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R. Carhart-Harris

The paradoxical psychological effects of lysergic acid diethylamide (LSD).

February 5, 2016 / LSD, Papers, Psychology, Publications / By / , , , , ,

Abstract

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.

Carhart-Harris, R. L., Kaelen, M., Bolstridge, M., Williams, T. M., Williams, L. T., Underwood, R., … & Nutt, D. J. (2016). The paradoxical psychological effects of lysergic acid diethylamide (LSD). Psychological medicine, 1-12. http://dx.doi.org/10.1017/S0033291715002901

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The Effects of Acutely Administered 3,4-Methylenedioxymethamphetamine on Spontaneous Brain Function in Healthy Volunteers Measured with Arterial Spin Labeling and Blood Oxygen Level-Dependent Resting State Functional Connectivity

October 15, 2015 / MDMA, Neuroscience, Papers, Psychology, Publications / By / , , , , , ,

Abstract

BACKGROUND:

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

METHODS:

In a double-blind, placebo-controlled, balanced-order study, MDMA was orally administered to 25 physically and mentally healthy individuals. Arterial spin labeling 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 administration. Participants underwent two arterial spin labeling and two blood oxygen level-dependent scans in a 90-minute scan session; MDMA and placebo study days were separated by 1 week.

RESULTS:

Marked increases in positive mood were produced by MDMA. Decreased CBF only was observed after MDMA, and this was localized 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 global subjective effects of MDMA. 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., … & Tanner, M. (2014). The Effects of Acutely Administered 3, 4-Methylenedioxymethamphetamine on Spontaneous Brain Function in Healthy Volunteers Measured with Arterial Spin Labeling 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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LSD enhances the emotional response to music

August 11, 2015 / LSD, Papers, Psychology, Publications / By / , , , , , ,

Abstract

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.

Kaelen, M., Barrett, F. S., Roseman, L., Lorenz, R., Family, N., Bolstridge, M., … & Carhart-Harris, R. L. (2015). LSD enhances the emotional response to music. Psychopharmacology, 1-8. https://dx.doi.org/10.1007/s00213-015-4014-y
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Finding the self by losing the self: Neural correlates of ego-dissolution under psilocybin

May 22, 2015 / Mushrooms / Psilocybin, Neuroscience, Papers, Psychology, Psychotic Disorders, Publications / By / , , , , ,

Abstract

Ego-disturbances have been a topic in schizophrenia research since the earliest clinical descriptions of the disorder. Manifesting as a feeling that one’s “self,” “ego,” or “I” is disintegrating or that the border between one’s self and the external world is dissolving, “ego-disintegration” or “dissolution” is also an important feature of the psychedelic experience, such as is produced by psilocybin (a compound found in “magic mushrooms”). Fifteen healthy subjects took part in this placebo-controlled study. Twelve-minute functional MRI scans were acquired on two occasions: subjects received an intravenous infusion of saline on one occasion (placebo) and 2 mg psilocybin on the other. Twenty-two visual analogue scale ratings were completed soon after scanning and the first principal component of these, dominated by items referring to “ego-dissolution”, was used as a primary measure of interest in subsequent analyses. Employing methods of connectivity analysis and graph theory, an association was found between psilocybin-induced ego-dissolution and decreased functional connectivity between the medial temporal lobe and high-level cortical regions. Ego-dissolution was also associated with a “disintegration” of the salience network and reduced interhemispheric communication. Addressing baseline brain dynamics as a predictor of drug-response, individuals with lower diversity of executive network nodes were more likely to experience ego-dissolution under psilocybin. These results implicate MTL-cortical decoupling, decreased salience network integrity, and reduced inter-hemispheric communication in psilocybin-induced ego disturbance and suggest that the maintenance of “self”or “ego,” as a perceptual phenomenon, may rest on the normal functioning of these systems.

Lebedev, A. V., Lövdén, M., Rosenthal, G., Feilding, A., Nutt, D. J., & Carhart‐Harris, R. L. (2015). Finding the self by losing the self: Neural correlates of ego‐dissolution under psilocybin. Human brain mapping. https://dx.doi.org/10.1002/hbm.22833
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Drug models of schizophrenia

February 5, 2015 / Ketamine, LSD, Mushrooms / Psilocybin, Neuroscience, Papers, Psychology, Psychotic Disorders, Publications, Salvia / Salvinorin A / By / , ,

Abstract

Schizophrenia is a complex mental health disorder with positive, negative and cognitive symptom domains. Approximately one third of patients are resistant to currently available medication. New therapeutic targets and a better understanding of the basic biological processes that drive pathogenesis are needed in order to develop therapies that will improve quality of life for these patients. Several drugs that act on neurotransmitter systems in the brain have been suggested to model aspects of schizophrenia in animals and in man. In this paper, we selectively review findings from dopaminergic, glutamatergic, serotonergic, cannabinoid, GABA, cholinergic and kappa opioid pharmacological drug models to evaluate their similarity to schizophrenia. Understanding the interactions between these different neurotransmitter systems and their relationship with symptoms will be an important step towards building a coherent hypothesis for the pathogenesis of schizophrenia.

Steeds, H., Carhart-Harris, R. L., & Stone, J. M. (2014). Drug models of schizophrenia. Therapeutic Advances in Psychopharmacology. https://dx.doi.org/10.1177/2045125314557797
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A Qualitative Report on the Subjective Experience of Intravenous Psilocybin Administered in an fMRI Environment

January 28, 2015 / Mushrooms / Psilocybin, Papers, Psychology, 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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LSD enhances suggestibility in healthy volunteers

September 23, 2014 / LSD, Papers, Psychology, 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 / Mushrooms / Psilocybin, Neuroscience, Papers, Psychology, 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 / MDMA, Mushrooms / Psilocybin, Neuroscience, Papers, Psychology, 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 / LSD, Mushrooms / Psilocybin, Neuroscience, Papers, Psychology, 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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