We tend to think of physical pain and emotional pain as separate entities – you don’t take aspirin for a bad break-up or eat chocolate ice cream for a headache. But research throughout the last decade suggests that physical and emotional pain may actually be strongly related. Depression, anxiety, and post-traumatic stress disorder have all been associated with increased risk of serious illnesses, but also with everyday pain such as back pain and headaches.

Even more surprising is the fact that some over the counter pain relievers seem to influence complex mental processes. Products containing acetaminophen (marketed as Tylenol in the United States and Panadol in Australia and the United Kingdom) have been shown to affect social behavior in both mice and humans.

Mice injected with 100 mg/kg* of acetaminophen spent more time interacting with other mice and showed increased preference for social novelty (Gould, et al., 2012). A similar effect was found in humans. Individuals who took acetaminophen for 3 weeks self-reported fewer feelings of social pain and rejection compared to those who took placebos (DeWall, et al., 2010). Functional magnetic resonance imaging (fMRI) data were in agreement with the behavioral findings. FMRI is a technique that measures oxygenated blood flow to different areas of the brain while participants experience stimuli or perform a mental task. Because active neurons require more energy in the form of glucose which is carried by the blood, blood flow is taken as an indicator of neural activity. In this case, fMRI data showed that participants taking Tylenol had less blood flow to brain areas traditionally associated with social pain such as the dorsal anterior cingulate cortex and anterior insula (DeWall, et al., 2010).

The mechanism through which acetaminophen affects social behavior has not yet been elucidated. However, researchers have hypothesized that it may act through endogenous cannabinoid receptors** to decrease anxiety. In the body, acetominophen is broken down into a compound called AM404. AM404 has been shown to decrease uptake of anandamide by neurons, resulting in greater amounts of free anandamide in the brain. Thus, there is more anandamide available to bind to receptors at the synapse. The chemical anandamide may reduce feelings of anxiety by acting on the cannabinoid receptor CB1. Data seems to support this hypothesis – both acetaminophen and anandamide decreased anxiety in mice. Furthermore, blocking the CB1 receptor before administering acetaminophen or anandamide prevented these drugs from having an anxiety reducing effect (Umathe, et al, 2009). Thus, it seems that these drugs reduce anxiety by binding to the CB1 receptor.

Although it seems likely that decreased anxiety may promote social interaction and decrease the amount that a person dwells on perceived social rejections, research specifically examining acetaminophen’s effects on social behavior through cannabinoid receptors remains to be done.

*For reference, two tablets of extra strength Tylenol contains 1000mg of acetaminophen, which for an average American male is only about 11 mg/kg. Do not take a larger dose of acetaminophen than recommended – overdose is one of the most common causes of liver failure in the United States.

**Although cannabinoids are perhaps best known for their association with marijuana (cannabis), there are many naturally occurring (endogenous) cannabinoids used as signaling molecules within the brain. The endocannabinoid system has been implicated in pain processing, reward, and anxiety, and may be useful in developing novel treatments for various neurodegenerative diseases (Pertwee 2012).

References

DeWall, C. C., MacDonald, G., Webster, G. D., Masten, C. L., Baumeister, R. F., Powell, C., & … Eisenberger, N. I. (2010). Acetaminophen reduces social pain: Behavioral and neural evidence. Psychological Science, 21(7), 931-937.

Gould, G. G., Seillier, A., Weiss, G., Giuffrida, A., Burke, T. F., Hensler, J. G., & … Schultz, S. T. (2012). Acetaminophen differentially enhances social behavior and cortical cannabinoid levels in inbred mice. Progress In Neuro-Psychopharmacology & Biological Psychiatry, 38(2), 260-269.

Pertwee, R.G. (2012). Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities. Philosophical Transactions of the Royal Society, Biological Sciences, 367(1607), 3353-3363.

Umathe, S. N., Manna, S. S., Utturwar, K. S., & Jain, N. S. (2009). Endocannabinoids mediate anxiolytic-like effect of acetaminophen via CB1 receptors. Progress In Neuro-Psychopharmacology & Biological Psychiatry, 33(7), 1191-1199.