Paper Summary
Title: The Hierarchy of Psychedelic Effects: Three Systematic Reviews and Meta-Analyses
Source: bioRxiv preprint
Authors: Kenneth Shinozuka et al.
Published Date: 2023-10-06
Podcast Transcript
Hello, and welcome to paper-to-podcast.
Today, we're diving deep into the mind-bending world of psychedelics without the side effect of actually taking them! So, sit back, relax, and prepare to have your consciousness expanded... academically speaking, of course.
Our journey begins with a fascinating paper titled "The Hierarchy of Psychedelic Effects: Three Systematic Reviews and Meta-Analyses," where Kenneth Shinozuka and colleagues took a trip through the data without the need for a sitter. Published on October 6, 2023, in the bioRxiv preprint, this research doesn't just dip its toes into the psychedelic pool; it cannonballs right in from the high dive!
Now, let's talk about the funny side of LSD versus psilocybin. It turns out LSD is somewhat of an overachiever when it comes to creating altered states of consciousness. Picture LSD and psilocybin as students—LSD is the one always raising its hand in class, while psilocybin is cool with just passing the course. Specifically, LSD scored higher brownie points in producing visual hallucinations (or as the researchers elegantly put it, "visionary restructuralisation") and that feeling of oneness with the universe (termed "oceanic boundlessness"). At medium doses, LSD was like, "Look at me, I'm the captain now," with significant p-values of 0.0283 for oceanic boundlessness and 0.0468 for visionary restructuralisation. High doses kept the visual party going with a significant p-value of 0.0417.
When it comes to brain connectivity, psychedelics are like social butterflies, increasing chatter between different brain networks while quieting down the chatter within them. Interestingly, the frontoparietal network got a significant boost, perhaps preparing for some serious cognitive acrobatics.
Pharmacologically speaking, LSD was the life of the party at the 5-HT2A receptor, inducing more activity in the inositol phosphate formation pathway compared to DMT and psilocybin. But when it came to calcium mobilisation and β-arrestin2 recruitment pathways, the drugs were like, "Let's call it a tie."
The methods behind this mind-expanding research? Three systematic reviews and meta-analyses that covered the whole gamut—phenomenology, neuroimaging, and molecular pharmacology. The team channeled their inner Sherlock Holmes to analyse subjective experiences with questionnaires and used fMRI data to spy on the brain's networking skills. They even assessed the binding affinities of our psychedelic substances like a matchmaker for neural receptors.
The strengths of this psychedelic saga are as impressive as the visual effects of a tie-dye T-shirt. The researchers' systematic approach and comprehensive analysis allowed for a multi-level exploration of the effects. They used meta-analytical techniques to consolidate findings, which is like making a smoothie out of various fruits of knowledge to strengthen the validity of their conclusions. They also created profiles based on neural correlates and receptor expression patterns, which, let's be honest, sounds like the LinkedIn for neurons.
However, the research wasn't without its limitations. Due to the experimental variety show, comparing subjective experiences was as tricky as comparing apples to... well, psychedelic apples. The neuroimaging studies had more variety than a box of chocolates, and the reliance on published data rather than raw data could be like trusting a magician's promise—take it with a grain of salt.
The potential applications of this research are as exciting as a surprise drop of your favorite band's album. The unique effects of psychedelics on brain connectivity and subjective experiences could revolutionize mental health treatments. Imagine a world where conditions like depression, anxiety, and addiction are treated with the same substances that once fueled Woodstock. And with a more personalized approach, we could see treatments tailored to individual brain networks, like a bespoke suit for your neurons.
We've reached the end of our psychedelic tour, but fear not! You can find this paper and more on the paper2podcast.com website. Until next time, keep your minds open and your neurons firing!
Supporting Analysis
One of the most interesting findings from the research is that while LSD almost always ranked higher than psilocybin in altered states of consciousness, significant differences were only found in the quality and intensity of visual hallucinations (visionary restructuralisation) for medium and high doses, and in the feeling of interconnectedness (oceanic boundlessness) for medium doses. Specifically, at medium doses, LSD scored significantly higher than psilocybin in these dimensions, with p-values of 0.0283 for oceanic boundlessness and 0.0468 for visionary restructuralisation. At high doses, the difference in visionary restructuralisation remained significant with a p-value of 0.0417. In functional brain connectivity, psychedelics showed a general increase in between-network connectivity and a decrease in within-network connectivity. However, the reductions in within-network connectivity were not statistically significant, except for the frontoparietal network, which showed a significant increase. Pharmacologically, LSD was found to induce significantly more activity in the inositol phosphate formation pathway at the 5-HT2A receptor compared to DMT and psilocybin. No significant between-drug differences were found for calcium mobilisation and β-arrestin2 recruitment pathways. The specificity for the 5-HT2A receptor relative to the 5-HT1A receptor did not differ significantly between the psychedelics studied.
