Psychedelics and Mental Health Series - 1/3 - Why research is coming back to it

Psychedelics and Psychiatry - Why Research is Returning - 1/3

For nearly twenty years, starting in the 1950s, psychiatrists used LSD and psilocybin as adjuncts to psychotherapy. The targeted indications already resembled those of today: treatment-resistant depression, addictions, and anxiety related to serious illness. Several tens of thousands of patients were treated, sometimes with striking results. Then everything stopped. The shift towards recreational use, the resulting moral panic, and the Schedule I classification in the United States froze research for an entire generation.

This freeze was not a scientific decision. This is an important fact when examining the current situation.

What is returning is not what had left

Since the early 2000s, academic teams have been returning to these molecules using modern tools: randomized controlled trials, functional imaging, and synaptic biomarkers. It is no longer just about observing a clinical effect, but about understanding what these substances do to the brain and to the circuits involved in depression and psychotrauma.

The conceptual shift is significant. Psychiatry has long reasoned with the chemical imbalance hypothesis, centered on monoamines and the restoration of their synaptic concentrations through chronic administration. This model supported pharmacology for fifty years, but it poorly accounts for what psychedelics produce: a rapid effect, sometimes after a single session, which extends far beyond the presence of the molecule in the body.

The emergence of the psychoplastogen concept

To account for this peculiarity, the term psychoplastogen was proposed. It refers to molecules that, after transient stimulation, induce lasting structural plasticity in neurons, particularly pyramidal neurons in layer V of the prefrontal cortex. Activation of 5-HT2A receptors triggers a cascade involving BDNF, mTOR, and TrkB pathways, which results in an increase in the density of dendritic spines and cortical synapses.

In concrete terms, these molecules awaken the brain's ability to create new connections between its nerve cells, particularly in the areas that regulate mood and thought control.

This process is now quantifiable in vivo, notably through PET imaging targeting the SV2A protein, which is considered a reliable marker of synaptic density. In other words, for the first time, we have a way to objectively verify whether these molecules actually produce the rewiring attributed to them.

A different intervention logic

The difference with SSRIs is conceptual, not just temporal. Classic antidepressants produce a gradual plasticity through prolonged administration. Psychoplastogens, on the other hand, aim to open a brief window of plasticity within a specific psychotherapeutic framework, with the idea that psychological work carried out during this window can produce stable modifications.

Therefore, the substance alone is not supposed to heal. It is the combination of a pharmacology that temporarily softens the circuits and therapeutic work conducted in a secure environment. The literature often refers to this combination by the acronym PAT, psychedelic-assisted therapy.

What this episode poses

Before examining the efficacy figures and the methodological debates surrounding them, we must hold onto this idea: psychedelic medicine is not a return to the experimentation of the 1960s. It is an attempt to re-read these molecules in the light of contemporary neuroscience, with a reconstructed clinical framework, new biomarkers, and its own theoretical model.

The question that follows is inevitable: when we look at clinical trials with the usual requirements of evidence-based medicine, what remains of the promise? That is the subject of the next episode.