Publications
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Singleton SP, Luppi AI, Carhart-Harris RL, et al., 2022, Receptor-informed network control theory links LSD and psilocybin to a flattening of the brain's control energy landscape, NATURE COMMUNICATIONS, Vol: 13
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- Citations: 12
Singleton SP, Luppi AI, Carhart-Harris RL, et al., 2021, LSD and psilocybin flatten the brain’s energy landscape: insights from receptor-informed network control theory
<jats:title>Abstract</jats:title><jats:p>Psychedelics like lysergic acid diethylamide (LSD) and psilocybin offer a powerful window into the function of the human brain and mind, by temporarily altering subjective experience through their neurochemical effects. A recent model postulates that serotonin 2a (5-HT2a) receptor agonism allows the brain to explore its dynamic landscape more readily, as reflected by more diverse (entropic) brain activity. We postulate that this increase in entropy may arise in part from a flattening of the brain’s control energy landscape, which can be observed using network control theory to quantify the energy required to transition between recurrent brain states measured using functional magnetic resonance imaging (fMRI) in individuals under LSD, psilocybin, and placebo conditions. We show that LSD and psilocybin reduce the amount of control energy required for brain state transitions, and, furthermore, that, across individuals, LSD’s reduction in control energy correlates with more frequent state transitions and increased entropy of brain state dynamics. Through network control analysis that incorporates the spatial distribution of 5-HT2a receptors from publicly available (non-drug) positron emission tomography (PET) maps, we demonstrate the specific role of this receptor in reducing control energy. Our findings provide evidence that 5-HT2a receptor agonist compounds allow for more facile state transitions and more temporally diverse brain activity. More broadly, by combining receptor-informed network control theory with pharmacological modulation, our work highlights the potential of this approach in studying the impacts of targeted neuropharmacological manipulation on brain activity dynamics.</jats:p><jats:sec><jats:title>Significance Statement</jats:title><jats:p>We present a multi-modal framework for quantifying the effects of two psychedelic drugs (LSD and psilocybin) on br
Sanz C, Pallavicini C, Carrillo F, et al., 2021, The entropic tongue: Disorganization of natural language under LSD, CONSCIOUSNESS AND COGNITION, Vol: 87, ISSN: 1053-8100
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- Citations: 17
Roseman L, 2019, Functional imaging investigation of psychedelic visual imagery
Psychedelics can induce eyes-closed imagery in which various visions can be experienced. These visions vary from simple geometrical patterns, to more complex imagery, to full immersion within “other realms”. Past studies suggest that the visual cortex is involved in processing these visions, yet these studies were limited into investigation of activity. In this thesis, the aim was to expand on the involvement of the visual cortex by investigating processes that are beyond simple activation maps, such as functional connectivity and dynamics. In study 1, it was hypothesized that the visual cortex will show increased functional connectivity with many cortical and subcortical regions. This was investigated with 15 subjects that were scanned using fMRI under the influence of 75 µg of LSD or placebo. The results of this study showed increased resting state functional connectivity (RSFC) between the primary visual cortex and many cortical and subcortical regions. This result correlated with subjective ratings of psychedelic imagery and with occipital alpha power suppression measured with MEG, which is a reliable neural correlate of the intensity of the psychedelic state. It study 2, it was hypothesized that connectivity within the visual cortex would match its retinotopic architecture. Retinotopic mapping is the representation of the visual field (the world we observe) in the visual cortex – e.g. areas which are near to each other in the visual field will be near each other in the visual cortex. In this study, it was found that under LSD (same procedure as study 1), with eyes closed, connectivity patterns between different subregions of the visual cortex matched the retinotopic mapping of these regions, suggesting that the visual system behaves as if it is seeing spatially localized input, with eyes-closed under LSD. In study 3, it was hypothesized that during the onset phase of psychedelic imagery, the activation of subregions of the visual cortex
Timmermann C, Spriggs MJ, Kaelen M, et al., 2017, LSD modulates effective connectivity and neural adaptation mechanisms in an auditory oddball paradigm., Neuropharmacology, ISSN: 0028-3908
Under the predictive coding framework, perceptual learning and inference are dependent on the interaction between top-down predictions and bottom-up sensory signals both between and within regions in a network. However, how such feedback and feedforward connections are modulated in the state induced by lysergic acid diethylamide (LSD) is poorly understood. In this study, an auditory oddball paradigm was presented to healthy participants (16 males, 4 female) under LSD and placebo, and brain activity was recorded using magnetoencephalography (MEG). Scalp level Event Related Fields (ERF) revealed reduced neural adaptation to familiar stimuli, and a blunted neural 'surprise' response to novel stimuli in the LSD condition. Dynamic causal modelling revealed that both the presentation of novel stimuli and LSD modulate backward extrinsic connectivity within a task-activated fronto-temporal network, as well as intrinsic connectivity in the primary auditory cortex. These findings show consistencies with those of previous studies of schizophrenia and ketamine but also studies of reduced consciousness - suggesting that rather than being a marker of conscious level per se, backward connectivity may index modulations of perceptual learning common to a variety of altered states of consciousness, perhaps united by a shared altered sensitivity to environmental stimuli. Since recent evidence suggests that the psychedelic state may correspond to a heightened 'level' of consciousness with respect to the normal waking state, our data warrant a re-examination of the top-down hypotheses of conscious level and suggest that several altered states may feature this specific biophysical effector.
