Neural correlates of the LSD experience revealed by multimodal neuroimaging

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 neuroimag-ing 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.

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Ecstasy users report different sleep to matched controls

Current and former ecstasy users report different sleep to matched controls: a web-based questionnaire study

This study sought to test the association between ecstasy use and abnormal sleep.

An anonymous web-based questionnaire containing questions on drug use and sleep was completed by 1035 individuals. From this large sample, a group of 89 ecstasy users were found who reported very little use of other drugs.

This ”ecstasy-only“ group was further divided into two groups of 31 current users and 58 abstinent users. The subjective sleep of current and former ecstasy-only users was compared with that of matched controls. Patients were asked to rate their sleep according to:

1) sleep quality
2) sleep latency
3) night time awakenings
4) total sleep time.

Current ecstasy-only users reported significantly worse sleep quality (P < 0.05) and a greater total sleep time (P < 0.001) than controls. It was inferred that these differences might be due to recovery from the acute effects of the drug. Abstinent ecstasy-only users reported significantly more nighttime awakenings than controls (P < 0.01). These subjective findings are in agreement with the objective findings of previous studies showing persistent sleep abnormalities in ecstasy users.

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How do hallucinogens work on the brain?

How do hallucinogens work on the brain?

Robin Carhart-Harris, Mendel Kaelen and David Nutt consider a big question on several levels

The ‘classic’ hallucinogens – such as LSD (derived from ergotamine found in ergot fungi), dimethyltryptamine (DMT, the major hallucinogenic component of ayahuasca) and psilocybin (from magic mushrooms) – possess a unique and arguably unrivalled potential as scientific tools to study the mind and the brain.

For those of us who are currently fortunate enough to be researching them, there is a real sense that we are exploring something destined to become the ‘next big thing’ in psychopharmacology. But how much do we really know about how they act on the brain to produce their many unusual effects? Here, we summarise the relevant research, beginning at the level of single neurons and moving towards networks in the brain.

The level of single neurons

All classic hallucinogens stimulate a particular serotonin receptor subtype expressed on neurons in the brain, the serotonin 2A receptor. This receptor appears to be central to the action of hallucinogens because blocking it (with another drug called ketanserin) abolishes the occurrence of the hallucinatory state (Vollenweider et al., 1998). Also, the affinity (or ‘stickiness’) of different hallucinogens for the serotonin 2A receptor correlates positively with their potency, or ‘strength’; for example, LSD has an extremely high affinity for the serotonin 2A receptor and is remarkably potent (Glennon et al., 1984). That hallucinogens ‘stimulate’ serotonin 2A receptors means that they mimic the action of serotonin at the receptor by binding to it, altering its conformation or ‘shape’, and ultimately altering the internal conditions and therefore behaviour of the neuron it sits on.

For the serotonin 2A receptor, the key functional effect of its stimulation is an increase in the excitability of the hosting neuron. Serotonin 2A receptors are primarily expressed on an important type of neuron or brain cell in the brain, excitatory pyramidal neurons. More specifically, serotonin 2A receptors are especially highly expressed on excitatory pyramidal neurons in ‘layer 5’ of the cortex. The cortex is organised into layers of different cell types, like the different layers of a cake, and layer 5 is a deep layer, nearer the base than the icing (Weber & Andrade, 2010). Layer 5 pyramidal neurons are especially important functional units in the brain as they are the principal source of output from a cortical region. They project to hierarchically subordinate, or ‘lower’, cortical and subcortical regions (e.g. from a visual association region to the primary visual cortex).

Layer 5 pyramidal neurons project heavily onto inhibitory interneurons and so the net effect of their excitation seems to be inhibitory (Bastos et al., 2012). This is important because hallucinogen-induced excitation of layer 5 pyramidal cells has been interpreted by some as evidence of a more general excitatory effect of these drugs, but as will be discussed in the forthcoming sections, recent animal electrophysiological and human neuroimaging recordings have cast further doubt on the assumption that hallucinogens have a general excitatory effect on cortical activity (Carhart-Harris et al., 2012; Wood et al., 2012).

Captured by the idiom ‘failing to see the woods for the trees’, these results are a reminder that one should not be too hasty to extrapolate from the activity of certain single units in the brain, since the interconnected nature of cortical circuits means that local excitation can translate into net inhibition, or rather ‘disorder’, at a higher level of the system. If John Donne was a neuroscientist, he might have said: ‘no neuron is an island, entire of itself’.

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Functional Connectivity Measures After Psilocybin Inform a Novel Hypothesis of Early Psychosis

Functional Connectivity Measures After Psilocybin Inform a Novel Hypothesis of Early Psychosis

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 different 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 psychedelic state. Increased DMN-TPN FC has also been observed in sedation, as has decreased thalamocortical FC, but here we found preserved thalamocortical FC after psilocybin. 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 phenomenology and that of the psychedelic state and supporting the utility of psilocybin as a model of early psychosis.

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The effects of psilocybin and MDMA on between-network resting state functional connectivity

The effects of psilocybin and MDMA on between-network resting state functional connectivity in healthy volunteers

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.

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Neural correlates of the psychedelic state

Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin

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 fl ow 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 brains key connector hubs, enabling a state of unconstrained cognition.

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