CATR: Can you define the term “psychedelics”? How do they work in the brain?

Dr. Bhatt: It’s not exact, but you can get a sense of the word’s meaning through its etymology, the word “psyche.” The idea is that psychedelics allow access to the hidden psyche, hidden realms of the mind. But we can also break the category down in a more scientific way. “Classic psychedelics” are those whose effects largely come from serotonin agonism. These are compounds like psilocybin, LSD, mescaline, and DMT. Then there are compounds whose effects may overlap with classic psychedelics but differ from the classic group in their mechanism of action. These include ketamine and MDMA. With classic psychedelics, we see immediate effects on mood and changes in perception without the cognitive changes or stupor that you might see with opioids or the hyperactivity and huge autonomic surge that you get with cocaine or methamphetamine. 

CATR: What are some of the applications of psychedelics being researched now?

Dr. Bhatt: Perhaps the best-known research is on ketamine and esketamine for treatment-refractory depression and acute suicidality. Those results are well publicized. MDMA has some promising early data for treatment of PTSD when combined with psychotherapy. It has many effects in the brain, but one of them is regulation of the amygdala, which is an area of the brain that generates fear responses. The idea is that MDMA allows people to feel safe enough to engage with memories without being overwhelmed by fear. They can process memories rather than running away from them. Psilocybin already has some promising results for distress at the end of life and is now being looked at as an addiction treatment as well (Griffiths RR et al, J Psychopharmacol 2016;30(12):1181–1197). 

CATR: You were involved in an investigation of psilocybin for the treatment of alcohol use disorder (AUD) that had impressive results. What’s the rationale there?

Dr. Bhatt: You are referring to the recent study with Dr. Michael Bogenschutz (Bogenschutz MP et al, JAMA Psychiatry 2022;79(10):953–962; see CATR Oct/Nov/Dec 2023 for more on this study). It’s not intuitive to use a psychedelic as a treatment for addiction, but there are two main reasons why we pursued this avenue. First, there are anthropologic data. Indigenous populations that use psychedelic compounds tend to have low rates of AUDs (Barbosa PCR et al, Front Psychiatry 2018;9:136). These are associational data, and it’s a big leap to go from sacramental use to medical use, but the results are still intriguing.

CATR: And what was the second reason?

Dr. Bhatt: We have a treasure trove of data on psychedelics going back to the 1950s and 1960s that has been almost entirely forgotten. As early as 1953, Osmond and Hoffer began to use LSD clinically to treat individuals with AUD. They describe participants emerging from their study with new motivation, new ideas, and new goals that ultimately helped them change their relationship to drinking. Other scientists continued the work in a research context until the Controlled Substances Act shut down research in 1970. In fact, a meta-analysis of six LSD studies from the 1960s found that LSD did help people cut down on drinking with a number needed to treat that is better than the medications we currently use, with benefits lasting three to six months (Krebs TS and Johansen PØ, J Psychopharmacol 2012;26(7):994–1002). 

CATR: But aren’t psychedelics addictive themselves?

Dr. Bhatt: At a basic level, classic serotonergic psychedelics are not particularly reinforcing. That’s true in animal models and human subjects (Johnson MW et al, Neuropharmacology 2018;142:143–166). But that is not to say that these substances can’t be misused, because they certainly can be. Mitigating risk of misuse is fairly straightforward within the confines of a research trial where we control medication access and dosage. But I think another important component was our extensive psychotherapy in the trial design.

CATR: Why do you think therapy mitigates the risk of misuse in this context?

Dr. Bhatt: Our study included 12 weeks of psychotherapy, with psilocybin being administered at weeks 4 and 8. Therapy sessions before administration focused on preparation. Our central questions were: “Why are you doing this? What are your goals? What do you hope to gain?” Sessions after drug administration focused on processing and integrating experiences they had: “What sort of meaning did you derive? How can you carry this forward in a positive way?” We never framed the drug as fun or recreational, and I think that really shaped the experiences and perceptions the participants had.

CATR: What kind of experiences did the participants have?

Dr. Bhatt: The experiences varied and were not always fun. They connected with past traumas and a lot of loss, often related to their drinking. This was a placebo-controlled trial, but at the end of the double-blind follow-up period, we broke the blind and participants were offered an additional open-label session. Most people who received the psilocybin were like “Nope. I’m done. I got out of it what I needed—no more for me, thanks.” These were not people who were going to go out and start using a bunch of psychedelics because the subjective experience of the trip was negative, even if they ultimately experienced benefits. Even so, the misuse potential is important to keep in mind as states pass legislation allowing psychedelic treatment, like in Oregon. We need a mechanism of identifying people at high risk of misusing psychedelics and to put safety parameters in place. We don’t know exactly how to do that yet—there is still research that needs to be done in this area. 

CATR: I think the proliferation of ketamine clinics can serve as a precautionary tale.

