The 2020s: The decade of psychedelic breakthroughs?

Beyond the bright colors and hallucinogenic imagery of psychedelic art—the visuals of Ram Dass’s 1971 book Be Here Nowhas never left public consciousness — there has long been a crusade to clinically research substances such as LSD, psilocybin, MDMA, DMT, and ibogaine. We’ve been informed, again and again and again, about the various ways that current pharmaceutical treatments in our for-profit mental health system is not only not working, but doing more damage than healing. Discussion over health care inevitably defaults to mechanisms for paying for a broken model, rarely touching upon the root causes of why so many people are depressed, sick, anxious, and suicidal in the first place.

We. Need. Better. Solutions.

In regard to psychedelics, an entire herd of elephants remain locked in a room. Thanks to the questionable (and admittedly racist) wars launched by the Nixon and Reagan administrations (first dreamed up during the Anslinger crusades), we’ve been denied access to these potentially therapeutic substances. Fortunately, a renaissance is occurring in psychedelics research, with ketamine being the first to be legally prescribed psychedelic for treatment-resistant depression and both psilocybin and MDMA being fast-tracked by the FDA after being labelled breakthrough therapies.

One challenge psychedelics advocates will have to face is how these drugs are treated moving through the current medical model. Regardless of personal feelings on the subject, these substances have to contend with a system that requires expensive clinical trials and will be sold in a capitalist marketplace. There will inevitably be patent issues and territorial fights. Unlike cannabis, which is a relatively mild substance with few documented consequences, psychedelics need to be rigorously evaluated and tested. While some label everyone working in medicine as minions of Big Pharma, we need to separate researchers and scientists from the shady dealings of shareholders and profiteers.

Michael Ehlers is an industry figure that has long taken an interest in psychedelics, predominantly from an outsider perspective. Now the former executive vice president for research and development at Biogen is accepting an advisory role with Field Trip Health, the psychedelics-focused organization that recently opened the world’s first psilocybin research center. (You can listen to my talk with Field Trip co-founder, Ronan Levy, here.)

I chatted with Ehlers, he is also the former chief scientific officer for neuroscience at Pfizer, about his interest in psychedelics, their potential efficacy, their historical usage in ritual, and how the current model will deal with their vetting and potential applications. With every question, he was informed and honest, offering what he knows and being truthful about what he does not. There is a lot of work ahead in pharmaceuticals, yet it is undeniable the mental health industry needs a reboot, in the same way psychedelics are said to reboot the neural circuitry of the brain, making this class of substances an ideal medicine for study.

Part of my conversation with Ehlers is below; you can read the full transcript here.

Photo courtesy of Michael Ehlers

Derek: You have an accomplished career in the pharmaceutical industry. Now you’ve taken on an advisory role with a company specializing in psychedelics. I would love to know when you first became interested in psychedelics as a potential therapeutic tool.

Michael: I’ve followed this area for quite some time. I’ve been intensely involved in different aspects of drug discovery and development, particularly, although not exclusively, within CNS or neuroscience drug discovery, including neuropsychiatric disease. I’ve followed more peripherally some of the efforts both in standard pharmacology and then some of the emerging work, whether it was more acute, high-dose psychedelics or microdosing psychedelics in neuropsychiatric disease.

At the same time, I was following a lot of the work on some of the core receptor biology and neurobiology, which was really advancing in systems neuroscience. Following this field and some of the early indications of potential clinical efficacy were some of the things that really got me quite excited. I was particularly close with aspects of what’s been done over the past 10 years with ketamine, which is a very different agent but also in the class, initially leading from small trials on ketamine for acute, anti-depressive actions, now to Janssen and J&J using a variation of this, esketamine, to get full-on FDA approval for the first new mechanism in depression in 20 years. The combination of these things indicated to me that there could be a new paradigm change or highly-active psychopharmacology to potentially treat some of these otherwise fairly intractable types of neuropsychiatric disorders.

There are some other things that were also on the horizon. The history of CNS drug development, particularly in neuropsychiatric disease, has been one where the empirical observations in human patients have really guided efficacious therapeutics by and large. Even though I know we like to talk a lot about rational drug discovery and development, at least in the field of neuropsychiatry, because there’s still so much that is not known that we’ve had to rely a lot more on empirical observations in humans.

