Research Article

Evidence for involvement of the insula in the psychotropic effects of THC in humans: a double-blind, randomized pharmacological MRI study

Hendrika H. van Hell^a1, Matthijs G. Bossong^a1, Gerry Jager^a1a2, Gert Kristo^a1a3, Matthias J. P. van Osch^a4, Fernando Zelaya^a5, René S. Kahn^a6 and Nick F. Ramsey^a1 c1

^a1 Rudolf Magnus Institute of Neuroscience, Department of Neurology and Neurosurgery, University Medical Center Utrecht, Utrecht, The Netherlands

^a2 Division of Human Nutrition, Wageningen University, The Netherlands

^a3 Department of Medical Psychology, University of Tilburg, The Netherlands

^a4 Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands

^a5 Institute of Psychiatry, King's College London, UK

^a6 Rudolf Magnus Institute of Neuroscience, Department of Psychiatry, University Medical Center Utrecht, Utrecht, The Netherlands

Abstract

The main reason for recreational use of cannabis is the ‘high’, the primary psychotropic effect of Δ⁹-tetrahydrocannabinol (THC). This psychoactive compound of cannabis induces a range of subjective, physical and mental reactions. The effect on heart rate is pronounced and complicates bloodflow-based neuroimaging of psychotropic effects of THC. In this study we investigated the effects of THC on baseline brain perfusion and activity in association with the induction of ‘feeling high’. Twenty-three subjects participated in a pharmacological MRI study, where we applied arterial spin labelling (ASL) to measure perfusion, and resting-state functional MRI to assess blood oxygen level-dependent signal fluctuation as a measure of baseline brain activity. Feeling high was assessed with a visual analogue scale and was compared to the imaging measures. THC increased perfusion in the anterior cingulate cortex, superior frontal cortex, and insula, and reduced perfusion in the post-central and occipital gyrus. Baseline brain activity was altered, indicated by increased amplitude of fluctuations in resting-state functional MRI signal after THC administration in the insula, substantia nigra and cerebellum. Perfusion changes in frontal cortex were negatively correlated with ratings of feeling high, suggesting an interaction between cognitive control and subjective effects of THC. In conclusion, an acute THC challenge altered baseline brain perfusion and activity, especially in frontal brain areas involved in cognitive and emotional processes, and the insula, associated with interoceptive awareness. These changes may represent the THC-induced neurophysiological correlates of feeling high. The alterations in baseline brain perfusion and activity also have relevance for studies on task-related effects of THC on brain function.

(Received October 04 2010)

(Reviewed December 13 2010)

(Revised March 08 2011)

(Accepted March 09 2011)

(Online publication April 14 2011)

Key Words:

• Arterial spin labelling;
• fMRI;
• perfusion;
• resting-state;
• THC

Correspondence:

^c1 Address for correspondence: Prof. Dr. N. F. Ramsey, Department of Neurology and Neurosurgery, Rudolf Magnus Institute for Neuroscience, University Medical Center Utrecht, Heidelberglaan 100, mail stop G.03.124, 3584 CX Utrecht, The Netherlands. Tel.: +31-(0)8875556863 Fax: +31-(0)302542100 Email: n.f.ramsey@umcutrecht.nl