Dr. Bhatt: In my opinion, for ketamine, clinical implementation got way ahead of the science. Sure, there are good data for treatment of depression and acute suicidality. There are even some data for substance use disorders combining IV ketamine with psychotherapy (Dakwar E et al, Am J Psychiatry 2020;177(2):125–133). But we don’t know optimal dosing strategies, long-term safety, or how to select the most appropriate patients. (Editor’s note: For more on ketamine, see our Q&A with Dr. Trujillo in this issue.) There’s a similar risk for psychedelics like psilocybin and MDMA, with some differences. Ketamine is FDA approved; it’s easy to prescribe and administer. As of now, that isn’t an issue with psychedelics; doctors can’t just write a script. 

CATR: Another concern about psychedelics is whether the benefits are generalizable to diverse populations.

Dr. Bhatt: This is a valid criticism and one of great interest to me. Across all psychedelic trials, 80% of participants are White, and in our study, the median annual income of the participants was about $100,000 (Michaels T et al, BMC Psychiatry 2018;18(1):1–14). Clearly, we need to diversify our participant pool. I think certain diversity requirements should be included in research grants. But we also need to do targeted community outreach. For example, the state of New Mexico, where I work, has 23 Indigenous tribes. There is a long history of exploitation and distrust; we need to partner with these groups. Also, as it stands now, treatments are expensive and labor-intensive. I’m not interested in developing a treatment exclusively for the rich and famous. How do we ensure that it is available for anyone who needs it? Part of that is going to be through state funding and grants. It’s often the stuff that goes around the drug that makes the treatment expensive. We are looking into measures that might cut costs without sacrificing safety or rigor, such as group-based models and having a single therapist present instead of two. 

CATR: How far away are we from writing a psychedelic prescription? What would need to happen to make this a reality?

Dr. Bhatt: We are still quite a ways away. First, we need to replicate findings in large rigorous studies. If those demonstrate good efficacy and safety, there is the FDA approval process to navigate. In the case of psychedelics, that would require controlled substance rescheduling and likely the development of a risk evaluation and mitigation strategy program. There are also practical considerations. Will psychotherapy be a mandated component? If so, what will the training entail? Who will manufacture the medication? How will it be supplied, distributed, and stored? 

CATR: Even though it’ll be a while before we’re prescribing psychedelics in everyday practice, we are seeing a tremendous interest from patients, largely driven by sensationalized news coverage. How should we discuss psychedelics with patients?

Dr. Bhatt: I agree that the media can blow up these studies and sensationalize them. It’s unfortunate, but that’s not going to change. So, the responsibility of patient education is going to fall on individual providers. I think it’s informative to look back to when cannabis was first starting to be legalized for medical use several years ago; states were opening dispensaries, medical evidence for cannabis efficacy was mostly lacking, media coverage was everywhere, and physicians were caught in the middle. We did an investigation into communication patterns around medical cannabis where we found that very little information was coming from physicians, who felt unprepared to discuss the topic in an informed way. So where did patients end up getting information? Budtenders and insurance companies, and a lot of that information was not evidence based. So, there was a real communication vacuum there, and I think, a lost opportunity.

CATR: And what about microdosing?

Dr. Bhatt: I get asked this question a lot! Microdosing has entered the collective cultural consciousness through the media and, more recently, personal testimonials that are disseminated largely online. We don’t have even rough estimates of prevalence, but clearly a lot of people are experimenting with it. Many of them report benefits, but there isn’t any research in this area and it’s important that our patients know that. I try to strike a balance between validating their experiences and pointing out that we simply don’t yet have scientific data when it comes to benefits and, importantly, risks. 

CATR: So taking this all together, what can we as providers do?

Dr. Bhatt: We need to engage our patients around psychedelics proactively. Don’t be afraid to ask “What have you heard about psychedelics? What are your thoughts about them?” Most patients will have heard of them; some will be curious to learn more. Occasionally, you might get an angry “Why are you asking me about that?” A good standard response is “I ask all my patients. It’s all over the news, so I want to make sure you have accurate and up-to-date information.” And here is where we can step up, fill in knowledge gaps with evidence-based information. We should be stressing the integral role of intensive psychotherapy in these trials. Unfortunately, patients may read a news story and walk away with the message that they can cure their depression or AUD by taking some psilocybin mushrooms or some other psychedelic drug at home by themselves, or with their friends. But we don’t know what sorts of effects that kind of use has. We need to give that message to our patients.

CATR: Any other tips?

Dr. Bhatt: Get comfortable saying “I don’t know.” The research is in its nascent stages, but for better or worse, patients are hearing all about it. We must impress upon them that many of our questions remain unanswered. Some ­professional ­organizations are publishing data in this area; one source I particularly recommend is the American Society of Addiction Medicine’s weekly newsletter. Finally, if your patient is requesting information about psychedelic treatment, gather a careful history of recreational psychedelic use. Patients with a history of psychedelic misuse might be particularly interested in ­psychedelic-assisted treatment but probably warrant additional caution. And you may uncover a condition that could benefit from a nonpsychedelic treatment.

CATR: Are there centralized resources for providers to learn more?

Dr. Bhatt: There is talk of a professional organization forming, but that has yet to happen. If one does, I expect it will be a great repository of information. In the meantime, websites for NYU’s Center for Psychedelic Medicine or the Johns Hopkins Center for Psychedelic and Consciousness Research (www.hopkinspsychedelic.org) are good resources for upcoming clinical trials that may be an option for patients. 

CATR: Thank you for your time, Dr. Bhatt.