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:

• 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.)
• 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.
• 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.”

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.
• Researchers had known opioids were involved in pain tolerance, but these studies were amongst the first to show they can be involved in the brain’s placebo response to pain.

Pot and Pain:

• Although naloxone blocks opiates like morphine, it has little to no effect upon less potent—but more widely used—drugs like non-steroidal anti-inflammatory drugs including ibuprofen. Given recent evidence that NSAIDs interact with cannabinoids and that their receptors are involved in pain tolerance, researcher Fabrizio Benedetti decided to go a step further and see if cannabinoid receptors are involved in the placebo response to pain. (Spoiler alert: they are.)
• To test this proposition, Benedetti performed experiments very similar to those previously described. But instead of using naloxone to block opiods, he used a drug called rimonabant to block endogenous cannabinoids. (Rimonabant binds the cannabinoid receptors (CB1), boxing out the cannabinoids.)
• Benedetti first established average pain tolerance in unmedicated study participants. By giving a second group solely rimonabant, he ensured the drug had no impact on pain tolerance by itself.
• As before with morphine, patients in one group (“group 5″) were given an NSAID called ketorolac for two trials. One the third occasion they were given a placebo labelled a “strong painkiller”; their tolerance was much higher than normal. The placebo effect!
• The same was done to people in “group 6.” But on the third treatment, besides being given the painkiller placebo, they were also given rimonabant. And voila! Their pain tolerance was back to normal, on par with the tolerance of people not given any drug or placebo treatment.
• By binding to CB1, rimonabant must have blocked the action of the brain’s own cannabinoids, which the brain apparently is able to produce in order  to effectively combat pain in this instance.

So What:

Reference: Fabrizio Benedetti, Martina Amanzio, Rosalba Rosato, Catherine Blanchard. Nonopioid placebo analgesia is mediated by CB1 cannabinoid receptors. Nature Medicine (2011). Published online 02 October 2011. DOI: 10.1038/nm.2435

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