The Impact of LSD on Brain Function and Neurochemistry

How LSD works in the brain

LSD binds to specific serotonin receptors in the brain, most notably the 5-HT2A receptor, which helps manage mood, perceptions, and thinking. When LSD binds to this receptor, it disrupts normal serotonin signaling and causes different parts of the brain to “talk” to each other in unusual ways.^[2] For example, regions that handle sensory experiences (like sight and sound) begin to interact more intensely, which can lead to vivid, emotional, and often unpredictable experiences commonly known as a “trip.”

At the same time, the areas of the brain responsible for clear, logical thinking and self-awareness become less active. This change can result in altered perceptions of time and even a temporary feeling of losing one’s sense of self—a phenomenon often described as “ego dissolution” or “ego death.”^[2][3]

Additionally, LSD lowers the activity of the default mode network (DMN), a network of brain regions that normally support self-reflection and our personal identity.^[3] Together, these effects help explain why LSD can dramatically shift how we experience ourselves and the world.

The key areas in the brain affected during this process are:^[4]

• Visual cortex: It becomes hyperactive, which explains the vivid hallucinations and heightened visual perception of colors, patterns, and light.
• Thalamus: This area is a central hub for sensory information that misinterprets incoming signals, leading to sensory blending or synesthesia—such as hearing colors or seeing sounds.
• Prefrontal cortex: This region, responsible for logical thinking and self-awareness, shows reduced activity under LSD, contributing to altered time perception and ego dissolution.

Short-term effects of LSD on the brain

LSD changes neurotransmitter function and connectivity between key regions in the brain, leading to the following psychological and perceptual changes:

• Altered sensory perception ^[4]
• Rapid mood changes ^[2] 
• Cognitive distortion ^[5]

Long-term effects of LSD use

Many people who use LSD experience flashbacks of previous “trips,” which are recurrences of effects associated with the drug occurring many days or months after the last dose of LSD. Flashbacks, also known as hallucinogen persisting perception disorder I (HPPD I), are short-term, reversible, and have a benign course. There have been reports of pleasant feelings accompanying the re-emergence of visual images, and people sometimes refer to this phenomenon as a free trip. However, some people may experience these flashbacks as distressing or intrusive, though they typically do not cause long-term impairment.^[6][7]

HPPD II differs from HPPD I, as it follows a long-term, irreversible, or slowly reversible and pervasive trajectory. The impairment of HPPD II is severe, and the prognosis is worse. Some patients struggle to adapt and cope with these persistent, recurring "trips," and a consistent portion of people require ongoing support and treatment.^[7]

Prolonged exposure can also lead to mood disorders, anxiety, and psychosis in vulnerable people due to long-term cognitive changes and potential impacts on neuroplasticity. People with certain genetic predispositions who use LSD are also at risk of developing schizophrenia.^[4]

LSD's therapeutic potential

LSD may hold clinical promise, particularly in treating:^{[2][8][9][10]}

• Depressive disorders
• Alcohol use disorder
• Existential anxiety in terminally ill patients
• General anxiety disorder

Final thoughts

LSD’s effects on the brain are salient and complex, disrupting serotonin signaling and altering functional connectivity, which changes perception, cognition, and self-awareness. Potent effects that contribute to LSD's reputation as a powerful psychedelic also come with psychological risks, particularly for individuals predisposed to mental health conditions.

A growing body of clinical research indicates that LSD does have therapeutic value; this, however, requires further studies, particularly for depression, anxiety, and addiction. However, its legal status and issues around long-term safety make advances in these areas challenging.

As scientific understanding of psychedelics advances, the conversation around LSD is evolving as a research tool, a therapeutic aid, and a recreational substance. Its role in neuroscience and mental health remains a fascinating and rapidly developing field that we will continue to follow and report on.