Study Shows How Psychedelic Drugs Rewire the Brain

A new study has revealed details about how the psychedelic drugs LSD and psilocin – the active ingredient in magic mushrooms – bind to receptors in the brain. The findings suggest that psychedelics exert their antidepressant effects by binding to receptors for the molecule brain-derived neurotrophic factor (BDNF), which is an important agent of neuroplasticity. Neuroplasticity is the process by which the brain’s connections reshape themselves, forming new connections. Neuroplasticity has been previously investigated as an important factor in the action of antidepressants.

The research also suggests that psychedelics’ antidepressant effects could be separated from vivid hallucinations, which some psychedelics advocates have claimed to be an essential part of the healing process.

The research, which is published in Nature Neuroscience, remains at a preclinical stage, with findings in the study taken from lab dish cell cultures and mice.

The rise of psychedelics

Psychedelic drugs have reinvigorated the field of psychiatric drug discovery, which has been unable to hold back a surging tide of mental health diagnoses. Promising results from small and limited clinical trials have raised the possibility of drugs that could relieve symptoms of depression, post-traumatic stress disorder and even addiction. The compounds appear to work far faster and with arguably fewer side effects than classical selective serotonin reuptake inhibitors (SSRI) antidepressants. 

One major roadblock in the drugs’ progress remains the lengthy hallucinatory trips they induce. Much psychedelic drug development has tried to circumvent these experiences, which would require a psychedelic drug clinic to implement costly in-patient supervision and make it far harder to license these drugs for at-home use.

Now, a new research effort led by scientists from the University of Helsinki has plotted a route to hallucination-free psychedelics by mining down to the core of how these drugs bind to the brain.

A molecular deep dive into psychedelics

The researchers used a suite of biochemical techniques that allowed them to assess how the psychedelic compounds LSD and psilocin bound to neurons in a dish. Given psychedelics’ role as drivers of neuroplasticity, BDNF and its receptor, TrkB, were the research group’s main targets. They found that LSD binds up to 1,000 times more strongly to TrkB than the SSRI fluoxetine and the rapidly acting antidepressant ketamine.

They then further identified the binding site that LSD uses to grab onto TrkB, showing that it targets the portion of the receptor that spans the neuronal membrane. To characterize exactly which sections of protein were crucial for binding, the researchers used genetically mutated neurons that had subtly different TrkB receptors. At least one of these changes, which altered a single amino acid in the protein’s chain, impaired how SSRIs could bind to TrkB, but had no effect on LSD. This finding wasn’t shared with other mutations, suggesting the two drugs share similar but subtly different binding regions.

The team then demonstrated that psychedelic binding didn’t increase the level of TrkB in neurons, but instead, like a biomolecular life raft, helped the receptor float closer to the surface of the neuron, making it far easier for it to bind to the pro-plasticity protein BDNF.

Depression in mouse and man

Finally, the researchers examined how TrkB signaling affected mice given psychedelics. Studying psychiatric disorders in mice is a challenging endeavor. As mice can’t be interviewed to ascertain their malaise, behavioral studies tend to instead center around how the animals respond to stressful situations. Mice given LSD showed increased antidepressant-like responses, but those mutated to disrupt how the molecule binds to TrkB did not. These latter mice still showed the characteristic “head-twitch” that the field uses to identify the activation of serotonin receptors. This would suggest that TrkB and not serotonin 5-HT2A receptors are the key mediator of psychedelic drugs’ mental health boost.

The finding is likely to further fuel the debate in the field as to whether non-hallucinogenic psychedelics will work. In-human clinical trials testing such compounds have been slated to begin this year, work that will likely define the progress of psychedelic psychiatry.

Reference: Moliner R, Girych M, Brunello CA et al. Psychedelics promote plasticity by directly binding to BDNF receptor TrkB. Nat. Neurosci. 2023. doi: 10.1038/s41593-023-01316-5