The study conducted three systematic reviews and meta-analyses across different levels to understand the effects of psychedelic substances such as DMT, LSD, and psilocybin. At the phenomenological level, they analyzed subjective experiences using questionnaires like the 5-dimensional Altered States of Consciousness Scale (5D-ASC) to capture altered states of consciousness. For neuroimaging, the research focused on changes in brain activity and functional connectivity using fMRI data. The team re-parcelled published functional connectivity data into the Yeo networks—a set of seven resting-state networks in the brain—and computed weighted sums of connections between these networks. Through this, they compared psychedelic literature to resting-state functional connectivity data from the Human Connectome Project. Pharmacologically, the researchers assessed the binding affinities of psychedelics for certain neural receptors, specifically serotonin and dopamine receptors, to determine selective affinity and relative functional activity. They used a random-effects model that included the drugs as covariates and analyzed the selective affinity of psychedelics for receptors relative to a reference receptor. They also measured the relative functional activity at the 5-HT2A receptor across three signaling pathways: inositol phosphate (IP) formation, calcium mobilization, and β-arrestin2 recruitment.
The most compelling aspects of the research are its systematic approach and comprehensive analysis across multiple levels of psychedelic effects. The researchers conducted three systematic reviews and meta-analyses, focusing on phenomenology (subjective experience), functional neuroimaging, and molecular pharmacology. This hierarchical framework allowed for an in-depth examination of the complex relationships between the subjective effects of psychedelics, brain activity patterns, and the drugs' interactions with neural receptors. The use of meta-analytical techniques to consolidate findings from various studies is particularly noteworthy, as it helps account for variability and strengthens the validity of the conclusions. The researchers also made efforts to create profiles based on neural correlates and receptor expression patterns, which is a novel way to link pharmacological data with neuroimaging and phenomenological outcomes. Another best practice was the acknowledgment of methodological heterogeneity within the studies analyzed, such as different doses, administration methods, and experimental procedures, which they attempted to control for in their analyses. They also highlighted the need for more primary datasets in neuroimaging studies and for the development of new tools to model the non-linear relationships observed. This level of critical analysis and the call for standardization in future research reflect a rigorous scientific approach.
The research presented potential limitations mainly related to the heterogeneity in experimental procedures and analysis methods across studies. The studies on phenomenology varied in the doses of psychedelics administered, which could impact subjective experiences and make direct comparisons challenging. The neuroimaging studies showed considerable variability in tasks administered to participants, which could confound BOLD activation findings. Moreover, different parcellations were used across studies, complicating the synthesis of functional connectivity data. The meta-analysis on functional connectivity was also limited by its reliance on published data rather than raw data, which could reflect methodological inconsistencies rather than true effects. Additionally, the pharmacology meta-analysis was confounded by the use of different radioligands across studies to label receptors of interest. There's also a call for more replication studies to verify findings from primary datasets, as many secondary analyses were performed on the same datasets. Lastly, the researchers pointed out the need for tools to model the nonlinear relationships between pharmacology, neuroimaging, and phenomenology, as the current methods mainly measure correlations without establishing causality.
The research into the effects of psychedelics could have significant applications in the field of mental health. The findings suggest that psychedelics like LSD, DMT, and psilocybin have distinct effects on brain connectivity and subjective experiences. This opens up possibilities for using these substances in therapeutic settings to treat conditions such as depression, anxiety, and addiction. By understanding how these drugs influence the brain's default mode network and other regions associated with self-awareness and cognitive function, clinicians could develop treatments that facilitate profound personal insights and emotional breakthroughs in patients. Moreover, the non-linear relationship between the pharmacology, neuroimaging, and phenomenology of psychedelics could lead to more personalized medicine approaches, tailoring treatments based on individual brain network configurations. Additionally, the study's insights into the brain's functional connectivity patterns could inform the development of non-pharmacological interventions that mimic the beneficial effects of psychedelics, potentially offering new avenues for patients who are unable or unwilling to use psychedelic substances directly.