Sunday, August 19, 2012

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

This article was published earlier this year in the Proceedings of National Academy of Science (PNAS) journal. The study sought to reveal what happens in the brain during psilocybin intoxication. Rather than the expected increases in brain activity predicted, the study revealed decreased activity in several areas, including the thalamus and anterior and posterior cingulate cortex. Overall, the results suggests that the subjective effects of psilocybin are caused by "decreased activity and connectivity in the brain’s key connector hubs, enabling a state of unconstrained cognition."

Full Citation:
Carhart-Harrisa, RL, Erritzoea, D, Williams, T, Stone, JM. (2012, Feb 7). Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin. PNASvol. 109 no. 6 2138-2143.

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

Robin L. Carhart-Harrisa, David Erritzoea, Tim Williams, James M. Stone, Laurence J. Reed, Alessandro Colasanti, Robin J. Tyacke, Robert Leech, Andrea L. Malizia, Kevin Murphy, Peter Hobden, John Evans, Amanda Feilding, Richard G. Wise, and David J. Nutta

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.

Psilocybin is the prodrug of psilocin (4-hydroxy-dimethyltryptamine), the primary hallucinogenic component of magic mushrooms, and a classic psychedelic (“mind-manifesting”) drug. Psilocybin has been used for centuries in healing ceremonies (1) and more recently in psychotherapy (2); it is capable of stimulating profound existential experiences (3), which can leave a lasting psychological impression (4). However, despite a wealth of literature on its phenomenology, we currently know very little about how its effects are produced in the brain. The present study sought to address this question using complementary functional MRI (fMRI) techniques and a protocol designed to image the transition from normal waking consciousness to the psychedelic state. Two groups of healthy subjects were scanned using arterial spin labeling (ASL) perfusion and blood-oxygen level-dependent (BOLD) fMRI during intravenous infusion of psilocybin. Infused over 60 s (2 mg in 10-mL saline), psilocybin’s subjective effects begin within seconds (5), allowing the capture of the corresponding change in brain state.


The fMRI studies reported here revealed significant and consistent outcomes. Psilocybin significantly decreased brain blood flow and venous oxygenation in a manner that correlated with its subjective effects, and significantly decreased the positive coupling of two key structural hubs (the mPFC and the PCC). Our use of fMRI to measure resting-state brain activity after a psychedelic is unique, and because the results are unexpected, they require some explanation.

The effect of psilocybin on resting-state brain activity has been measured before with PET and glucose metabolism (8). This study found a global increase in glucose metabolism after oral psilocybin, which is inconsistent with our fMRI results. One possible explanation for this discrepancy relates to the fact that the radio tracer used to measure glucose metabolism (18 F-fluorodeoxyglucose) has a long half-life (110 min). Thus, the effects of psilocybin, as measured by PET, are over much greater timescales than indexed by our fMRI measures. It is therefore possible that phasic or short term effects of psilocybin show some rebound that is detected by longer-term changes in glucose metabolism. More direct measures of neural activity will help inform this hypothesis, but in support of the inference that psilocybin does decrease neural activity, direct recordings of cortical local field potentials (LFPs) in rats found broadband decreases in resting state LFP power after psilocybin infusion—including γ-power (9)—changes in which are known to correlate with changes in the BOLD signal (10).

It has been commonly assumed that psychedelics work by increasing neural activity; however, our results put this into question. Psilocin is a mixed serotonin receptor agonist, but there is a general consensus that the characteristic subjective and behavioral effects of psychedelics are initiated via stimulation of serotonin (5-Hydroxytryptamine, 5-HT) 2A receptors (11). It is possible that the deactivations observed in the present studies were caused by stimulation of 5-HT receptors other than 5-HT2A; however, this seems unlikely given that the affinity of psychedelics for the 5-HT2A receptor correlates with their potency (12) and 5-HT2A antagonists block the subjective effects of psychedelics (13). There is a large body of preclinical evidence that stimulation of 5-HT2A receptors increases GABAergic transmission and pyramidal cell inhibition (14–21), which may explain the deactivations observed here (Figs. 2 and 4). fMRI studies with serotonergic compounds that stimulate other 5-HT receptors, such as the 5-HT2C (22) or (mainly) the 5-HT1A receptor (23), have not found comparable results to those shown here, and 5-HT2A receptors are present in high concentrations in the cortical regions that were significantly deactivated and decoupled after psilocybin (Table S2).

