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Placebos And The Brain's Own Pot

Neuroskeptic iconNeuroskepticBy NeuroskepticOctober 15, 2011 6:23 PM


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According to a neat little new paper, the placebo effect relies on the brain's own marijuana-like chemicals, endocannabinoids.

Or rather, some kinds of placebo effects involve endocannabinoids. It turns out that "the placebo effect" is not one thing.


The authors, led by Fabrizio Benedetti, have previously shown that placebo "opioids" - i.e. when you expect to get a painkiller such as morphine, but actually it's just water - relieve pain via the brain's own opioid system (endorphins). Blocking endorphins with certain drugs blocks the power of placebo morphine.

But there are many painkillers that aren't opioids, leaving open the question of whether all placebo effects on pain are mediated by endorphins.

The new study claims that endocannabinoids are involved in non-opioid placebo analgesia. They used rimonabant, a weight loss drug that was pulled from the market shortly after it appeared, because it caused depression. Rimonabant worked by blocking CB1 receptors, which are the main target of the psychoactive chemicals in cannabis - and also key players in the endogenous cannabinoid system.

Here's the headline result:

The graph on the left shows the relationship between the pain relieving power of morphine, and the pain relief caused by placebo "morphine" given on a subsequent day. As you can see, there was a strong correlation. People who had a strong response to real morphine, later responded well to the fake morphine. But rimonabant had no effect at all.


Pain relief was measured using tolerance to the pain caused by a tightly fitting tourniquet.

However, rimonabant did have a strong effect on the placebo response to a different drug, ketorolac, which is related to the better-known ibuprofen (Nurofen). As you can see in the graph on the right, people given rimonabant had a much lower response to the placebo "ketorolac".

In other experiments, they showed that rimonabant alone had no effect on pain tolerance.

This is a nice result. It shows that the placebo effect is not a single thing, but that it depends upon the nature of the drug that you believe you've got. It also reminds us that the placebo effect is not some magical power of mind-over-matter, but is in fact, well, matter-over-matter.

Interestingly, ketorolac has no effect on endocannabinoids, or at least no direct effect. The mechanism of action, which is fairly well understood, has nothing to do with cannabinoids. Yet placebo "ketorolac" still seems to set endocannabinoids buzzing.


Benedetti F, Amanzio M, Rosato R, & Blanchard C (2011). Nonopioid placebo analgesia is mediated by CB1 cannabinoid receptors. Nature medicine, 17 (10), 1228-30 PMID: 21963514

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