Anxiety Reduction: Exploring the Role of Cannabinoid Receptors
Posted on by Dr. Francis Collins
Relief of anxiety and stress is one of the most common reasons that people give for using marijuana . But the scientific evidence is rather sparse about whether there’s a biological explanation for that effect.
More than a decade ago, researchers set out to explore the link between marijuana and anxiety reduction, but the results of their experiments were inconclusive . Recently, a team led by NIH-funded researchers at Vanderbilt University Medical Center in Nashville decided to tackle the question again, this time using more sensitive tools that have just become available in recent years.
In humans, mice, and other mammals, the body makes natural chemicals, called endocannabinoids, that interact with certain proteins, called type 1 cannabinoid receptors (CB1), that are located on the surface of nerve cells. We know that the endocannabinoid system is critical for normal brain development and activity, immunity, and the physiological regulation of stress responses. We also know that CB1 receptors interact with the primary cannabinoid in marijuana, a mind-altering chemical known as delta-9-tetrahydrocannabinol (THC).
To investigate whether there’s a biological basis for the anxiety-relieving effects associated with marijuana use, the Vanderbilt-led team decided to conduct a mouse study to search for CB1 receptors in the central amygdala—a region of the brain that, among other things, controls anxiety and response to stress. And, in a paper published in the journal Neuron, the researchers reported they did indeed detect CB1 receptors in the central amygdala of the mouse brain.
In addition, the researchers found that when endocannabinoids interacted with CB1 receptors of neurons located in the central amygdala, the natural chemicals reduced the excitability of these brain cells. This suggests that THC and/or other external cannabinoids found in marijuana may also serve to reduce anxiety by binding to CB1 receptors in the amygdala, rendering neurons less active . However, this hypothesis must be confirmed by further studies.
Last year, also in a mouse study, these same researchers showed that if they inhibited an enzyme called cyclooxygenase-2 (COX-2), which deactivates natural endocannabinoids, the levels of these chemicals remain higher in the brain and reduce anxious behaviors in the animals . These findings have prompted the researchers to investigate whether a new class of COX-2 inhibiting drugs might provide an alternative to marijuana-based cannabinoids for anxiety relief.
Such alternatives may be especially valuable when it comes to protecting developing human brains from the adverse effects of marijuana. We all know that the teenage years can be filled with anxiety, and, perhaps in an effort to ease such anxiety, 6.5% of high school seniors report using marijuana regularly . However, frequent or heavy marijuana use among adolescents should be a cause of major concern. High doses of marijuana can have exactly the opposite effect, resulting in panic attacks and paranoia. Perhaps of greatest concern, scientific studies have shown that regular use in adolescents can be associated with addiction as well as altered brain development and permanently lowered IQ, not to mention a variety of other health problems [6, 7].
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 Distribution of CB1 cannabinoid receptors in the amygdala and their role in the control of GABAergic transmission. Katona I, Rancz EA, Acsady L, Ledent C, Mackie K, Hajos N, Freund TF. J Neurosci. 2001 Dec 1;21(23):9506-18.
 Multiple mechanistically distinct modes of endocannabinoid mobilization at central amygdala glutamatergic synapses. Ramikie TS, Nyilas R, Bluett RJ, Gamble-George JC, Hartley ND, Mackie K, Watanabe M, Katona I, Patel S. Neuron. 2014 Mar 5;81(5):1111-25.
 Substrate-selective COX-2 inhibition decreases anxiety via endocannabinoid activation. Hermanson DJ, Hartley ND, Gamble-George J, Brown N, Shonesy BC, Kingsley PJ, Colbran RJ, Reese J, Marnett LJ, Patel S. Nat Neurosci. 2013 Sep;16(9):1291-8.
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 Adverse health effects of non-medical cannabis use. Hall W, Degenhardt L. Lancet. 2009 Oct 17;374(9698):1383-91.
 The association between earlier marijuana use and subsequent academic achievement and health problems: a longitudinal study. Brook JS, Stimmel MA, Zhang C, Brook DW. Am J Addict. 2008 Mar-Apr;17(2):155-60.
Patel Lab, Vanderbilt University Medical Center, Nashville, TN
NIH support: National Institute on Drug Abuse; National Institute of Mental Health