Stimulation of the 5-HT2A receptor increases excitation in the host cell by reducing outward potassium currents (24). Thus, if the 5-HT2A receptor did mediate the observed deactivations, then it may have been via 5-HT2A-induced excitation of fast-spiking interneurons terminating on pyramidal cells (e.g., ref. 24) or 5-HT2A-induced excitation of pyramidal cells projecting onto interneurons (25).

Regardless of how these effects were initiated at the receptor level, it is necessary for us to offer a functional explanation for them. It is noteworthy that the regions which showed the most consistent deactivations after psilocybin (e.g., the PCC and mPFC) are also those that show disproportionately high activity under normal conditions (26). For example, metabolism in the PCC is ∼20% higher than most other brain regions (27), yet psilocybin decreased its blood flow by up to 20% in some subjects. There issome mystery about the function of the PCC; its large size, buffered location, and rich vasculature means that it is well protected from damage. The high metabolic activity of the PCC and the default-mode network (DMN) with which is it associated (26) has led some to speculate about its functional importance, positing a role in consciousness (28) and high-level constructs, such as the self (29) or “ego” (30, 31). Indeed, the DMN is known to be activated during self-referencing (28) and other high-level functions linked to the self-construct (27). Moreover, DMN regions are also known to host the highest number of cortico-cortical connections in the brain, making them important “connector hubs” (32). These hubs may be critical for efficient information transfer in the brain by allowing communication between different regions via the fewest number of connections (33). However, such an integrative function would confer a significant responsibility on these regions, which may explain why their deactivation has such a profound effect on consciousness, as shown here.

These results may have implications beyond explaining how psilocybin works in the brain by implying that the DMN is crucial for the maintenance of cognitive integration and constraint under normal conditions. This finding is consistent with Aldous Huxley’s “reducing valve” metaphor (34) and Karl Friston’s “free-energy principle” (35), which propose that the mind/brain works to constrain its experience of the world.

The pharmaco-physiological interaction results were particularly intriguing, revealing significant decreases in the positive coupling between the PCC and mPFC after psilocybin. This result can be understood in terms of a regression of PCC activity on mPFC activity, in which the regression slope decreases. This finding can either be interpreted as a decrease in the (backward or top-down) connectivity from prefrontal to parietal regions or, equivalently, an increase in the reciprocal (forward or bottom-up) direction from parietal to prefrontal regions. This asymmetrical change in coupling, induced by psilocybin, is consistent with a reduction in the sensitivity of superficial pyramidal cells in the parietal region targeted by prefrontal afferents, which may or may not be associated with a compensatory increase in the influence of parietal regions on prefrontal activity. Whatever the underlying synaptic mechanisms, these results provide clear evidence for a perturbation in reciprocal coupling between these two association areas and speak to a rebalancing of hierarchical activity in distributed high-level modes.

Finally, consistent with their history of use as adjuncts to psychotherapy, the idea has recently re-emerged that psychedelics may be useful in the treatment of certain psychiatric disorders (36). It seems relevant therefore that activity in (37) and connectivity with (38) the mPFC is known to be elevated in depression and normalized after effective treatment (39). The mPFC was consistently deactivated by psilocybin (Fig. 4) and the magnitude of the deactivations correlated with the drug’s subjective effects (Fig. 3). Depression has been characterized as an “overstable” state, in which cognition is rigidly pessimistic (39). Trait pessimism has been linked to deficient 5-HT2A receptor stimulation (40, 41), particularly in the mPFC (40), and mPFC hyperactivity has been linked to pathological brooding (42). Recent work has shown that psilocybin can increase subjective well-being (4) and trait openness (43) several months after an acute experience, and depression scores in terminal cancer patients were significantly decreased 6 mo after treatment with psilocybin (2). Our results suggest a biological mechanism for this: decreased mPFC activity via 5-HT2A receptor stimulation. Further work is required to test this hypothesis and the putative utility of psilocybin in depression.

We also observed decreased CBF in the hypothalamus after psilocybin (Fig. 2), which may explain anecdotal reports that psychedelics reduce symptoms of cluster headaches (44). Increased hypothalamic CBF was observed during acute headache in cluster headache sufferers (45) and inhibition of the hypothalamus via direct electrical stimulation can provide therapeutic relief for this condition (46).

To conclude, here we used an advanced and comprehensive fMRI protocol to image the brain effects of psilocybin. These studies offer the most detailed account to date on how the psychedelic state is produced in the brain. The results suggest decreased activity and connectivity in the brain’s connector hubs, permitting an unconstrained style of cognition.

You can read the whole article online.
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