Does LSD Change Your Brain Forever? Exploring the Effects of Psychedelics on the Brain
Findings suggest that psychedelics exert their antidepressant effects by binding to receptors for an important agent of neuroplasticity.
A study has revealed details about how the psychedelic drugs lysergic acid diethylamide (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. Rather than permanent rewiring, these changes may reflect enhanced neural flexibility.
What is 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.
A 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
Traditionally, the effects of psychedelics were attributed to activation of serotonin 5-HT2A receptors. While this receptor is responsible for hallucinations, evidence indicates that TrkB binding is key to the antidepressant and plasticity-related effects of LSD and psilocin.
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 (Table 1).
Table 1. Comparative binding affinity for TrkB receptors
| Compound | Relative Binding Strength to TrkB |
| LSD | Very high (≈1,000 times fluoxetine) |
| Psilocin | High |
| Ketamine | Moderate |
| Fluoxetine | Low |
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 mediators of psychedelic drugs’ mental health boost.
Effects of psilocin and LSD on the brain
Psilocin and LSD interact with TrkB receptors to boost BDNF signaling. This cascade enhances synaptic remodeling and may underlie claims that magic mushrooms “rewire” the brain. Rather than permanent rewiring, these changes reflect enhanced flexibility, giving neural circuits the capacity to escape maladaptive patterns associated with depression.
In practical terms, these compounds promote the growth of new dendritic spines, increase the number of synaptic connections, and stabilize these connections through BDNF-TrkB signaling. While the effects are long-lasting, they are not irreversible; the brain remains adaptable, which is a hallmark of neuroplasticity.
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Toward hallucination-free psychedelics
One of the central challenges in psychedelic therapy is the hallucinatory experience. Extended hallucinogenic episodes require supervised administration in controlled clinical environments, which increases cost and complicates large-scale use. Research suggesting that antidepressant effects can be separated from hallucinations opens a pathway to “non-hallucinogenic psychedelics.”
Compounds designed to selectively engage TrkB without strongly activating 5-HT2A receptors could potentially deliver therapeutic benefits without requiring psychedelic trips. This approach may make it easier for regulatory bodies to approve and for clinicians to prescribe these treatments outside of specialized clinics.
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 shown some initial success. DLX-001, a novel neuroplastogen, demonstrated a favorable safety and tolerability profile, with no evidence of psychotomimetic, hallucinatory or dissociative effects in Phase 1 trials in healthy volunteers. These results supported the continued evaluation of the compound in ongoing Phase 1b studies in patients with major depressive disorder.
The question of does LSD change your brain forever is best answered by examining the molecular and cellular processes it influences. LSD and psilocybin do not permanently rewire the brain, but they do facilitate neuroplasticity through powerful interactions with BDNF and its receptor TrkB. These changes allow the brain to adapt and escape maladaptive circuits, providing a foundation for new approaches in mental health treatment.
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