the placebo effect and how it has been somewhat demeaned in our culture to imply that patients experiencing it have been fooled in some way. He is fascinated with our ability to engender hope in patients to effect healing—whether or not a drug is used.
A woman was attacked by a family member with a knife. She had self-defense wounds. Her hand was very badly injured. She went to the emergency room. They patched it up and referred her to Stanford but she had to wait two weeks to get an appointment. In the intervening time, she had horrible nightmares.
She was unable to sleep, unable to function, and unable to talk about the event without bursting into tears. That's how Boris’ colleague found her in the pre-op area at Stanford. The team gave the patient light sedation and a regional anesthetic for the arm.
Then one of the team with experience inducing dreams decided to induce a dream with anesthesia while monitoring her with an EEG. She woke up as they were finishing and she started crying—not tears of anxiety—but of joy.
Upon awakening, she recalled the knife but the emotional weight of the narrative shifted. She remembered going to the emergency room, and going back to the operating room—all in her dream—and then being at home with her hand fully recovered, running errands like it was no big deal.
After that, her symptoms were gone. That's amazing, but you may be thinking, “did it stick?” After all, this is a patient who you might expect would convert from an acute stress disorder to full-on PTSD.
We followed her for eight months, and from that day forward, she no longer met criteria for a stress disorder. She was able to talk calmly when I asked her to recount the experience.
She reported no more nightmares and being able to sleep and function with family.
This patient didn't even get anything that exotic; She got propofol and a little touch of fentanyl, something that we use every day in millions of surgeries every year.
There seems to be this convergence between dream-like states, expectations/placebo effects, and psychedelics.
We don’t understand the neurobiology of this dream state. Humans aren’t supposed to be in a prolonged dream state given that immobility makes us vulnerable.
Usually, when you have a nightmare, you have an autonomic escape. Your heart rate and your blood pressure will rocket you out of dreams, into conscious awareness. That's something that modern anesthetics are able to mitigate. Meanwhile, we're able to produce these longer states of dreaming and we really don't know their full potential.
I think we'll see some interesting things when we start combining psychedelics with this stabilized kind of quasi-sleep. This to me is so exciting.
The article was originally published in the Northern California Psychiatric Society magazine.
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