Erritzoe D, Nutt DJ, Carhart-Harris R, 2017, Concerns regarding conclusions made about LSD-treatments, HISTORY OF PSYCHIATRY, Vol: 28, Pages: 257-258, ISSN: 0957-154X
Kaelen M, Roseman L, Lorenz R, et al., 2016, Effects of LSD and music on brain activity, 29th Congress of the European-College-of-Neuropsychopharmacology (ECNP), Publisher: ELSEVIER SCIENCE BV, Pages: S130-S130, ISSN: 0924-977X
Family N, Vinson D, Vigliocco G, et al., 2016, Semantic activation in LSD: evidence from picture naming, Language Cognition and Neuroscience, Vol: 31, Pages: 1320-1327, ISSN: 2327-3798
Lysergic acid diethylamide (LSD) is a classic psychedelic drug that alters cognition in a characteristic way. It has been suggested that psychedelics expand the breadth of cognition via actions on the central nervous system. Previous work has shown changes in semantic processing under psilocybin (a related psychedelic to LSD) that are consistent with an increased spread of semantic activation. The present study investigates this further using a picture-naming task and the psychedelic, LSD. Ten participants completed the task under placebo and LSD. Results revealed significant effects of LSD on accuracy and error correction that were consistent with an increased spread of semantic activation under LSD. These results are consistent with a generalised “entropic” effect on the mind. We suggest incorporating direct neuroimaging measures in future studies, and to employ more naturalistic measures of semantic processing that may enhance ecological validity.
Lebedev AV, Kaelen M, Lövdén M, et al., 2016, LSD-induced entropic brain activity predicts subsequent personality change, Human Brain Mapping, Vol: 37, Pages: 3203-3213, ISSN: 1097-0193
Personality is known to be relatively stable throughout adulthood. Nevertheless, it has been shown that major life events with high personal significance, including experiences engendered by psychedelic drugs, can have an enduring impact on some core facets of personality. In the present, balanced-order, placebo-controlled study, we investigated biological predictors of post-lysergic acid diethylamide (LSD) changes in personality. Nineteen healthy adults underwent resting state functional MRI scans under LSD (75µg, I.V.) and placebo (saline I.V.). The Revised NEO Personality Inventory (NEO-PI-R) was completed at screening and 2 weeks after LSD/placebo. Scanning sessions consisted of three 7.5-min eyes-closed resting-state scans, one of which involved music listening. A standardized preprocessing pipeline was used to extract measures of sample entropy, which characterizes the predictability of an fMRI time-series. Mixed-effects models were used to evaluate drug-induced shifts in brain entropy and their relationship with the observed increases in the personality trait openness at the 2-week follow-up. Overall, LSD had a pronounced global effect on brain entropy, increasing it in both sensory and hierarchically higher networks across multiple time scales. These shifts predicted enduring increases in trait openness. Moreover, the predictive power of the entropy increases was greatest for the music-listening scans and when "ego-dissolution" was reported during the acute experience. These results shed new light on how LSD-induced shifts in brain dynamics and concomitant subjective experience can be predictive of lasting changes in personality. Hum Brain Mapp, 2016. © 2016 Wiley Periodicals, Inc.
