Lessons From Psychedelics on Binding and Functional Activity
How psilocybin, LSD, and mescaline hit 5‑HT2A—and why downstream signaling, not binding alone, may shape future psychedelic care.
John J. Miller, MD, previewed an editorial set to appear in the September 2026 issue of Psychiatric Times, focused on the receptor pharmacology of psychedelic compounds under active clinical study.
The editorial, titled "Lessons From Psychedelics on Receptor Binding and Subsequent Functional Activity," addresses growing interest in psychedelic-assisted treatment amid anticipated US Food and Drug Administration approval of psilocybin-based therapies. Miller connected this clinical momentum to his longstanding interest in pharmacodynamics, specifically, how a drug's receptor binding properties translate into downstream functional activity within the cell, a principle he described as relevant well beyond psychedelics to psychopharmacology broadly.
"I think you'll enjoy looking at a lot of information that is well established on 3 of the psychedelics that we all have heard about and being studied extensively, especially psilocybin and lysergic acid diethylamide (LSD)," Miller said of his upcoming piece.
The editorial examines 3 psychedelics with established research bases: psilocybin, LSD, and mescaline. Miller reported that all three compounds share a common pharmacologic property: partial agonism at the serotonin 5-HT2A receptor. His analysis compares the relative binding affinity, tight versus weak, of each compound at this receptor and connects those binding characteristics to the functional activity that follows. Miller framed this receptor-to-function pathway as central to understanding why compounds that act on the same receptor can still differ meaningfully in their clinical effects.
"What I've done is a deep dive into the existing literature, looking at how these three psychedelics bind to the serotonin 5-HT2A receptor, which is their shared property and at which they are all partial agonists," Miller said.
Miller emphasized that receptor binding alone does not determine a compound's clinical effect; the subsequent functional activity generated within the intracellular environment following that binding is equally central to understanding how psilocybin, LSD, and mescaline ultimately produce their effects. He positioned this binding-to-function distinction as a key pharmacodynamic principle for clinicians to understand as psychedelic compounds move closer to potential regulatory approval and broader clinical use.
Dr Miller is the medical director of Brain Health in Exeter, New Hampshire; editor in chief of Psychiatric Times; a voluntary consulting psychiatrist at Seacoast Mental Health Center in Exeter/Portsmouth, New Hampshire; and a consulting psychiatrist at Insight Meditation Society in Barre, Massachusetts.
References
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