In this study, we employed pharmacological fMRI to investigate the shared and distinct effects of LSD, d-amphetamine, and MDMA on various large-scale connectivity measures. These included network integrity (within-network iFC), network segregation (between-network iFC), voxel-wise seed-based iFC of distinct RSNs, and global connectivity (degree centrality; DC). Additionally, we explored the associations between functional connectivity changes and 5-HT2AR density, as well as subjective effects. Our findings revealed both commonalities and unique alterations induced by the three substances. Notably, compared to the amphetamines, LSD led to (i) decreased integrity in the DMN, (ii) more extensive increases in between-network iFC, (iii) broader connectivity increases between most of the investigated RSNs and other brain regions, (iv) stronger associations between voxel-wise RSN iFC and 5-HT2AR density, and (v) increased DC in the basal ganglia and thalamus. These results underscore the distinctive neurobiological effects of LSD, shedding light on the unique alterations induced by this psychedelic compound.
Distinct effects of LSD
The present study sheds new light on the effects of classic psychedelics compared to other mind-altering substances. Notably, we found that LSD had unique effects on distinct connectivity measures, compared both to d-amphetamine and the ‘atypical psychedelic’ MDMA. We observed that only LSD reduced the network integrity in the DMN, compared to placebo. This finding is in line with several previous reports of psychedelic-induced DMN integrity decreases [21, 24, 25, 38, 39]. This reduction in integrity showed a trend association with an increased feeling of “experience of unity” and “oceanic boundlessness”, which is also consistent with previous findings concerning psychedelic phenomena [39, 40]. These observations suggest that alterations in DMN integrity may underlie some of the unique subjective experiences associated with LSD.
LSD induced more extensive changes in between-network connectivity compared to the amphetamines, leading to a general increase in connectivity between transmodal networks (e.g., DMN, FPN) and between these and unimodal networks (e.g., ASM, VIS). This increase potentially underlies the breakdown of conventional cognitive and perceptual boundaries, contributing to the characteristic psychedelic experience [36]. Notably, no decreases in between-network connectivity were observed for LSD. While not all effects were unique, direct comparisons between LSD and d-amphetamine and MDMA, respectively, demonstrated that connectivity between the DMN, FPN, and SAL was stronger for LSD than for the amphetamines. This pattern was also observed in voxel-wise seed-based iFC analyses, where LSD induced greater connectivity between the RSNs covering transmodal cortices (SAL, FPN, DMN, and DAN) than both placebo and the amphetamines. Increases in between-network iFC are among the most frequently reported imaging findings for psychedelics [21, 24, 26, 36] and have been suggested as a relevant mechanism behind the therapeutic effects of these compounds [41]. The transmodal cortices covered by the DMN, FPN, DAN, and SAL also contain the highest density of 5-HT2A receptors [37, 42]. Therefore, it is not surprising that the associations between these networks’ iFC and 5-HT2AR density were stronger for LSD than for the amphetamines and placebo. These findings are consistent with recent reports for psilocybin, LSD, and N,N-dimethyltryptamine (DMT), emphasizing the link between connectivity changes and 5-HT2AR [24, 43].
We also observed stronger connectivity of the sensorimotor cortices following LSD compared to the other conditions. Interestingly, beyond iFC, we also found increased global connectivity (i.e., degree centrality – DC) in these areas but also in the basal ganglia, and the thalamus following LSD compared to placebo. Psychedelic-induced increased global connectivity in the basal ganglia and thalamus has been linked to the thalamic filter model [22, 27, 36]. This model suggests that psychedelics impair the filter function of the thalamus, thereby leading to an information overflow to the cortex, which is in turn linked to psychedelic phenomena [44,45,46]. While psychedelic-induced changes in global connectivity have been investigated with various methods, leading to somewhat inconsistent results in the literature (see supplementary discussion and Table S7), increased global connectivity in the basal ganglia and thalamus is the most consistent finding across the various studies, independent of the used methodology [20, 27, 36]. Surprisingly, although seed-based hyperconnectivity between the ASM and the thalamus was observed for all substances (Fig. 3) and reported previously [17, 18], thalamic DC was not increased for the amphetamines compared to placebo, suggesting that the thalamus may play a more central role in the overall brain network for psychedelics than amphetamines.
Together, these findings indicate that several of the consistently reported psychedelic-induced changes in neuroimaging metrics (e.g., alterations in DMN, increased between-network connectivity, and global connectivity in the basal ganglia and thalamus) may be unique to serotonergic psychedelics and are not induced (or less extensively) by other mind-altering compounds with partly overlapping neuropharmacological profiles. This is highly relevant, as it informs on psychedelic-specific targets for therapeutic action. Notably, these effects have mostly been reported in acute states (for exceptions see [41, 47, 48]) and it is unclear how they relate to presumably slower-acting neuroplastic processes, previously reported for psychedelics [49, 50]. Future studies need to clarify this putative link.
Comparison between d-amphetamine and MDMA
d-Amphetamine and MDMA elicited similar changes across several investigated metrics. For instance, their effects on network integrity were nearly identical with notable specific decreases observed in the ASM and SAL, consistent with previous findings [19, 51]. Furthermore, both substances increased between-network connectivity, primarily between the VIS and several transmodal networks. Additionally, nearly identical patterns were observed for the SAL and ASM in the seed-based voxel-wise analysis. These similarities are intriguing given the mainly distinct pharmacological profiles and neurotransmitter systems influenced by each substance—predominantly dopaminergic for d-amphetamine and serotonergic for MDMA [7]. However, both compounds are structurally related and stimulate norepinephrine release [52], possibly leading to similar pharmacodynamic properties, resulting in more aligned fMRI-derived functional outcomes. The structural similarity or norepinephrinergic effects may facilitate comparable interactions with certain neural circuits, especially those involved in sensory processing and cognitive control. Additionally, interactions between dopaminergic and serotonergic neurotransmitter systems [16]…
Large-scale brain connectivity changes following the administration of lysergic acid
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