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This is your brain on psilocybin…

The views expressed are those of the author and are not necessarily those of Scientific American.

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…and this is a paper which is not quite what it’s cracked up to be. Because while it does, indeed, have great pictures of your brain on drugs, it doesn’t really go any further than that. It doesn’t explore why these changes are occurring or what they say about the functions of psilocybin. So while it provides some nice correlations, the causation is still lacking.


Carhart-Harris et al. “Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin” PNAS, 2012.

There are several hundred references to studies on psilocybin on Pubmed. We know that it is classified as a hallucinogen and has high affinity for the serotonin 2A type of receptor (through which it is thought to have its sensory distorting effects). We know how its metabolized, what dose related effects and subjective effects can be. But no one had ever put people on psilocybin into an fMRI and looked at the results.

fMRI is functional magnetic resonance imaging, a technique which can measure brain activity by measuring the changes in blood flow to different areas of the brain over time. Keep in mind, though, that this techniques has its limitations. It measures changes in blood flow, and can tell you where and when those changes are occurring. But that is all. There’s some debate over how correlated these changes really are with what activities are taking place, and what the changes themselves really mean for various aspects of function.

For this experiment, the authors put 15 subjects in an fMRI, and did studies using BOLD (measures of blood oxygenation), and ASL (arterial spin labeling, which also measures blood flow, but not oxygenation) while the participants were under the influence of psilocybin or placebo. They using i.v. injections of psilocybin instead of the usual oral route of administration, in an effort to get the results in real time. And they got some very pretty pictures.

What this shows are areas of decreased blood flow, relative to placebo, in various areas of the brain while the participants were on psilocybin. The areas of greatest decrease included the cingulate cortex, the thalamus, and medial prefrontal cortex. The thalamus is involved in a lot of relays and processing from one area of the brain to another, while the cingulate cortex is involved in emotional processing, and the medial prefrontal cortex in higher executive function.

As you can see here, there was a negative correlation between the blood flow to these areas and the intensity of the subjective experience by the subjects, so the lower the blood flow, the more intense the subjective experience.

This is all well and good. But unfortunately, I think…that was ALL. The authors spoke somewhat about the “pharmaco-physiological interaction”, but while that’s very intense sounding, what it actually means it that the drug is affecting your brain, which is not exactly big news. They also hypothesized that these blood flow changes enable “a state of unconstrained cognition”, but which blood flow changes? And via what mechanism? Does simply reducing blood flow in these regions induce subjective effects that feel like psilocybin? Does free and wild “unconstrained” thinking involve decreases in blood flow in these areas? What about serotonin receptors in these areas? Psilocybin is a strong agonist of serotonin 2A receptors, and the authors hypothesize that the effects of psilocybin on these areas of the brain are through the actions of serotonin 2A receptors on GABA neurons, reducing brain activity in these areas. But they have no evidence for this, they did not give a serotonin 2A antagonist to try and block the decreases in blood flow, or a GABA antagonist to try and block the subjective effects. While some of these effects couldn’t necessarily be done in humans (like the decreases in blood flow in specific regions), several of them could have been (using a serotonin 2A antagonist or a GABA antagonist).

So while psilocybin is bound to grab people’s interests, and ideas about “unconstrained cognition” may grab imaginations, this does nothing to address a mechanism, and without it, it’s only a picture of your brain on drugs.

EDIT: To be clear (since the commenters point out that I wasn’t), I do not think this study is BAD. It’s small and incremental. But not BAD (though I think the interpretation leaves something to be desired). What I find rather odd about this paper is that it is small and incremental…but it’s published in PNAS, one of the bigger journals in the field (the level “below” Cell, Nature, and Science). In a journal like PNAS, one usually expects to see mechanism, an effort at finding out WHY. This is a picture of your brain on drugs, and while nice, doesn’t show anything about why the drug is producing these effects or how the effects are occurring. So I was surprised, and somewhat confused to see it in PNAS. Is it because of the drug involved and the potential controversy? Or is there something about this publication that I’ve missed? I don’t know. But I was, and am, surprised.

Carhart-Harris, R., Erritzoe, D., Williams, T., Stone, J., Reed, L., Colasanti, A., Tyacke, R., Leech, R., Malizia, A., Murphy, K., Hobden, P., Evans, J., Feilding, A., Wise, R., & Nutt, D. (2012). From the Cover: Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin Proceedings of the National Academy of Sciences, 109 (6), 2138-2143 DOI: 10.1073/pnas.1119598109

Scicurious About the Author: Scicurious is a PhD in Physiology, and is currently a postdoc in biomedical research. She loves the brain. And so should you. Follow on Twitter @Scicurious.

The views expressed are those of the author and are not necessarily those of Scientific American.

