OPEN Foundation

D. Nutt

A Qualitative Report on the Subjective Experience of Intravenous Psilocybin Administered in an fMRI Environment

January 28, 2015 / Mushrooms / Psilocybin, Mystical experiences, Papers, Phenomenology, Psychology, Psychopharmacology, Publications / By / , ,

Abstract

Background: This report documents the phenomenology of the subjective experiences of 15 healthy psychedelic experienced volunteers who were involved in a functional magnetic resonance imaging (fMRI) study that was designed to image the brain effects of intravenous psilocybin.

Methods: The participants underwent a semi-structured interview exploring the effects of psilocybin in the MRI scanner. These interviews were analysed by Interpretative Phenomenological Analysis. The resultant data is ordered in a detailed matrix, and presented in this paper.

Results: Nine broad categories of phenomenology were identified in the phenomenological analysis of the experience; perceptual changes including visual, auditory and somatosensory distortions, cognitive changes, changes in mood, effects of memory, spiritual or mystical type experiences, aspects relating to the scanner and research environment, comparisons with other experiences, the intensity and onset of effects, and individual interpretation of the experience.

Discussion: This article documents the phenomenology of psilocybin when given in a novel manner (intravenous injection) and setting (an MRI scanner). The findings of the analysis are consistent with previous published work regarding the subjective effects of psilocybin. There is much scope for further research investigating the phenomena identified in this paper.

Turton, S., Nutt, D. J., & Carhart-Harris, R. L. (2015). A Qualitative Report on the Subjective Experience of Intravenous Psilocybin Administered in an fMRI Environment. Current Drug Abuse Reviews, 7(2), 117-127. https://dx.doi.org/10.2174/1874473708666150107120930
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Making a medicine out of MDMA

January 5, 2015 / Anxiety disorders / PTSD, MDMA, Neuroscience, Papers, Psychiatry, Psychology, Psychopharmacology, Psychotherapy, Publications, Safety, Toxicology / By / ,

Abstract

From its first use 3,4,-methylenedioxymethamphetamine (MDMA) has been recognised as a drug with therapeutic potential. Research on its clinical utility stopped when it entered the recreational drug scene but has slowly resurrected in the past decade. Currently there is enough evidence for MDMA to be removed from its Schedule 1 status of ‘no medical use’ and moved into Schedule 2 (alongside other misused but useful medicines such as heroin and amphetamine). Such a regulatory move would liberate its use as a medicine for patients experiencing severe mental illnesses such as treatment-resistant post-traumatic stress disorder.

Sessa, B., & Nutt, D. (2015). Making a medicine out of MDMA. The British Journal of Psychiatry, 206, 4-6. https://dx.doi.org/10.1192/bjp.bp.114.152751

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LSD enhances suggestibility in healthy volunteers

September 23, 2014 / LSD, Other subjects, Papers, Personality, Psychology, Psychopharmacology, Publications / By / , , , , ,

Abstract

Rationale
Lysergic acid diethylamide (LSD) has a history of use as a psychotherapeutic aid in the treatment of mood disorders and addiction, and it was also explored as an enhancer of mind control.

Objectives
The present study sought to test the effect of LSD on suggestibility in a modern research study.

Methods
Ten healthy volunteers were administered with intravenous (i.v.) LSD (40–80 μg) in a within-subject placebo-controlled design. Suggestibility and cued mental imagery were assessed using the Creative Imagination Scale (CIS) and a mental imagery test (MIT). CIS and MIT items were split into two versions (A and B), balanced for ‘efficacy’ (i.e. A≈B) and counterbalanced across conditions (i.e. 50 % completed version ‘A’ under LSD). The MIT and CIS were issued 110 and 140 min, respectively, post-infusion, corresponding with the peak drug effects.

Results
Volunteers gave significantly higher ratings for the CIS (p = 0.018), but not the MIT (p = 0.11), after LSD than placebo. The magnitude of suggestibility enhancement under LSD was positively correlated with trait conscientiousness measured at baseline (p = 0.0005).

Conclusions
These results imply that the influence of suggestion is enhanced by LSD. Enhanced suggestibility under LSD may have implications for its use as an adjunct to psychotherapy, where suggestibility plays a major role. That cued imagery was unaffected by LSD implies that suggestions must be of a sufficient duration and level of detail to be enhanced by the drug. The results also imply that individuals with high trait conscientiousness are especially sensitive to the suggestibility-enhancing effects of LSD.

