Placebos are inactive treatments that shouldn't, in some sense, have a real effect. And yet they often do. But the chemical basis of the placebo effect, despite its enormous importance, is still largely a mystery. A study published this week in Nature Medicine shows that cannabinoid receptors are involved in the placebo response to pain, which hasn't been demonstrated before. The finding implies that the brain's own endocannabinoids can fight pain, and actually do it via the same pathway as several compounds in the cannabis plant. What's the Context:

Much of what we know about placebo chemistry comes from studies of pain. Pain tolerance, in contrast to more slippery traits like anxiety, can be relatively easily quantified---i.e., the length of time someone can withstand a painful sensation (which doesn't cause lasting damage). The current study employed a tourniquet that painfully tightens around the arm like the cuff of a blood-pressure monitor until participants said it was "unbearable."

The placebo effect has a impressive ability to confound expectations. For example, in a 1999 study researchers gave participants an inert substance but said it was a stimulant. The patients became stimulated and tense. Stranger still, they gave people a muscle relaxant, also calling it a stimulant. The patients still tensed up.

For most drugs and treatments to be approved today, they must be favorably compared to ineffective placebos to prove that the therapeutics actually work. (This comparison is not simple, and whether certain drugs—like many antidepressants—are actually better than placebos is a matter of considerable debate .)

Painful Lessons:

Several previous studies (in 1999 and 2007) found that if you give somebody morphine only twice, and then the third time give them a placebo that they think is as strong pain-killer, their pain tolerance will shoot up almost as high as it was on the drug; this is the placebo effect in action. Let's call this group A.

Another control group was given morphine on three consecutive occasions, but the third time they were also knowingly given naloxone, a drug that blocks opiates like morphine and heroin from binding to opioid receptors in the brain and exerting an effect (for this reason naloxone can be used to treat heroin overdoses). As you might expect, naloxone prevented morphine from doing its thing and also squelched the placebo effect, as subjects expected the morphine not to work. Pain tolerance amongst these people was the same as that in the unmedicated control group.

This is where it gets weird. Researchers then treated another group of people (let's call them group C) just as they did those in group A, except for one important difference: on the third treatment, with placebo, people were also unknowingly administered naloxone. Unlike group A, the placebo effect on pain tolerance vanished: people did not have a significantly increased pain tolerance.

These results suggest that after being "conditioned" with an opiate drug like morphine, people were capable of producing their own natural opiate-like chemicals that bind to some of the same receptors as morphine. These are called the brain's endogenous opioids, a class that includes well-known natural painkillers like endorphins, which are released for example during exercise.