New study shows LSD changes brain connectivity in unique ways compared to MDMA and amphetamines

A new brain imaging study has revealed that lysergic acid diethylamide (LSD) alters brain connectivity in ways that are notably different from methylenedioxyamphetamine (MDMA) and d-amphetamine. While all three substances disrupt communication within certain brain networks, LSD produces broader and more distinctive changes—especially in regions associated with self-awareness and sensory processing. The findings suggest that not all substances often labeled as “psychedelics” affect the brain in the same way, and highlight the importance of making clear distinctions between different drug classes based on their biological effects.

The research was published in Molecular Psychiatry.

LSD, MDMA, and d-amphetamine are all psychoactive compounds known to produce changes in mood, perception, and cognition. LSD is a classic psychedelic known for inducing visual distortions, a sense of interconnectedness, and altered perception of time and self. It works primarily by activating serotonin 2A receptors in the brain, although it also influences dopamine and other neurotransmitters.

MDMA, often described as an “empathogen,” is known for enhancing feelings of emotional closeness and well-being. It mainly increases serotonin availability but also affects dopamine and norepinephrine. D-amphetamine, commonly used to treat attention deficit hyperactivity disorder, boosts dopamine levels and promotes wakefulness and focus.

“Our main interest lies in comparative psychedelic research. While psychedelics share a common mechanism — agonism at the serotonin 2A receptor (5-HT2AR) — they also have distinct neuropharmacological profiles,” said study author Mihai Avram, a senior researcher at the University of Lübeck, where he leads research on comparative psychedelic neuroimaging.

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“Although doses can be matched based on 5-HT2AR activity, their effects on other receptors and transporters are often overlooked, despite their potential influence on both subjective experiences and therapeutic outcomes. These receptors and transporters are also relevant because they contribute to broader pharmacological effects, such as enhanced monoamine release and increased arousal.”

“In this study, we investigated whether a compound primarily associated with these general effects (d-amphetamine) induces similar changes in brain neurophysiology as a prototypical psychedelic (LSD). Additionally, we examined MDMA, which has some psychedelic-like properties and also produces such general pharmacological effects, albeit via different mechanisms. Understanding these differences is essential for advancing personalized psychiatry and optimizing the therapeutic applications of these substances.”

For their study, Avram and his colleagues used functional magnetic resonance imaging (fMRI) to measure brain activity in 25 healthy volunteers who participated in a clinical trial in Basel, Switzerland. Each participant underwent four different sessions, receiving either 0.1 milligrams of LSD, 125 milligrams of MDMA, 40 milligrams of d-amphetamine, or a placebo, in randomized order. The study followed a double-blind, placebo-controlled, crossover design, meaning that participants received each substance at different times, but neither they nor the researchers knew which substance was given during a particular session.

Brain scans were collected while participants were at rest, allowing researchers to examine how different areas of the brain communicated with each other under the influence of each drug. The study focused on several different measures of brain connectivity: how tightly linked areas within the same network were (called “network integrity”), how separate or interconnected different networks were (“network segregation”), and how strongly individual brain regions communicated across the entire brain (“global connectivity”). The researchers also examined how these connectivity patterns related to the distribution of serotonin 2A receptors in the brain, using existing brain maps.

One of the study’s key findings was that all three substances reduced network integrity in the visual system and the frontoparietal network, which is involved in higher-level cognitive functions like attention and decision-making. These reductions suggest that sensory and cognitive systems become less cohesive under the influence of these drugs. However, the similarities largely stopped there.

“Psychedelics — specifically classic serotonergic psychedelics such as LSD, psilocybin, mescaline, and DMT — are often lumped together with related compounds like ketamine and MDMA,” Avram told PsyPost. “While what qualifies as a ‘psychedelic’ depends on the definition, one can distinguish ‘psychedelics’ based on their pharmacological properties (mechanism of action, with classic psychedelics acting primarily as 5-HT2AR agonists), phenomenological effects (such as pseudo-hallucinations, synesthesia, and mood changes), and neurophysiological effects, which we investigated using resting-state fMRI.”

“Our study clearly shows that MDMA is somewhat ‘unpsychedelic’ in terms of its neurophysiological effects: its effects on the brain more closely resemble those of d-amphetamine than those of LSD. This highlights the importance of distinguishing between different classes of psychoactive substances rather than assuming they have similar effects simply because they share certain subjective or therapeutic properties.”

