Psychedelics for Postpartum Depression: 5 Questions for OB-GYN Camille Hoffman
Hoffman discusses Reunion's clinical trial using RE104 to treat postpartum depression.
Pregnancy carries many potential complications, but among those, perinatal anxiety and depression in the weeks, or sometimes months, immediately before or after birth are the most common, says Camille Hoffman, professor of maternal fetal medicine at the University of Colorado School of Medicine. In fact, mental health issues — specifically suicide and substance abuse — are leading causes of maternal mortality. Additionally, maternal mental health issues can have far reaching implications for fetal development and children’s early life. Impaired bonding and attachment between mothers and babies, and early trauma, Hoffman says, could set children “on a trajectory for autonomic nervous system dysregulation, and put them at risk for poor mental health, substance use, and poor health outcomes.”
Hoffman, an obstetrician-gynecologist with training in perinatal mental health, perinatal psychiatry and integrative medicine, has desperately wanted to give her patients better options for managing their anxiety and depression. In 2018, she connected with colleagues studying psychedelics about the potential of using them with her patients. An OB-GYN at the University of Utah mentioned to her that she’d heard of a company called Reunion that was studying the use of psychedelics for postpartum depression. Soon, Hoffman was in touch with Mark Theeuwes, Reunion’s chief operating officer, and she became an investigator in the company’s RECONNECT Phase 2 clinical trial, which uses a psychedelic they call RE104 to treat postpartum depression. The Microdose spoke with Hoffman about what RE104 is, and the trial’s preliminary results.
What are the current treatments for perinatal and postpartum depression? For example, I’ve heard from pregnant friends that doctors have told them conflicting things about antidepressants — what do OB-GYNs recommend?
We always recommend that people with perinatal or postpartum depression receive some kind of psychotherapy, but whether someone can access that is a different story. In 2023, the FDA approved Zurzuvae, the first oral medication indicated specifically to treat postpartum depression. It’s a sedative, similar to a benzodiazepine — patients are given a 14 day course that they take around bedtime, and you’re instructed not to operate heavy machinery or anything like that — not that a lot of people in that phase of life are doing that. It has shown an improvement in people’s symptoms compared to placebo but hasn’t been compared yet to any antidepressants or other medications.
For the last 20 to 30 years, antidepressants have been the main approach. People are telling pregnant people all sorts of things about staying on antidepressants or stopping them, or when to restart — or whether to switch so that they have a more favorable lactation profile. It’s super messy, and there was recently an FDA panel that made it even messier. My approach, and those of us who practice in this area, is that if you’re on an antidepressant that’s working, you should continue it, and probably even increase the dose in the third trimester because you’re going to metabolize it more rapidly. We know that untreated or suboptimally treated depression or anxiety are the biggest predictors of postpartum depression, so we want to try to do everything we can to prevent it, which includes keeping people on their treatments. It’s better to get it in control in the prenatal period because it gets even riskier in the postpartum period as you have additional big life stressors that can worsen depression, like sleep deprivation, or appetite and weight changes.
What is RE104, the drug you used in this clinical trial you were part of?
I tell my patients that it’s a psilocybin-like compound — it has the same compound that is the psychoactive part of magic mushrooms. In presenting data, we call it a psilocin analog: RE104 is similar to psilocin, the psychoactive chemical that results from metabolizing psilocybin. We know that psychedelics have helped people with depression, and we know that in some older studies on LSD, classic psychedelics might increase oxytocin production, which is important for connection and lactation, as well — so that might be important in the postpartum stage. Anecdotally, the participants I’ve seen have said that they feel more self-compassion after their sessions. One said they regretted having missed some time with their infant but felt more optimism about the future. Another, who had a scary experience during their session and needed a lot of support from monitors, said she had no memory of that but that she felt like she’d faced her fears and now had nothing to fear.
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Who was eligible to participate in this clinical study, and what kind of treatment did they get?
Across the study sites, we had 72 participants, and we screened 8 or 9 at my site. The eligibility criteria were quite strict; we were looking for people who met the definition of postpartum depression — defined by the DSM as developing depression symptoms in the third trimester or within the first four weeks after giving birth. [Reporter’s note: the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, or DSM, is used by clinicians around the world to diagnose conditions.] People with more recent psychiatric history were not included to try to limit the possibility that you had someone with, say, treatment resistant depression or bipolar disorder in this trial. For instance, if someone had a history of depression, they needed to have had a period of time in their 1st and 2nd trimesters where they weren’t experiencing symptoms to be eligible.
Those who were eligible for the trial were randomized to two conditions: either a journey-level dose of RE104 or a microdose. Before that, a blinded independent rater assessed them using the MADRS [Reporter’s note: the Montgomery-Asberg Depression Rating Scale, or MADRS, is a standard questionnaire clinicians use to measure depression symptoms]. At first each site had their own rater but that often was difficult to schedule so Reunion eventually ended up having raters meet with people on Zoom to complete that portion.
On the day of the dosing session, participants would come in and put on a mask, and begin listening to a playlist of music Reunion designed for the experience. Then a pharmacist or nurse would come in to administer the RE104, which is a subcutaneous injection. The overall experience is shorter than psilocybin — the average journey was 3.5 to 4 hours — but we still monitored them for 8 hours. And in that time, they were supported by two session monitors, who were therapists who underwent a training tailored to this study put on by the company Fluence. I did the training, too, just out of curiosity, and they tell us that no formal psychotherapy should be given, just support for physical symptoms, helping them get to the restroom, and how to calm people down if they are starting to get panicky. There were also two preparation sessions before the dosing about intention setting and how to work with your disappointment if you weren’t having a journey, and then two integration sessions after.
Reunion recently released preliminary results from that clinical trial. What have you all found so far? And what do we know about the safety profile of giving psychedelics to people postpartum — is there any risk to breastfed babies?
There were improvements in both the microdose control group and the treatment group, which is common in psychedelic trials, but there was a much bigger improvement with the treatment group; nearly 70% of those participants were in remission 28 days after receiving RE104, which was the last time point in the study. I’ve been impressed with those results; there’s really nothing else I’ve seen that has gotten postpartum depression into remission so rapidly.
I know Reunion has done a lactation study but I haven’t seen the data. I believe it included 12 healthy volunteers whose breast milk and blood were monitored to see how long RE104 persists, and what the relative infant dose would be. From what Reunion has told us, the drug would be washed out of breastmilk within 24 to 48 hours, so perhaps people would need to pump and dump for a day or two. In the Phase 2 trials we just ran, participants had to have weaned their babies - they could not be lactating any more.
When might there be a Phase 3 trial, and what do you hope to see in it?
It’s in the works. Now the FDA has to review the data, so a realistic timeline for starting Phase 3 would likely be next summer. I’d love to be a part of it.
As far as I know, Reunion is going to ask for abbreviated monitoring time on study day since the journey time for RE104 is shorter than the 8 hours that is standard for psilocybin studies. I believe they also want to incorporate more clinical measures to better understand how results translate into general clinical practice. For instance, also using the Edinburgh Postnatal Depression scale and psychedelic measures like MEQ. I’d also like to see them follow people for longer, to plan check-in measures further out to better understand how long is this remission sustained? In looking at other psilocybin studies, sometimes 1 or 2 doses can last for years. That would be great information to know for postpartum patients; for instance, if RE104 helps with symptoms long enough to cover one postpartum period, perhaps they can plan to receive another dose if they have another baby.
This interview has been edited and condensed for clarity and length.