Roseman L, Sereno MI, Leech R, et al., 2016, LSD alters eyes-closed functional connectivity within the early visual cortex in a retinotopic fashion, Human Brain Mapping, Vol: 37, Pages: 3031-3040, ISSN: 1097-0193
The question of how spatially organized activity in the visual cortex behaves during eyes-closed, lysergic acid diethylamide (LSD)-induced "psychedelic imagery" (e.g., visions of geometric patterns and more complex phenomena) has never been empirically addressed, although it has been proposed that under psychedelics, with eyes-closed, the brain may function "as if" there is visual input when there is none. In this work, resting-state functional connectivity (RSFC) data was analyzed from 10 healthy subjects under the influence of LSD and, separately, placebo. It was suspected that eyes-closed psychedelic imagery might involve transient local retinotopic activation, of the sort typically associated with visual stimulation. To test this, it was hypothesized that, under LSD, patches of the visual cortex with congruent retinotopic representations would show greater RSFC than incongruent patches. Using a retinotopic localizer performed during a nondrug baseline condition, nonadjacent patches of V1 and V3 that represent the vertical or the horizontal meridians of the visual field were identified. Subsequently, RSFC between V1 and V3 was measured with respect to these a priori identified patches. Consistent with our prior hypothesis, the difference between RSFC of patches with congruent retinotopic specificity (horizontal-horizontal and vertical-vertical) and those with incongruent specificity (horizontal-vertical and vertical-horizontal) increased significantly under LSD relative to placebo, suggesting that activity within the visual cortex becomes more dependent on its intrinsic retinotopic organization in the drug condition. This result may indicate that under LSD, with eyes-closed, the early visual system behaves as if it were seeing spatially localized visual inputs. Hum Brain Mapp, 2016. © 2016 Wiley Periodicals, Inc.
Carhart-Harris RL, Muthukumaraswamy S, Roseman L, et al., 2016, Neural correlates of the LSD experience revealed by multimodal neuroimaging, Proceedings of the National Academy of Sciences of the United States of America, Vol: 113, Pages: 4853-4858, ISSN: 1091-6490
Lysergic acid diethylamide (LSD) is the prototypical psychedelic drug, but its effects on the human brain have never been studied before with modern neuroimaging. Here, three complementary neuroimaging techniques: arterial spin labeling (ASL), blood oxygen level-dependent (BOLD) measures, and magnetoencephalography (MEG), implemented during resting state conditions, revealed marked changes in brain activity after LSD that correlated strongly with its characteristic psychological effects. Increased visual cortex cerebral blood flow (CBF), decreased visual cortex alpha power, and a greatly expanded primary visual cortex (V1) functional connectivity profile correlated strongly with ratings of visual hallucinations, implying that intrinsic brain activity exerts greater influence on visual processing in the psychedelic state, thereby defining its hallucinatory quality. LSD’s marked effects on the visual cortex did not significantly correlate with the drug’s other characteristic effects on consciousness, however. Rather, decreased connectivity between the parahippocampus and retrosplenial cortex (RSC) correlated strongly with ratings of “ego-dissolution” and “altered meaning,” implying the importance of this particular circuit for the maintenance of “self” or “ego” and its processing of “meaning.” Strong relationships were also found between the different imaging metrics, enabling firmer inferences to be made about their functional significance. This uniquely comprehensive examination of the LSD state represents an important advance in scientific research with psychedelic drugs at a time of growing interest in their scientific and therapeutic value. The present results contribute important new insights into the characteristic hallucinatory and consciousness-altering properties of psychedelics that inform on how they can model certain pathological states and potentially treat others.
Tagliazucchi E, Roseman L, Kaelen M, et al., 2016, Increased Global Functional Connectivity Correlates with LSD-Induced Ego Dissolution, Current Biology, Vol: 26, Pages: 1043-1050, ISSN: 1879-0445
Kaelen M, Roseman L, Kahan J, et al., 2016, LSD modulates music-induced imagery via changes in parahippocampal connectivity, European Neuropsychopharmacology, Vol: 26, Pages: 1099-1109, ISSN: 1873-7862
Psychedelic drugs such as lysergic acid diethylamide (LSD) were used extensively in psychiatry in the past and their therapeutic potential is beginning to be re-examined today. Psychedelic psychotherapy typically involves a patient lying with their eyes-closed during peak drug effects, while listening to music and being supervised by trained psychotherapists. In this context, music is considered to be a key element in the therapeutic model; working in synergy with the drug to evoke therapeutically meaningful thoughts, emotions and imagery. The underlying mechanisms involved in this process have, however, never been formally investigated. Here we studied the interaction between LSD and music-listening on eyes-closed imagery by means of a placebo-controlled, functional magnetic resonance imaging (fMRI) study. Twelve healthy volunteers received intravenously administered LSD (75µg) and, on a separate occasion, placebo, before being scanned under eyes-closed resting conditions with and without music-listening. The parahippocampal cortex (PHC) has previously been linked with (1) music-evoked emotion, (2) the action of psychedelics, and (3) mental imagery. Imaging analyses therefore focused on changes in the connectivity profile of this particular structure. Results revealed increased PHC-visual cortex (VC) functional connectivity and PHC to VC information flow in the interaction between music and LSD. This latter result correlated positively with ratings of enhanced eyes-closed visual imagery, including imagery of an autobiographical nature. These findings suggest a plausible mechanism by which LSD works in combination with music listening to enhance certain subjective experiences that may be useful in a therapeutic context.