Carhart-Harris, R. L., Kaelen, M., Whalley, M. G., Bolstridge, M., Feilding, A. & Nutt, D.J. (2014). LSD enhances suggestibility in healthy volunteers. Psychopharmacology. http://dx.doi.org/10.1007/s00213-014-3714-z
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Enhanced repertoire of brain dynamical states during the psychedelic experience

July 2, 2014 / Consciousness, Mushrooms / Psilocybin, Neuroscience, Other disciplines, Papers, Psychology, Psychopharmacology, Publications / By / , , , ,

Abstract

The study of rapid changes in brain dynamics and functional connectivity (FC) is of increasing interest in neuroimaging. Brain states departing from normal waking consciousness are expected to be accompanied by alterations in the aforementioned dynamics. In particular, the psychedelic experience produced by psilocybin (a substance found in `magic mushrooms`) is characterized by unconstrained cognition and profound alterations in the perception of time, space and selfhood. Considering the spontaneous and subjective manifestation of these effects, we hypothesize that neural correlates of the psychedelic experience can be found in the dynamics and variability of spontaneous brain activity fluctuations and connectivity, measurable with functional Magnetic Resonance Imaging (fMRI). Fifteen healthy subjects were scanned before, during and after intravenous infusion of psilocybin and an inert placebo. Blood-Oxygen Level Dependent (BOLD) temporal variability was assessed computing the variance and total spectral power, resulting in increased signal variability bilaterally in the hippocampi and anterior cingulate cortex. Changes in BOLD signal spectral behavior (including spectral scaling exponents) affected exclusively higher brain systems such as the default mode, executive control and dorsal attention networks. A novel framework enabled us to track different connectivity states explored by the brain during rest. This approach revealed a wider repertoire of connectivity states post-psilocybin than during control conditions. Together, the present results provide a comprehensive account of the effects of psilocybin on dynamical behaviour in the human brain at a macroscopic level and may have implications for our understanding of the unconstrained, hyper-associative quality of consciousness in the psychedelic state.

Tagliazucchi, E., Carhart-Harris, R. L., Leech, R., Nutt, D., & Chialvo, D. R. (2014). Enhanced repertoire of brain dynamical states during the psychedelic experience. Human Brain Mapping, 35(11), 5442-5456. http://dx.doi.org/10.1002/hbm.22562
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The effects of psilocybin and MDMA on between-network resting state functional connectivity in healthy volunteers

May 27, 2014 / Consciousness, MDMA, Mushrooms / Psilocybin, Neuroscience, Papers, Psychology, Psychopharmacology, Publications / By / , , , ,

Abstract

Perturbing a system and observing the consequences is a classic scientific strategy for understanding a phenomenon. Psychedelic drugs perturb consciousness in a marked and novel way and thus are powerful tools for studying its mechanisms. In the present analysis, we measured changes in resting-state functional connectivity (RSFC) between a standard template of different independent components analysis (ICA)-derived resting state networks (RSNs) under the influence of two different psychoactive drugs, the stimulant/psychedelic hybrid, MDMA, and the classic psychedelic, psilocybin. Both were given in placebo-controlled designs and produced marked subjective effects, although reports of more profound changes in consciousness were given after psilocybin. Between-network RSFC was generally increased under psilocybin, implying that networks become less differentiated from each other in the psychedelic state. Decreased RSFC between visual and sensorimotor RSNs was also observed. MDMA had a notably less marked effect on between-network RSFC, implying that the extensive changes observed under psilocybin may be exclusive to classic psychedelic drugs and related to their especially profound effects on consciousness. The novel analytical approach applied here may be applied to other altered states of consciousness to improve our characterization of different conscious states and ultimately advance our understanding of the brain mechanisms underlying them.

Roseman, L., Leech, R., Feilding, A., Nutt, D. J., & Carhart-Harris, R. L. (2014). The effects of psilocybin and MDMA on between-network resting state functional connectivity in healthy volunteers. Frontiers in Human Neuroscience, 8, 1-11. http://dx.doi.org/10.3389/fnhum.2014.00204
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The entropic brain: a theory of conscious states informed by neuroimaging research with psychedelic drugs

February 3, 2014 / Consciousness, LSD, Mushrooms / Psilocybin, Neuroscience, Papers, Psychology, Psychopharmacology, Publications / By / , , , , , , ,