LSD was the only substance to significantly reduce integrity in the default mode network—a brain system associated with self-reflection and daydreaming—which may help explain why LSD often produces a sense of ego dissolution. By contrast, MDMA and d-amphetamine did not significantly affect this network. In fact, LSD stood out in nearly every measure of between-network connectivity, increasing communication between brain networks more extensively than either amphetamine. This suggests that LSD leads to a breakdown of typical network boundaries, a pattern often reported in psychedelic research and believed to be linked to the vivid and interconnected experiences the drug induces.

Further analyses showed that LSD also increased connectivity between networks that handle sensory information and those responsible for internal thoughts and emotions. These changes were particularly pronounced in areas of the brain with high concentrations of serotonin 2A receptors, reinforcing the idea that LSD’s effects are strongly tied to this receptor system.

When the researchers examined “global connectivity,” or how central different brain regions were in the brain’s overall communication network, they found another major difference. LSD increased global connectivity in the thalamus and basal ganglia—areas involved in filtering sensory information and coordinating movement and motivation—while the amphetamines did not. These increases support the “thalamic filter” hypothesis of psychedelics, which proposes that these substances temporarily impair the brain’s ability to filter incoming information, allowing a flood of sensory and emotional data to reach conscious awareness.

In contrast, both MDMA and d-amphetamine decreased connectivity in some sensory regions and produced similar changes in the brain overall, despite their differing pharmacological targets. These similarities were surprising to the researchers, who had expected MDMA to resemble LSD more closely. Instead, the data showed that MDMA’s effects on the brain are more aligned with those of d-amphetamine, particularly in terms of which brain networks are disrupted and how.

“One of the most striking findings was that the connectivity patterns induced by d-amphetamine and MDMA were often nearly identical,” Avram said. “This is particularly intriguing given their distinct primary pharmacological profiles — d-amphetamine primarily affects the dopaminergic system, while MDMA is more serotonergic. We report such common effects in two previous publications as well. However, both compounds are structurally related and promote norepinephrine release, which may help explain the overlapping pharmacodynamic effects and, consequently, similar functional connectivity changes in the brain.”

But as with all research, there are some caveats to consider. For instance, the study used a crossover design, which means that participants took all four substances across multiple sessions. While the order of administration was randomized, there is still a chance that one drug’s effects could influence the next, especially if any long-lasting brain changes occur. Although the researchers found no evidence that this significantly skewed their results, they note that longer-term effects of these substances, particularly MDMA and amphetamines, remain poorly understood.

“One potential limitation lies in the randomized crossover design of our study, which could introduce confounds related to delayed effects,” Avram explained. ” A recent study by Siegel and colleagues demonstrated that psychedelics can induce changes in brain connectivity that persist for weeks. We cannot completely rule out the possibility that d-amphetamine and MDMA also produce long-term effects, although presumably less likely. Even if they do not, the order of substance administration (e.g., taking LSD first) could still influence connectivity patterns observed in subsequent sessions, potentially affecting our results.”

Another consideration is that the study focused solely on healthy participants. While the results provide a detailed picture of how these drugs affect the brain under controlled conditions, it’s still unclear how these connectivity changes relate to therapeutic outcomes in people with mental health conditions.

“The next step is to compare different psychedelics directly,” Avram said. “We are nearing completion of a project comparing LSD, psilocybin, and mescaline. While our colleagues in Basel (Liechti lab) have conducted extensive research on the pharmacodynamics and pharmacokinetics of these substances, a direct comparison of their neural effects is still missing. In fact, direct imaging-based comparisons between psychedelics remain relatively rare, with some notable exceptions—such as recent work by the Ramaekers lab in Maastricht.”

“Our mid- to long-term goal is to extend these investigations to clinical populations to better understand how these neural effects translate to therapeutic outcomes. Identifying potential predictors of treatment response could help refine the use of psychedelics in psychiatric settings and advance personalized treatment approaches.”

“We are grateful to the Liechti lab for pioneering comparative research in this field—for example, their studies comparing various stimulants (such as methylphenidate, MDMA, and modafinil) and different psychedelics (LSD, psilocybin, and mescaline),” Avram added. “The extensive data collected by their team has the potential to be highly valuable for advancing psychedelic neuroimaging research, providing a foundation for further investigations into the neural mechanisms underlying these substances.”

The study, “Large-scale brain connectivity changes following the administration of lysergic acid diethylamide, d-amphetamine, and 3,4-methylenedioxyamphetamine,” was authored by Mihai Avram, Lydia Fortea, Lea Wollner, Ricarda Coenen, Alexandra Korda, Helena Rogg, Friederike Holze, Patrick Vizeli, Laura Ley, Joaquim Radua, Felix Müller, Matthias E. Liechti, and Stefan Borgwardt.