Three Key Questions for the Psychedelic Renaissance
David Hellerstein, MD
Director, Depression Evaluation Service, NY State Psychiatric Institute
Professor of Clinical Psychiatry, Columbia University
Every week seems to bring news about the psychedelic renaissance.
Recent papers in the New England Journal of Medicine and JAMA Psychiatry report that psilocybin benefits major depression. Laws in Oregon and elsewhere are changing to decriminalize psychedelic use. The FDA has fast-tracked the development of psilocybin for treatment of depression. Clearly, we are in an amazing time, a renaissance of psychedelic use and research.
In 2019 our Depression Evaluation Service at Columbia Psychiatry and the New York State Psychiatric Institute became a site for a Phase 2B study of psilocybin in treatment-resistant depression. As a researcher doing studies of psilocybin, it is wonderful to be part of this renaissance, and at the same time quite worrisome to see unrealistic expectations generated by such breathless news.
As I see it, there are three key questions for psychedelic compounds as possible treatments of psychiatric disorders:
- Do they work?
- How do they work?
- Which drug works best for which conditions, for which patient?
- Do they work?
Whether based on personal experience or media reports, many people will say, “Yes of course they do!” But if you look at the scientific literature, as we did in a 2022 review published in Psychopharmacology, recent psychedelic clinical trials are small, and have many flaws. There are few high quality double-blind placebo-controlled clinical trials, the gold standard to determining drug ‘efficacy’.
As of July, 2021 there have been only 14 modern published studies of classical psychedelics (LSD, psilocybin, ayahuasca) enrolling a total of 315 patients conducted world-wide. Of these, only 8 studies, enrolling 226 subjects, were double-blind.
To really show that psilocybin alleviates depression, or that LSD is effective in OCD, we need more, and much larger, clinical trials, meeting FDA standards to test benefits and side effects.
And psychedelic studies are very difficult to do. For one thing, psychedelic treatments are very labor-intensive. They are combined treatments of medication and psychotherapy and require many hours of preparation and therapist time. Furthermore, it is difficult to do placebo-controlled psychedelic studies. Regardless of which drug is used as a comparison—sugar pill, niacin (which causes flushing), or amphetamines (which cause stimulation but don’t make you trip)—patients, therapists and research staff can almost always guess which treatment is being received.
- How do they work?
Classic psychedelic drugs—LSD, psilocybin, and ayahuasca—act on the serotonin system: they stimulate so-called 5HT2A receptors, which are highly concentrated in brain areas related to thinking, working memory, and attention. While psychedelic effects such as visions and distorted perceptions generally fade within several hours, psychological effects often persist long afterward. But why?
Neuroimaging expert Robin Carhart Harris believes psychedelics increase ‘neuroplasticity’—and introduce ‘entropy’ into overly rigid brain circuits. People with depression seem to have overactive, reverberating brain circuits, and spend much time ruminating, preoccupied with negative thoughts and feelings. Do psychedelics ‘reset’ these dysfunctional brain circuits—and if so, how?
Yet it is not impossible that the therapeutic benefits of psychedelics are only placebo effects! Certainly, patients come into treatment with vast expectations. Could psychedelics, which induce powerful sensory experiences, actually be hyper-charged placebos?
At this point, it is fair to say that we are only starting to answer these questions.
- Which drug is best for which condition?
Despite decades of wisdom from psychedelic users and advocates, we have precious little scientific guidance. Here are a few key questions:
- what dose is most effective—how many milligrams of psilocybin or LSD for which disorder?
- how many doses are needed to get the best initial effect?
- which psychedelic is best for which disorder—depression, OCD, anorexia, PTSD, addiction, end-of-life existential anxiety?
- How can we best sustain remission in order to keep people well?
Dozens of studies must be done to sort these issues out.
It is also worth noting that we don’t know much about side effects and serious adverse events (such as suicidality) in people with psychiatric diagnoses. We need better research on psychedelic treatment of people with depression in the real world, not only in highly selective clinical trials
Today, clinical trialists and other researchers are at the very beginning of an amazing period of discovery. We desperately need top-quality studies following the FDA framework required for drug approval. But that’s only part of it. We also need profound scientific investigations—in cell cultures, in organoids, and in animal models—to truly understand and optimize the use of such drugs. And we need to be cautious before jumping wholeheartedly on the psychedelic bandwagon.
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