Psychedelics are fascinating compounds that seem to trigger an almost irresistible interest in many of us. Perhaps it’s the allure of distinct, alien worlds, where the rules of physics bend and distort. In psychiatry and neuroscience, psychedelics have made quite the comeback, leaving an impression that’s likely to last. While it’s not realistic to consider psychedelics as a panacea for all mental disorders, evidence suggests that these substances may, in a controlled clinical setting and alongside psychotherapeutic treatment, tackle difficult-to-treat conditions such as treatment-resistant depression1, 2, substance use disorder3, and others4, 5. However, our journey is still in its early stages, as we do not yet fully understand how these compounds produce their distinctive effects or achieve symptom relief across various mental disorders, nor if these subjective and therapeutic effects are even related.
The Research Question and Motivation
One reason for the uncertainty surrounding psychedelics lies in their neuropharmacological complexity, which affect various neurotransmitter systems and have broad downstream effects. Comparative studies of related substances—those impacting similar neurotransmitter systems and producing parallel alterations in consciousness—may help elucidate the neurobiological mechanisms underlying psychedelics. To this end, our study compared a prototypical psychedelic (lysergic acid diethylamide, or LSD), a stimulant (d-amphetamine), and an entactogen (3,4-methylenedioxymethamphetamine, or MDMA) concerning their effects on large-scale brain connectivity. Alterations in connectivity are believed to underpin the modulatory effects of neurotransmitters6. Therefore, common connectivity changes induced by these substances could suggest shared effects on neurotransmitter systems or on downstream processes. Conversely, distinct connectivity changes might indicate the modulation of different pathways by these compounds. For example, while all these substances influence the dopaminergic system (though to varying extents), d-amphetamine primarily targets this system, MDMA’s effects are more pronounced on the serotonergic system, and LSD acts agonistically on serotonergic 2A receptors (5-HT2AR).
Research Question
How do LSD, d-amphetamine, and MDMA differentially affect brain connectivity, and what do these effects reveal about their underlying neurobiological mechanisms?
The Research Journey
To investigate the effects of these compounds, data from 25 healthy volunteers were analyzed. The data were sourced from the clinical trial NCT03019822, which used a double-blind, placebo-controlled, crossover design with four sessions to compare the effects of 0.1 mg LSD, 40 mg d-amphetamine, 125 mg MDMA, and a placebo. Resting-state fMRI data were acquired during the peak effects of each active substance. The connectivity measures of interest focused on prototypical resting-state networks (RSNs) and included changes in: (i) within-network connectivity, (ii) between-network connectivity, (iii) RSN seed-based connectivity, and (iv) global connectivity. RSNs are large-scale patterns of brain activity observed during rest (i.e., participants are not involved in any task), reflecting the brain’s intrinsic functional organization. These networks include unimodal areas (e.g., visual and sensorimotor networks) and transmodal areas (e.g., the default mode network (DMN), which is involved in self-referential and introspective processes). Different RSNs are characterized by distinct receptor distributions, making them relevant to our research. For example, the DMN includes regions with high densities of 5-HT2AR, which are particularly relevant for understanding the effects of psychedelics. Previous research has consistently reported that psychedelics decrease within-network connectivity, particularly in the DMN7, and increase between-network connectivity, and global connectivity in the basal ganglia and thalamus among other regions8. MDMA has shown similar effects9, although it has been less extensively investigated than classical psychedelics. Finally, the effects of d-amphetamine on brain connectivity are less documented, and direct comparisons between these substances are missing in the literature.
Key Findings and Their Significance
Our study provides new insights into the effects of LSD, d-amphetamine, and MDMA on brain connectivity, revealing both unique and shared effects among these substances.
LSD’s Unique Connectivity Pattern
The findings related to LSD underscore its distinctive impact on brain connectivity. We observed a reduction in within-DMN connectivity (Figure 1), which was specific for LSD and is consistent with previous research on psychedelics. LSD also induced the most extensive alterations in between-network connectivity and RSN seed-based connectivity (Figure 2). Importantly, the latter connectivity changes were spatially aligned with a PET map of 5-HT2AR density, emphasizing the critical role of the 5-HT2AR in LSD’s effects on brain connectivity. Furthermore, LSD was found to increase global connectivity in regions such as the basal ganglia and thalamus, reinforcing the idea that these areas are central to the brain’s overall network connectivity during psychedelic experiences.
Figure 1: Within-Network Connectivity. LSD uniquely reduced the within-network connectivity in the DMN, indicating a disruption in the communication between brain regions belonging to this network. Figure originally published in Avram et al., 2024, Molecular Psychiatry, DOI: 10.1038/s41380-024-02734-y.
Unexpected Findings with d-Amphetamine and MDMA
Contrary to expectations, d-amphetamine and MDMA elicited more pronounced within-network connectivity changes than LSD, suggesting these substances may have more significant effects on network-specific activity.
Interestingly, MDMA’s connectivity changes were more similar to those of d-amphetamine than to LSD. This similarity is notable given MDMA’s classification as an “atypical psychedelic.” While unexpected, the structural and pharmacological similarities between MDMA and d-amphetamine—both amphetamines affecting the norepinephrine system—may explain their comparable connectivity patterns.
Common Effects Across Substances
Despite the unique effects observed with LSD, our study also found commonalities across all substances. For instance, all three substances led to reduced within-network connectivity and global connectivity in the visual network. We interpreted these shared effects as a common modulation of the dopaminergic system, with d-amphetamine showing the most pronounced impact on the visual network, aligning with its primary action on the dopaminergic system.
Figure 2: Seed-Based RSN Connectivity. Increased connectivity between the seed-RSN and other RSNs is shown in yellow/orange. Decreased connectivity within the seed-RSN is shown in blue. Across networks, LSD induced greater between-network connectivity than the amphetamines. Figure originally published in Avram et al., 2024, Molecular Psychiatry, DOI: 10.1038/s41380-024-02734-y.
Significance
These findings emphasize that LSD has a unique profile in terms of brain connectivity effects, reflecting its distinctive neuropharmacological and subjective properties. In contrast, MDMA and d-amphetamine exhibited similar connectivity alterations that suggest their effects may be rooted in shared structural and pharmacological characteristics.
Reflections and Future Directions
Our study provides valuable insights into the unique and shared effects of LSD, MDMA, and d-amphetamine on brain connectivity. However, it is important to acknowledge certain limitations and potential avenues for future research. While based on a relatively small dataset typical of similar state-of-the-art research, future studies could benefit from larger datasets. This could be achieved either by increasing participant numbers or merging datasets from multiple investigations to enhance the ability to detect subtle effects. Building on our current study, future comparative research could extend to other psychoactive substances. Investigating additional psychedelics, such as psilocybin and mescaline, could provide further insights into the neuropharmacological effects of psychedelics. Similarly, exploring other stimulants, like methylphenidate, and even substances from different pharmacological classes could enrich our understanding of how psychedelics specifically affect brain connectivity. Finally, as psychedelics are increasingly being tested as treatments for various mental disorders, it is crucial to understand how our findings might translate to clinical populations. Future research should investigate whether the connectivity changes observed in healthy volunteers are consistent across different mental health conditions. Such studies could help determine how these substances might affect individuals with specific psychiatric or neurological disorders and contribute to refining treatment approaches.
Conclusion
Our research underscores the complexity of psychoactive substances’ impact on brain connectivity and provides valuable insights into the distinct and overlapping neurobiological mechanisms of psychedelics, stimulants, and entactogens.
References
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