Abstract

Entropy is a dimensionless quantity that is used for measuring uncertainty about the state of a system but it can also imply physical qualities, where high entropy is synonymous with high disorder. Entropy is applied here in the context of states of consciousness and their associated neurodynamics, with a particular focus on the psychedelic state. The psychedelic state is considered an exemplar of a primitive or primary state of consciousness that preceded the development of modern, adult, human, normal waking consciousness. Based on neuroimaging data with psilocybin, a classic psychedelic drug, it is argued that the defining feature of “primary states” is elevated entropy in certain aspects of brain function, such as the repertoire of functional connectivity motifs that form and fragment across time. Indeed, since there is a greater repertoire of connectivity motifs in the psychedelic state than in normal waking consciousness, this implies that primary states may exhibit “criticality,” i.e., the property of being poised at a “critical” point in a transition zone between order and disorder where certain phenomena such as power-law scaling appear. Moreover, if primary states are critical, then this suggests that entropy is suppressed in normal waking consciousness, meaning that the brain operates just below criticality. It is argued that this entropy suppression furnishes normal waking consciousness with a constrained quality and associated metacognitive functions, including reality-testing and self-awareness. It is also proposed that entry into primary states depends on a collapse of the normally highly organized activity within the default-mode network (DMN) and a decoupling between the DMN and the medial temporal lobes (which are normally significantly coupled). These hypotheses can be tested by examining brain activity and associated cognition in other candidate primary states such as rapid eye movement (REM) sleep and early psychosis and comparing these with non-primary states such as normal waking consciousness and the anaesthetized state.

Carhart-Harris, R. L., Leech, R., Hellyer, P. J., Shanahan, M., Feilding, A., Tagliazucchi, E., Chialvo, D. R., & Nutt, D. (2014). The entropic brain: a theory of conscious states informed by neuroimaging research with psychedelic drugs. Frontiers in Human Neuroscience, 8, 1-22. http://dx.doi.org/10.3389/fnhum.2014.00020
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The Effects of Acutely Administered 3,4-Methylenedioxymethamphetamine on Spontaneous Brain Function in Healthy Volunteers Measured with Arterial Spin Labelling and Blood Oxygen Level-Dependent Resting-State Functional Connectivity

January 10, 2014 / MDMA, Neuroscience, Other subjects, Papers, Psychology, Psychopharmacology, Publications / By / , , , , , ,

Abstract

Background
3,4-methylenedioxymethamphetamine (MDMA) is a potent monoamine releaser that produces an acute euphoria in most individuals.

Methods
MDMA was orally administered to 25 physically and mentally healthy individuals in a double-blind, placebo-controlled, balanced-order study. Arterial spin labelling (ASL) and seed-based resting state functional connectivity (RSFC) were used to produce spatial maps displaying changes in cerebral blood flow (CBF) and RSFC after MDMA. Participants underwent two ASL and two BOLD scans in a 90 minute scanning session and the MDMA and placebo study days were separated by one week.

Results
MDMA produced marked increases in positive mood. Only decreased CBF was observed after MDMA and this was localised to the right medial temporal lobe (MTL), thalamus, inferior visual cortex and the somatosensory cortex. Decreased CBF in the right amygdala and hippocampus correlated with ratings of the intensity of MDMA’s global subjective effects. The RSFC results complemented the CBF results, with decreases in RSFC between midline cortical regions, the medial prefrontal cortex and MTL regions, and increases between the amygdala and hippocampus. There were trend-level correlations between these effects and ratings of intense and positive subjective effects.

Conclusions
The MTLs appear to be specifically implicated in the mechanism of action of MDMA but further work is required to elucidate how the drug’s characteristic subjective effects arise from its modulation of spontaneous brain activity.

Carhart-Harris, R. L., Murphy, K., Leech, R., Erritzoe, D., Wall, M. B., Ferguson, B., … Nutt, D. J. (2014). The Effects of Acutely Administered 3,4-Methylenedioxymethamphetamine on Spontaneous Brain Function in Healthy Volunteers Measured with Arterial Spin Labelling and Blood Oxygen Level-Dependent Resting-State Functional Connectivity. Biological Psychiatry. http://dx.doi.org/10.1016/j.biopsych.2013.12.015
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Effects of Schedule I drug laws on neuroscience research and treatment innovation

June 12, 2013 / Ayahuasca, Cacti / Mescaline, DMT, LSD, MDMA, Mushrooms / Psilocybin, Neuroscience, Other disciplines, Other subjects, Other substances, Papers, Publications, Salvia / Salvinorin A / By / , ,

Abstract

Many psychoactive drugs are used recreationally, particularly by young people. This use and its perceived dangers have led to many different classes of drugs being banned under national laws and international conventions. Indeed, the possession of cannabis, 3,4‑methylenedioxy‑N‑methylamphetamine (MDMA; also known as ecstasy) and psychedelics is stringently regulated. An important and unfortunate outcome of the controls placed on these and other psychoactive drugs is that they make research into their mechanisms of action and potential therapeutic uses — for example, in depression and post‑traumatic stress disorder — difficult and in many cases almost impossible.

