Worlds fastest fMRI trip

There is no such thing as pure pleasure; some anxiety always goes with it ~ Publius (Ovid)ius Naso (43 BC – AD 17)

The neuroscience writer Mo Costandi recently asked me for a comment on an article he was writing about the fMRI psilocybin (Magic Mushroom) study by Carhart-Harris and colleagues (2012). Naturally, this research generated a great deal of press attention - mostly concerning psilocybin as a potential treatment for depression - even though no data were presented on that topic.

Anyway, what did Carhart-Harris et al do in their pioneering study? Using fMRI (Arterial Spin Labelling [ASL] and BOLD) they compared brain activity in 15 individuals following a placebo (10-mL saline) and after psilocybin (2 mg in 10-mL saline). And they reported:

"...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."

Fig 1. Significant deactivation of mPFC and PCC following psilocybin

  

Looking at the pattern of results, I raised the possibility of anxiety being a confound for this profile of brain deactivation. The pattern of reduced mPFC, PCC activity has strong parallels with patterns seen in clinically anxious individuals and healthy individuals under threat. For example, Zhao et al (2007) examined the responses of clinically anxious and healthy individuals when listening to threat-related words (alternating with emotionally neutral words). Clinically anxious individuals showed mPFC, PCC deactivation and the healthy control group even more so.

Fig 2. Zhao et al: significant deactivation of MPFC & PCC

Anticipatory anxiety is also a potential confound here as the psilocybin scan always occurred after the placebo control scan - so, participants could predict that the second scan would be the trip. Several imaging studies of normal healthy individuals experiencing transient anticipatory anxiety have also reported similar deactivations to those reported by Carhart-Harris and colleagues. For example, Simpson et al (2001) found that normal subjects anticipating uncertain pain intensity (finger shock) display decreased mPFC blood flow.

Does psilocybin study itself provide information about participant anxiety? Some data appear not in the paper itself, but in the supplementary materials, where two relevant questions are posed:

• I feared losing control of my mind increased from 3.3 to 18.0% (ASL) & 3.1 to 14.6 % (BOLD)
• I felt afraid increased from 5.8 to 13.7% (ASL) & from 6.5 to 20.4% (BOLD)

So, psilocybin increased ratings for fear of losing mind by 4-5 times; and for I felt afraid doubled or nearly tripled in percentage terms.

Lack of a significant effect does not equal lack of an effect that is significant - Ratings for I felt afraid failed to reach significance - unfortunately sufficient information is not available to derive effect sizes and therefore any issue of power (given the small sample size n=15). Nevertheless in the earlier mock fMRI psilocybin study of Carhart-Harris et al (2011), they did report enough anxiety details to derive Cohen's d, which was greater than 1 - a large effect - again non-significant only because of the low power of the study (n=9).

Fig 3. Subjective intensity ratings (10=extremely intense effect) maximising in <60 secs

The world's fastest trip in a scanner? The psilocybin was administered intravenously, with a very rapid onset (see Fig 3). As the authors themselves remarked, finding deactivation was surprising -especially as others report increased activation following the oral ingestion of psilocybin (see Vollenweider & Kometer 2010), which is much slower acting (and was scanned one-hour later). Although Carhart-Harris et als participants had previously tripped (which is an issue itself, but left aside here), their history would not prepare them for zero to tripping in seconds!

An intravenously administered dose of psilocybin, an anticipated trip that maximises in seconds and left alone in an fMRI scanner ~ anxiety-provoking? It seems quite likely that people experienced anticipatory anxiety and anxiety during the scan itself. And most importantly, both types of anxiety are associated with the functional imaging profile documented by Carhart-Harris et al. Nobody denies the effect of psilocybin on the brain, the how much is 'trip' and how much is 'trip anxiety'.

References

A video of Carhart-Harris talking about the work

Carhart-Harris RL, Williams TM, Sessa B, Tyacke RJ, Rich AS, Feilding A, Nutt DJ (2012) Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin. Proc Natl Acad Sci. 109:2138-2143


Carhart-Harris RL; Williams TM; Sessa B; Tyacke RJ; Rich AS; Feilding A; Nutt DJ. (2011). The administration of psilocybin to healthy, hallucinogen-experienced volunteers in a mock-functional magnetic resonance imaging environment: a preliminary investigation of tolerability. J Psychopharmacol. 25:1562-1567

Simpson JR Jr, Drevets WC, Snyder AZ, Gusnard DA, Raichle ME (2001): Emotion-induced changes in human medial prefrontal cortex: II. During anticipatory anxiety. Proc Natl Acad Sci 98:688–693.


Vollenweider FX and Kometer M (2010) The neurobiology of psychedelic drugs: implications for the treatment of mood disorders. Nat Rev Neurosci 11: 642–651Nat Rev Neurosci 11: 642–651

Zhao, X.H., Wang, P.J., Li, C.B., Hu, Z.-H., Xi, Q., Wu,W.-Y., Tang, X.-W., (2007). Altered default mode network activity in patients with anxiety disorders: an fMRI study. Eur. J. Radiol. 63, 373–378.