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  1. 1. Sean McCann 12:47 pm 02/8/2012

    I don’t really understand your beef with this paper. It demonstrates an interesting and somewhat unexpected result and suggests an interpretation. At no stage of the game did they suggest that their interpretation was ironclad. It is the FIRST FMRI study with the substance. I am sure that there will be more in the future, that will assess the effect of receptor antagonists, political affiliation of subjects and history of watching the Jetsons.
    This is solid, incremental science. If you find it trivial, why would you bother to write a blog post about it?

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  2. 2. DownWThat 1:34 pm 02/8/2012

    I have to second Sean’s sentiments here. While his comments made me laugh, the finer points are very relevant. Why are you so critical? Do you have more information that would justify the lampooning that you wish to share? Perhaps, you were just having a bad morning.If you want more of the neuro-science behind it, tout the intial study and call for more funding. If it is a waste in your eyes, explain yourself more reasonably. As of now, you have only offered what amount to personal attacks on the researchers. Shame…

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  3. 3. scicurious 2:04 pm 02/8/2012

    It’s actually not the study I have an issue with, per se. It is, as you said, a small, incremental study. Where I feel the lack is the fact that it was published in PNAS, a journal that is very “high end” and usually associated with mechanistic effects. A study this small and this incremental…well I’m very surprised that it was published there and I am wondering why. So it’s not that it’s a BAD study (I’m sorry, I was unclear), it’s that I’m surprised it was in PNAS. I’ll amend my post to include that.

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  4. 4. Sean McCann 2:16 pm 02/8/2012

    I agree. Usually PNAS is more high-end. I think though with psychedelic research there are strong pressures for incrementalism, as a strict consequence of regulatory difficulties.

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  5. 5. Sean McCann 9:38 pm 02/8/2012

    I apologize for the snarky comment. Thanks for your reply.

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  6. 6. donnawanna 9:52 pm 02/8/2012

    It would’ve been a huge study in the 60s had there been funding and MRIs.

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  7. 7. TigerWild 8:21 am 02/9/2012

    I would point out that the statistical projection for, “there was a negative correlation between the blood flow to these areas and the intensity of the subjective experience by the subjects”, refers to a sample that FAR and AWAY is not large enough to conclusively state what is conclusively stated.

    We as humans like to jump to conclusions and the math helps back this up leading to BAD or at least POOR science when small sample groups are used. I can easily see how a doubling of the sample size shown could rapidly invalidate the conclusion generated.

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  8. 8. Sean McCann 12:35 pm 02/9/2012

    The data are what the data are. Your imagination of what the parameter may or may not do in no way invalidates the result. You realize that, right?

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  9. 9. Sean McCann 12:43 pm 02/9/2012

    and just for fun, why don’t you submit a rebuttal to the paper to PNAS, with your argument “My hunch is the sample size is too low…The end”. I am sure they would be dumbstruck by your insight and rush to publish a retraction.

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  10. 10. thoughtsinchaos 4:13 am 05/3/2012

    It is true that the study does not investigate ‘mechanistic’ causation of psilocybin-induced functional anticorrelation directly. However, anatomical distribution, synaptic and intracellular effects of 5-HT2a agonism are fairly well-characterized in literature. The authors posit an overarching molecular->functional model for psilocybin mechanism of action in the discussion section.

    The authors show a strong correlation with 5-HT2a receptor availability to the anatomical regions that displayed the most hypoactivation. Furthermore, the authors cite a large body of literature characterizing 5-HT2a agonism resulting in pyramidal cell inhibition in cortical areas via excitation of GABAergic interneurons that synapse on pyramidal cells. There is not “no evidence” of this; these conclusions are reasonably extrapolated, your suggestions for further investigation are well beyond the scope of this study. I am not sure what you are trying to get at with “via what mechanism [blood flow decreases],” but increased blood deoxygenation levels is concretely correlated with neuronal action-potentions; inhibition of neurons results in less APs and thus less blood flow. BOLD contrasts are the basis of fMRI studies–all of them would be invalidated if this were refuted.

    Why is this article in PNAS? It finds that psilocybin impacts two of the most implicated cortical structures in psychiatric disorders. It finds that a compound with a very specific neurochemical mechanism of action results in profound changes in functional connectivity across large portions of the cortex. And, it does a beautiful job of utilizing existing literature on synaptic/cellular effects of 5-HT2a agonism to create a model to explain their findings.

    @TigerWild fMRI studies, especially in cognitive neuroscience, generally contain groups consisting only of around 15 subjects.

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  11. 11. thoughtsinchaos 4:23 am 05/3/2012

    Oh, the authors probably use the term “unconstrained cognition” since the structures that show the most hypoactivation are primary structures of the executive system, particularly in mediating attentional modulation of cognitive resources.

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