Nutt, D. J., King, L. A., & Nichols, D. E. (2013). Effects of Schedule I drug laws on neuroscience research and treatment innovation. Nature Reviews Neuroscience, 14, 577-585. http://dx.doi.org/10.1038/nrn3530
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Functional Connectivity Measures After Psilocybin Inform a Novel Hypothesis of Early Psychosis

October 8, 2012 / Mushrooms / Psilocybin, Neuroscience, Papers, Psychiatry, Psychology, Psychosis, Publications / By / , , , , , ,

Abstract

Psilocybin is a classic psychedelic and a candidate drug model of psychosis. This study measured the effects of psilocybin on resting-state network and thalamocortical functional connectivity (FC) using functional magnetic resonance imaging (fMRI). Fifteen healthy volunteers received intravenous infusions of psilocybin and placebo in 2 task-free resting-state scans. Primary analyses focused on changes in FC between the default-mode- (DMN) and task-positive network (TPN). Spontaneous activity in the DMN is orthogonal to spontaneous activity in the TPN, and it is well known that these networks support very differ -ent functions (ie, the DMN supports introspection, whereas the TPN supports externally focused attention). Here, inde -pendent components and seed-based FC analyses revealed increased DMN-TPN FC and so decreased DMN-TPN orthogonality after psilocybin. Increased DMN-TPN FC has been found in psychosis and meditatory states, which share some phenomenological similarities with the psy -chedelic state. Increased DMN-TPN FC has also been observed in sedation, as has decreased thalamocortical FC, but here we found preserved thalamocortical FC after psi -locybin. Thus, we propose that thalamocortical FC may be related to arousal, whereas DMN-TPN FC is related to the separateness of internally and externally focused states. We suggest that this orthogonality is compromised in early psychosis, explaining similarities between its phenomenol -ogy and that of the psychedelic state and supporting the utility of psilocybin as a model of early psychosis.

Carhart-Harris, R. L., Leech, R., Erritzoe, D., Williams, T. M.,  Stone, J. M.,  Evans, J., …. Nutt, D. J. (2012). Functional Connectivity Measures After Psilocybin Inform a Novel Hypothesis of Early Psychosis. Schizophrenia Bulletin, 39(6), 1343-1351. http://dx.doi.org/10.1093/schbul/sbs117
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Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin

January 29, 2012 / Mushrooms / Psilocybin, Neuroscience, Other subjects, Papers, Psychology, Publications / By / , , , , , ,

Abstract

Psychedelic drugs have a long history of use in healing ceremonies, but despite renewed interest in their therapeutic potential, we continue to know very little about how they work in the brain. Here we used psilocybin, a classic psychedelic found in magic mushrooms, and a task-free functional MRI (fMRI) protocol designed to capture the transition from normal waking consciousness to the psychedelic state. Arterial spin labeling perfusion and blood-oxygen level-dependent (BOLD) fMRI were used to map cerebral blood flow and changes in venous oxygenation before and after intravenous infusions of placebo and psilocybin. Fifteen healthy volunteers were scanned with arterial spin labeling and a separate 15 with BOLD. As predicted, profound changes in consciousness were observed after psilocybin, but surprisingly, only decreases in cerebral blood flow and BOLD signal were seen, and these were maximal in hub regions, such as the thalamus and anterior and posterior cingulate cortex (ACC and PCC). Decreased activity in the ACC/medial prefrontal cortex (mPFC) was a consistent finding and the magnitude of this decrease predicted the intensity of the subjective effects. Based on these results, a seed-based pharmaco-physiological interaction/functional connectivity analysis was performed using a medial prefrontal seed. Psilocybin caused a significant decrease in the positive coupling between the mPFC and PCC. These results strongly imply that the subjective effects of psychedelic drugs are caused by decreased activity and connectivity in the brain’s key connector hubs, enabling a state of unconstrained cognition.

Carhart-Harris, R. L., Erritzoe, D., Williams, T., Stone, J. M., Reed, L. J., Colasanti, A., … Nutt, D. J. (2012). Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin. Proceedings of the National Academy of Sciences of the United States of America, 109(6), 2138-2143. http://dx.doi.org/10.1073/pnas.1119598109
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30 April - Q&A with Rick Strassman

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