There’s probably no more profound CNS pharmacology out there than that with psychedelics like psilocybin or LSD or ketamine. I’ve actually long thought it was just a matter of figuring out what a treatment paradigm could look like—how maybe when you dose it could you alter aspects of its dose exposure and distribution and then in what exact disease or syndrome.

Derek: You have a history of working with rare diseases. Field Trip is going to tackle a wide range of studies, but the ones that are really on everyone’s mind (in terms of what psychedelics could potentially help) ranges from PTSD to treatment-resistant depression and anxiety. These are much more common diseases. Do you have any background in those diseases and, in the advisory role, what will you be doing for them?

Michael: I’ve got a lot of background in that. I worked for nine years in large biopharma, six years at Pfizer. I started in neuroscience and pain, but ultimately ran several divisions of Pfizer R & D, that did include rare disease, but included a bunch of other things. Then I ran R & D advising for three-and-a-half years. I’ve done clinical trials in depression, schizophrenia, PTSD, generalized anxiety disorder, Alzheimer’s disease, and Parkinson’s disease. I’ve done both rare diseases and a lot of common disorders: hemophilia, genetic disease, and some of the rare diseases as well. I’ve done stroke trials. I’ve had experience across a range.

One thing I like is about what Field Trip is doing and the prospect of these diseases is that they’re incredibly common. Roughly 25 percent of people will have some experience with major depression in their lives. One percent of the world has schizophrenia. These are serious and significant disorders. I really love the fact that this field—and Field Trip is really part of that in a leadership role—is looking to take some of these on.

Although the lore has been that there hasn’t been that much innovation, I actually think that’s not true. I think we’re just at the beginning of a whole new era of advances in neuropsychiatric disease. I can point to several things that indicate that. I have a feeling that if we really understand that the best way to dose and conduct trials with psychedelics like psilocybin and be able to segment patients who are the most likely to benefit, this can become quite important.

The future of psychedelic-assisted psychotherapy | Rick Doblin

Derek: You mentioned that pharma companies stepping away from neuropsychiatric disease. There is obviously a problem with SSRIs over the long-term. Efficacy rates tend to be high in the short-term, but over the long-term prove problematic. When you’re stepping into substances that potentially could help treatment-resistant mental health diseases in one dose (or just a couple of doses), how do you think that companies are going to be able to monetize this, especially given the incredible amounts of money that have to go into R & D and clinical trials?

Michael: It’s a very good question. I think we haven’t solved that problem yet. There are a lot of open questions. Will some of these therapies really be single dose or short regiments and you’re done? Will it have to be that there’s some degree of maintenance where there’s some regularity in the need for therapy? Will it really be like antibiotics or gene therapy? We don’t know.

A lot of these neuropsychiatric diseases, although they’re complex, have genetic features that are polygenetic but they’re related. Whether you’re talking about, schizophrenia, autism, bipolar disorder, ADHD, there’s a complex genetic architecture that has shared features across all of those. The risk of relapse and occurrences will be there in a given population. I tend to think the likelihood of things like ketamine or psychedelic treatments for depression will be one of periodic needs.

The question you raised is an excellent one, which is what ultimately is the commercial model for that? Certainly, the hope is that it doesn’t go down the road of antibiotics for which the commercial incentivization for real R & D and drug development has been catastrophic. I don’t see that in this space. I just don’t think it’s going to be quite as simple as “one and done.” The prevalence alone will be a strong incentive for investment when there’s real efficacy potential.

Derek: Please correct me if I’m wrong; I’m fascinated by neuroscience, but not having an academic background my knowledge is limited. That’s why I love talking to people about this. From my understanding, SSRIs work in a much different manner in terms of the serotonin release then psychedelics. Do you see any potential benefits or dangers in the ways that psychedelics deal with the serotonergic system?

Michael: It is quite different. From a simple pharmacology point of view, SSRIs are, as their name indicates, selective serotonin reuptake inhibitors: they block serotonin transporters that would normally release serotonin back up into nerve cells so that it increases serotonergic tone. Once released, it stays released in the extracellular space for longer, acting on all the different receptors in the places that it does.

