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:
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
9 comments:
I think you're under a mis-perception here. Now, I've only read the abstract but if this paper is anything like the other papers by Benedetti then he conditioned participants with either opiod drugs or ketrolac on trial one, and then administered the antagonist on trial 2.
These kinds of placebo effects are mediated by conditioning (which then influences expectancies) and as such, its not what the participants believe about the drug they got that has the substantial impact (you could tell them it was fairy dust, and conditioning would have the same effect) its the fact that their body has learned to associate a particular stimulus in a particular setting with pain relief.
Disgruntled PhD : You're right, that's how the experiment works. You get the real drug first, then the placebo (and rimonabant, or not).
I'm not sure that it's conditioning though. I know that is one explanation, but conditioning generally requires multiple exposures and in this case, there were only 2 real drug exposures and then the 3rd was placebo.
You're right of course that you could tell people it was fairy dust, but what I mean is that people expect to get what they got last time.
If they think morphine is "fairy dust", then they still expect to get morphine.
i dunno, the literature on placebo conditioning indicates that it normally only takes one time. It may be due to the influence of expectation only. Did they reduce the pain in phase 2 along with the drug? If so, that would probably explain the one trial learning.
Its pretty tricky to disentangle the effects of conditioning and expectation in this kind of situation though.
Incidentally, thanks for pointing me towards this paper, its very interesting and useful to me.
I don't exactly study the placebo effect, so I'm not too clear on this, but wouldn't one expect that all placebo effects are due to conditioning?
Based upon the previous morphine study, one would assume that rimonabant attenuates ketorolac-induced analgesia. Did they not test this directly? This seems to be pretty important to me because if CB1 receptors are not involved in the ketorolac-mediated effect, then it suggests that they might mediate a diverse set of placebo effects. This seems like an inference that they should have attempted to falsify.
Given that we have no idea how ibuprofen acts on pain (even see the mechanism part of the wiki you linked), then we don't know if its effects are mediated by CB1 or not. You might want to edit that statement ("relatively well understood") because it's not at all true. We have no idea how that or even Tylenol work on pain. Cannabinoids are thus still a possibility.
Anonymous: True, we don't know exactly how it works on pain, but what we do know (prostaglandins etc.) is not cannabinoid related. Granted that's not a complete understanding but the point is, it's not like morphine & naloxone, where it's obvious that naloxone would block morphine.
endocannabinoid is a long word.
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.
CB1 is a retrograde inhibitory neurotransmisson process. Depression is often associated with "racing brain". Loss of CB1 regulation may increase neuronal excitability?
Vaguely now but I think you'll find that THC has a downstream effect on opoids. I imagine the true may be true for any CB 1 agonist.
This is so interesting.
I wonder if the inverse might also be true, than ingesting cannabis + placebo would increase the placebo effect.
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