Terhune DB, Luke DP, Kaelen M, et al., 2016, A placebo-controlled investigation of synaesthesia-like experiences under LSD, Neuropsychologia, Vol: 88, Pages: 28-34, ISSN: 1873-3514
The induction of synaesthesia in non-synaesthetes has the potential to illuminate the mechanisms that contribute to the development of this condition and the shaping of its phenomenology. Previous research suggests that lysergic acid diethylamide (LSD) reliably induces synaesthesia-like experiences in non-synaesthetes. However, these studies suffer from a number of methodological limitations including lack of a placebo control and the absence of rigorous measures used to test established criteria for genuine synaesthesia. Here we report a pilot study that aimed to circumvent these limitations. We conducted a within-groups placebo-controlled investigation of the impact of LSD on colour experiences in response to standardized graphemes and sounds and the consistency and specificity of grapheme- and sound-colour associations. Participants reported more spontaneous synaesthesia-like experiences under LSD, relative to placebo, but did not differ across conditions in colour experiences in response to inducers, consistency of stimulus-colour associations, or in inducer specificity. Further analyses suggest that individual differences in a number of these effects were associated with the propensity to experience states of absorption in one's daily life. Although preliminary, the present study suggests that LSD-induced synaesthesia-like experiences do not exhibit consistency or inducer-specificity and thus do not meet two widely established criteria for genuine synaesthesia.
Speth J, Speth C, Kaelen M, et al., 2016, Decreased mental time travel to the past correlates with default-mode network disintegration under lysergic acid diethylamide, Journal of Psychopharmacology, Vol: 30, Pages: 344-353, ISSN: 1461-7285
This paper reports on the effects of LSD on mental time travel during spontaneous mentation. Twenty healthy volunteers participated in a placebo-controlled crossover study, incorporating intravenous administration of LSD (75 μg) and placebo (saline) prior to functional magnetic resonance imaging (fMRI). Six independent, blind judges analysed mentation reports acquired during structured interviews performed shortly after the functional magnetic resonance imaging (fMRI) scans (approximately 2.5 h post-administration). Within each report, specific linguistic references to mental spaces for the past, present and future were identified. Results revealed significantly fewer mental spaces for the past under LSD and this effect correlated with the general intensity of the drug’s subjective effects. No differences in the number of mental spaces for the present or future were observed. Consistent with the previously proposed role of the default-mode network (DMN) in autobiographical memory recollection and ruminative thought, decreased resting-state functional connectivity (RSFC) within the DMN correlated with decreased mental time travel to the past. These results are discussed in relation to potential therapeutic applications of LSD and related psychedelics, e.g. in the treatment of depression, for which excessive reflection on one’s past, likely mediated by DMN functioning, is symptomatic.
