LSD, MDMA And d-Amphetamine: Study Provides New Insights Into Neurobiological Effects

A new study is shedding light on the complex brain connectivity changes induced by three psychoactive substances: lysergic acid diethylamide (LSD), 3,4-methylenedioxyamphetamine (MDMA) and d-amphetamine. These compounds, while distinct in their classification—psychedelic, entactogen and stimulant, respectively—share overlapping effects on neurotransmitter systems, influencing large-scale brain connectivity in unique ways.

The study, which analyzed data from 25 healthy volunteers, used a placebo-controlled, double-blind crossover design to compare the effects of these substances on brain function. Data revealed both shared and unique patterns of brain connectivity, offering critical insights into their neurobiological mechanisms.

LSD's Distinctive Brain Connectivity Impact

LSD, long known for its profound impact on perception and consciousness, demonstrated a striking reduction in within-network connectivity in the default mode network (DMN), a brain region associated with self-referential thinking and introspection. This effect is consistent with prior research suggesting that psychedelics diminish the DMN's role, facilitating experiences of ego dissolution.

LSD's most extensive alterations were observed in between-network connectivity, with specific changes linked to areas dense in 5-HT2A receptors. These findings reinforce the crucial role of this serotonin receptor in LSD's effects, particularly its modulation of large-scale brain networks.

Surprising Results From MDMA And d-Amphetamine

Contrary to expectations, both MDMA and d-amphetamine produced more pronounced changes in connectivity than LSD. Despite being categorized as an “atypical psychedelic,” MDMA showed brain connectivity patterns more aligned with d-amphetamine, emphasizing their structural and pharmacological similarities, particularly in their effects on the norepinephrine system, which helps to mobilize the brain and body for action.

Interestingly, all three substances led to reduced connectivity within the visual network, with d-amphetamine having the most significant impact. This finding suggests a shared dopaminergic influence across the substances, though each demonstrated distinct connectivity changes elsewhere in the brain.

The Bigger Picture

These results offer valuable insights into the neuropharmacological complexity of these substances and their overlapping but distinct effects on brain connectivity. LSD's unique profile highlights its potential for targeting specific brain networks, particularly those related to introspective processes. Meanwhile, similarities between MDMA and d-amphetamine offer clues into how stimulants and entactogens may operate through shared neural pathways.

The study’s findings have important implications for potential therapeutic uses of psychedelics and stimulants, particularly in treating mental health conditions such as depression, substance use disorders and post-traumatic stress disorder. Understanding how these substances affect brain connectivity can help refine future treatment protocols and contribute to developing more targeted interventions.

Future Directions

While the study provides a critical foundation for understanding the effects of these psychoactive compounds, future research with larger datasets could offer even more nuanced insights. Expanding this work to include other psychoactive substances, such as psilocybin and mescaline, could further illuminate the neurobiological underpinnings of psychedelics. Additionally, research into clinical populations will be essential to determine how connectivity changes translate to therapeutic outcomes for individuals with mental health conditions.

Cover image made with AI