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The Journal of Neuroscience, March 5, 2008, 28(10):2313-2319; doi:10.1523/JNEUROSCI.5603-07.2008

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Behavioral/Systems/Cognitive
Cannabinoid Modulation of Amygdala Reactivity to Social Signals of Threat in Humans

K. Luan Phan,¹ Mike Angstadt,¹ Jamie Golden,² Ikechukwu Onyewuenyi,³ Ana Popovska,⁴ and Harriet de Wit²

¹Department of Psychiatry, University of Michigan and Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, Michigan 48109, ²Human Behavioral Pharmacology Laboratory, Department of Psychiatry, University of Chicago, Chicago, Illinois 60637, ³Howard University, Washington, DC 20059, and ⁴Amherst College, Amherst, Massachusetts 01002

Correspondence should be addressed to Dr. K. Luan Phan, Department of Psychiatry, University of Michigan, Rachel Upjohn Building, 4250 Plymouth Road, Box 5765, Ann Arbor, MI 48109. Email: luan{at}umich.edu

The cannabinoid (CB) system is a key neurochemical mediator of anxiety and fear learning in both animals and humans. The anxiolytic effects of ⁹-tetrahydrocannabinol (THC), the primary psychoactive ingredient in cannabis, are believed to be mediated through direct and selective agonism of CB₁ receptors localized within the basolateral amygdala, a critical brain region for threat perception. However, little is known about the effects of THC on amygdala reactivity in humans. We used functional magnetic resonance imaging and a well validated task to probe amygdala responses to threat signals in 16 healthy, recreational cannabis users after a double-blind crossover administration of THC or placebo. We found that THC significantly reduced amygdala reactivity to social signals of threat but did not affect activity in primary visual and motor cortex. The current findings fit well with the notion that THC and other cannabinoids may have an anxiolytic role in central mechanisms of fear behaviors and provide a rationale for exploring novel therapeutic strategies that target the cannabinoid system for disorders of anxiety and social fear.

Key words: THC; cannabinoid; fMRI; amygdala; fear; anxiety

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Received Sept. 25, 2007; revised Jan. 21, 2008; accepted Jan. 21, 2008.

Correspondence should be addressed to Dr. K. Luan Phan, Department of Psychiatry, University of Michigan, Rachel Upjohn Building, 4250 Plymouth Road, Box 5765, Ann Arbor, MI 48109. Email: luan{at}umich.edu

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