The persistence of depression is not always rational. It can take hold gradually, recur intermittently, and refuse to leave even when the world that shaped it has moved on. Neuroscience has long treated this persistence not as a flaw of character, but as a feature of circuitry: reinforced patterns of neural activity that, once established, become difficult to interrupt.
The question that follows is deceptively simple: Can those patterns be changed quickly — not over months, but within minutes to hours.
In laboratories across the world, that question has taken an unexpected turn.
Certain compounds, broadly grouped as psychedelics, have been observed to produce swift shifts in perception, emotion and behaviour, often within a single session. For a field accustomed to slow-acting psychiatric treatments, that speed is both intriguing and unsettling.
“These drugs have very powerful effects, but they have many effects. So it is important to understand them well before you can think about clinical translation,” says Prof. Vidita Vaidya, neuroscientist and Senior Professor in the Department of Biological Sciences at the Tata Institute of Fundamental Research (TIFR), Mumbai.
Her lab at TIFR is among the few, if not the only, groups in India actively mapping these mechanisms. In a 2024 study published in Neuron, her team identified a precise ‘switch’ for the acute anti-anxiety effects of the synthetic, long-acting serotonergic psychedelic DOI, part of the DOx family.
Importantly, this switch — the activation of parvalbumin-positive interneurons in the ventral hippocampus — was found to reduce anxiety-like behaviour in animal models without necessarily driving the hallucinatory effects typically associated with psychedelics.
This raises the possibility of developing more targeted, ‘psychedelic-inspired’ drugs for anxiety, depression and Post-Traumatic Stress Disorder (PTSD).
But observing change is one thing; explaining it, and ensuring it can be applied safely, is another.
For years, scientists relied on functional brain imaging to understand what these substances were doing. The scans were visually striking, with networks lighting up and signals spreading in unusual ways. But interpretations were inconsistent. Some neuroscientists described a breakdown of order; others, a form of reorganisation.
A more recent attempt to consolidate these findings has begun to sharpen that picture.
An April 2026 large-scale analysis in Nature Medicine, pooling over 500 brain scans from studies involving five classic psychedelics — LSD, psilocybin, mescaline, DMT, and ayahuasca — revealed a consistent pattern: increased cross-talk between brain systems that usually operate separately. Sensory regions interacted more freely with networks involved in internal thought, memory and self-reflection. The usual boundaries between perception and interpretation softened, creating overlap rather than chaos.
“This overlap and temporary reconfiguration of rigid pathways could, in theory, interrupt patterns linked to anxiety or depression,” explains Prof. Vidita Vaidya.
That possibility is now driving a new phase of research.
Clinical trials globally are beginning to test whether these shifts translate into measurable outcomes. A recent randomised study using psilocybin alongside psychotherapy reported clinically meaningful reductions in treatment-resistant depression, even as primary endpoints showed mixed results, highlighting a familiar tension: promising signals without definitive proof.
“At a biological level, these compounds act primarily on serotonin systems, particularly the 5-HT2A receptor, altering how information is processed rather than simply increasing or decreasing neural activity,” says Prof. Vidita Vaidya.
At a deeper level, she explains, there is growing evidence that psychedelics do not ‘treat’ the brain in the way conventional drugs do. Instead, they appear to transiently increase its plasticity — the brain’s capacity to change. Preclinical studies point to elevated levels of brain-derived neurotrophic factor (BDNF), along with changes in synaptic structure.
What emerges is a brain that is temporarily more adaptable, but not inherently directed towards improvement.
“So the short answer is they don’t ‘add something new’; they loosen the brain’s existing structure. Psychedelics are anything but a cure-all or a shortcut,” she says.
This raises a more complicated question: if the brain becomes more flexible, what determines the direction of that change?
The answer does not lie in the compound alone, explains Dr Sudheer, a neurologist at Apollo Hospitals. Outcomes depend heavily on ‘set and setting’: the individual’s mindset, expectations and psychological state, as well as the environment in which the experience occurs. Dose, context and support systems all shape whether the session leads to insight, distress, or something in between.
He notes that in controlled clinical settings, participants are carefully screened, guided and supported before and after administration. Unsupervised or recreational use, however, can trigger bad trips, prolonged psychological complications, or unpredictable reactions. Even structured approaches face hurdles, including difficulties in blinding trials and uncertainty about the durability of benefits.
“This is not a typical pharmacological model,” researchers often note. “The context is part of the treatment.” This is the thin line: not between drug and no drug, but between controlled intervention and uncontrolled exposure.
In other words, the science of psychedelics is advancing globally, with some compounds entering advanced trials and limited medical use in select countries. But it remains far from settled.
In India, this trajectory remains largely observational. Under the Narcotic Drugs and Psychotropic Substances Act, 1985, these substances remain illegal outside tightly regulated research settings. There is no approved therapeutic use, no established clinical framework, and no routine pathway for prescription.
Depression may not be rational in its persistence. But the pursuit of its relief, neuroscientists maintain, must be.