Kaelen M, Roseman L, Lebedev A, et al., 2016, Effects of LSD and music on brain activity, ECNP Workshop for Junior Scientists in Europe, Publisher: ELSEVIER SCIENCE BV, Pages: S80-S81, ISSN: 0924-977X
Carhart-Harris RL, Kaelen M, Bolstridge M, et al., 2016, The paradoxical psychological effects of lysergic acid diethylamide (LSD), Psychological Medicine, Vol: 46, Pages: 1379-1390, ISSN: 1469-8978
BACKGROUND: Lysergic acid diethylamide (LSD) is a potent serotonergic hallucinogen or psychedelic that modulates consciousness in a marked and novel way. This study sought to examine the acute and mid-term psychological effects of LSD in a controlled study. METHOD: A total of 20 healthy volunteers participated in this within-subjects study. Participants received LSD (75 µg, intravenously) on one occasion and placebo (saline, intravenously) on another, in a balanced order, with at least 2 weeks separating sessions. Acute subjective effects were measured using the Altered States of Consciousness questionnaire and the Psychotomimetic States Inventory (PSI). A measure of optimism (the Revised Life Orientation Test), the Revised NEO Personality Inventory, and the Peter's Delusions Inventory were issued at baseline and 2 weeks after each session. RESULTS: LSD produced robust psychological effects; including heightened mood but also high scores on the PSI, an index of psychosis-like symptoms. Increased optimism and trait openness were observed 2 weeks after LSD (and not placebo) and there were no changes in delusional thinking. CONCLUSIONS: The present findings reinforce the view that psychedelics elicit psychosis-like symptoms acutely yet improve psychological wellbeing in the mid to long term. It is proposed that acute alterations in mood are secondary to a more fundamental modulation in the quality of cognition, and that increased cognitive flexibility subsequent to serotonin 2A receptor (5-HT2AR) stimulation promotes emotional lability during intoxication and leaves a residue of 'loosened cognition' in the mid to long term that is conducive to improved psychological wellbeing.
Kaelen M, Barrett FS, Roseman L, et al., 2015, LSD enhances the emotional response to music., Psychopharmacology, Vol: 232, Pages: 3607-3614, ISSN: 1432-2072
RATIONALE: There is renewed interest in the therapeutic potential of psychedelic drugs such as lysergic acid diethylamide (LSD). LSD was used extensively in the 1950s and 1960s as an adjunct in psychotherapy, reportedly enhancing emotionality. Music is an effective tool to evoke and study emotion and is considered an important element in psychedelic-assisted psychotherapy; however, the hypothesis that psychedelics enhance the emotional response to music has yet to be investigated in a modern placebo-controlled study. OBJECTIVES: The present study sought to test the hypothesis that music-evoked emotions are enhanced under LSD. METHODS: Ten healthy volunteers listened to five different tracks of instrumental music during each of two study days, a placebo day followed by an LSD day, separated by 5-7 days. Subjective ratings were completed after each music track and included a visual analogue scale (VAS) and the nine-item Geneva Emotional Music Scale (GEMS-9). RESULTS: Results demonstrated that the emotional response to music is enhanced by LSD, especially the emotions "wonder", "transcendence", "power" and "tenderness". CONCLUSIONS: These findings reinforce the long-held assumption that psychedelics enhance music-evoked emotion, and provide tentative and indirect support for the notion that this effect can be harnessed in the context of psychedelic-assisted psychotherapy. Further research is required to test this link directly.
Carhart-Harris RL, Kaelen M, Whalley MG, et al., 2015, LSD enhances suggestibility in healthy volunteers, PSYCHOPHARMACOLOGY, Vol: 232, Pages: 785-794, ISSN: 0033-3158
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- Citations: 159
Carhart-Harris RL, Nutt DJ, 2010, User perceptions of the benefits and harms of hallucinogenic drug use: A web-based questionnaire study, Journal of Substance Use: for nursing, health and social care, Vol: 15, Pages: 283-300, ISSN: 1357-5007
This study used a web-based questionnaire to investigate user perceptions of the benefits and harms of hallucinogenic drug use. Over 600 forms were submitted. Users were asked to comment on the acute and prolonged effects of different drugs and to provide more specific information on how particular drugs have harmed and/or helped them. Subjects reported relatively less harm associated with the classic hallucinogens, LSD and psilocybin, than other drugs specifically focused on in the questionnaire (MDMA, cannabis, ketamine and alcohol). A wide-range of benefits was reported, including: help with mood disorders, addictions and migraine as well as more general long-term improvements in wellbeing. Symptoms of hallucinogen persisting perceptual disorder were reported by a number of subjects and these were most closely associated with use of LSD; however, few users regarded these effects as troubling. Eighty-one per cent of users reported having had a ‘spiritual experience’ on a hallucinogenic drug and over 90% considered ‘access to the unconscious mind’ to be a specific property of the classic hallucinogens. With caution, these findings support recent calls for a systematic investigation of the therapeutic potential of the classic hallucinogens and highlight the scope for empirical investigations of spiritual and psychodynamic phenomena.
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