The psychedelics typically act directly on serotonin receptors within serotonin transporters, but their action at different receptors has different potency. It’s not a clean pharmacology. People will talk about 5-HT-2A receptors and they’re clearly important, and there’s been a lot of study on that, but we also know that if you just give a pure 5-HT-2A receptor an agonist you do not reproduce the effects of psilocybin or LSD.

The pharmacology is complex; it’s clearly different than SSRIs. Obviously, the behavioral and therapeutic groups are very different. It just highlights that we really need to understand it better. It’s going to reveal I think very important things about psychiatric disease and fundamental neuroscience.

A shaman gathers the raw materials to make ayahuasca in the jungle outside of Iquitos.

Photo by Andrew Lichtenstein/Corbis via Getty Images

Derek: One of the criticisms of the way that the industry is right now is that, why would a doctor spend an hour talking to a patient when you can see six patients in an hour and write a script? Efficacy rates are different for different people, dealing with the microbiome, for example, and the way that their gut processes drugs. It’s a very complex issue. One thing I believe is going to be important is that psychotherapy is going to be tethered with psychedelics, especially if people have never done them before. Will that coupling provide a sustainable model?

Michael: Here’s an aspect of what’s important to understand: the field has understandably taken a cautious approach, which I think is warranted in this whole guided therapy concept and that will probably be required for certain dosing regimens. I would personally like to see this converted into what is a very standard thing in a lot of drug administration in practice or trials, which is more about medical monitoring. Change it from the notion of it’s guided therapy to monitoring like you would for a lot of things. People go to IV infusion centers to get their IV drug. It’s different, but there’s nothing that unusual about the notion of having a monitored pharmaceutical or pharmacological drug intervention even in standard practice. This will likely be part of that.

If you’re a neurologist treating MS and you’ve got MS patients on Alemtuzumab or Natalizumab as your IV drugs. They come in, you’ve got your IV clinic. They come in regularly, every month or every quarter depending on the drug, and they get their IV infusion. They get monitored while it happens because they can have an immune response. I see a future for some of these psychoactive therapeutics where you have something similar.

Now the question will be to what extent does the guided as opposed to monitoring aspect of that influence the degree of efficacy? That’s something which really would need to be studied. To the extent it really requires some special type of guided activity that will be a little bit more of a limitation. To the extent that it can be ultimately the design in a more monitoring approach with education, the more widespread this can become.

Does that analogy make sense to you? There’s a lot of precedence for this in other areas. The way this has gotten utilized now is still a remnant of causing people to have profound hallucinations and behavioral stuff and paranoia. Some people get afraid of that, so we need to have some monitoring.

We need to understand doses. We need to know the extent to which those experiences are part and parcel to a therapeutic response or not associated with a therapeutic response.

Derek: How much do you think anecdote is going to matter? One main issue I have with the whole cannabis legalization process is the extraction of CBD being sold for every possible ailment out there when the actual evidence is almost nothing at this point, besides epilepsy. At the same time, dealing with mental health disorders, how much are we going to rely on anecdote? If people think they’re getting better, there’s placebo, and it actually helps them get better.

Michael: I hope we moved beyond anecdotes, and I think that you’re right about CBD, but it’s interesting the way you put that because of the fact that rigorous trials have been done in rare epilepsies, like Dravet and Lennox-Gastaut syndrome, nobody disputes that. Patients in need can get insurance companies or health systems in other countries to reimburse for that. That’s what I mean by saying real location impact is going to require that component of it too. You’d like to be able to generate the evidence because nothing comes without safety concerns. The nice thing about putting this all through the lens of drug discovery and development is that it allows the community—and here I mean the medical community, policymakers, others —to have a much clearer view of the benefit-risk, and where the benefit-risk is positive, in which case that’s usually a required element for real access for patients.

Of course, you could argue and say, “well, if it’s just out there, people can try it, we’ll see and that’s fine,” but this doesn’t allow us from a clinical scientific vantage point to really know when and where we are going to provide benefits. That’s what we really need to work toward. There’s enough anecdotal evidence out there to justify rigorous evaluation.

—

Stay in touch with Derek on Twitter and Facebook. His next book is Hero’s Dose: The Case For Psychedelics in Ritual and Therapy.