In clinical trials, new drugs are often compared to older treatments, but sometimes they're also compared to placebos—inert treatments that ought to have no effect. Except that's not what happens. The placebo effect can actually be pretty strong, and even more strangely, placebos can work even when the patient knows they're being given one.

Most of what we know about placebos results from studies on how we process pain, since it's more ethical to give someone a placebo instead of a painkiller than it would be to replace an anti-cancer drug or insulin. Some of the analgesic (painkilling) effect of placebo treatment is due to endogenous opioids, ones made by the body. Now, evidence has emerged that suggests an additional effect results from the cannabinoid pathway, according to a publication in Nature Medicine.

Placebo-activated opioid analgesia doesn't work all the time. Experimentally, researchers can induce it by preconditioning a research subject with an actual opioid analgesic. Or, to explain that in plain English, you give the subject a painful stimulus then give them an opioid to treat it. You do this several times then, instead of giving them a real drug, you give them a placebo, which will block the pain. What's more, you can actually inhibit the action of the placebo by giving the subject an opioid antagonist like naloxone, which blocks the effect of opioids. Still with me? Good.

Here's where things get more complicated. You can also use a nonsteroidal anti-inflammatory (NSAID), like ibuprofen, to create a placebo analgesic effect. But this time, it can't be blocked with naloxone. So there's more than one biochemical pathway responsible for the analgesic effects of sugar pills. The new paper involves an attempt to look for alternate pathways.

The Nature Medicine study involved several test groups, and measured their pain response to a tourniquet on five non-consecutive days. The first group receive no treatment at all during the study, and they showed no variation in pain threshold across its duration. A second group was given morphine on days 2 and 3, and a placebo on day 4, which had the same analgesic effect as morphine. The normal placebo effect worked.

A third group were given, without their knowledge (beyond general informed consent) a drug called rimbonant (marketed as Accomplia and also know as SR141716A). Rimbonant largely works by blocking a receptor called CB1. CB1 is activated in the body by a molecule called anandamide, and it's also the same receptor that cannabinoids activate. Rimbonant didn't have any effect on pain tolerance in this group, which had very similar responses to the subjects who received no drugs at all in the study. From this we can infer that blocking cannabinoid signaling through CB1 has no effect on the type of pain being measured.

Another group got the morphine treatment described above, but also got rimbonant with the placebo. Again, in this group, rimbonant had no effect, meaning that the opioid placebo effect isn't working through the body's cannabinoid pathway.

Finally, there were two more groups that were given ketorolac—an NSAID—instead of morphine on days 2 and 3. One of these groups was given a placebo on day 4, which worked just as well as ketorolac.

The other group got a placebo plus rimbonant. Normally, the placebo would block the pain but, in this case the rimbonant+placebo had no effect. This indicates that rimbonant blocked the placebo effect. This suggests that cannabinoids are playing an important role in nonopioid preconditioned placebo effects.

I should mention that this was only a fairly small study, and more work needs to be done in the area to fully flesh out this idea. Rimbonant can also have effects that are not all mediated through CB1 receptors, as I found out during the course of my Ph.D. But it is a neat little study, and one that expands our understanding of the pharmacology of placebos, to the degree such a thing is possible.

Nature Medicine, 2011. doi: 10.1038/nm.2435