The endocannabinoid system and the placebo effect: Molecular mechanisms of placebo responses in humans
Pain and the placebo effect
“The placebo effect” has become somewhat of a buzz word in modern pain management, but what systems actually regulate this effect, and can they be utilized to decrease the need for drugs in a clinical setting?
This paper reviews the neurobiological underpinnings of placebo analgesia - pain reduction resulting from a placebo - and explores how this might lead to individual differences in the placebo response.
Historically, the endogenous opioid system has been implicated in the placebo effect, but other systems contribute to placebo analgesia as well. For example, the opioid receptor antagonist naloxone blocks placebo analgesia, particularly when people are preconditioned to believe that morphine will reduce their pain.
However, naloxone only partially blocks placebo analgesia in people who are preconditioned to think that a non-opioid drug will reduce their pain. Therefore, both opioid and non-opioid mechanisms may be responsible for the placebo effect.
The implication of the endocannabinoid system
The endocannabinoid system (ECS) is also implicated in placebo analgesia. The cannabinoid type 1 receptor antagonist rimonabant blocks non-opioid placebo analgesia, but not opioid placebo analgesia when subjects are preconditioned with morphine.
Interestingly, people with a mutation knocking out the FAAH enzyme that breaks down cannabinoids in the body (meaning that they have higher baseline ECS activity) have lower placebo responses and a more negative affective state compared to people with functional FAAH enzymes. Neuroimaging data from placebo administration in FAAH-deficient people show that they have hyperactive ECS, but lower activation in the opioid systems, leading to a depressed placebo response.
Other factors also impact how individuals might respond differently to a placebo
Traits related to stress resilience change our susceptibility to a placebo effect. Ego-resiliency and altruism were positive predictors of placebo analgesia, and anger and hostility were negative predictors to name a few.
Variations in the internal opioid or endocannabinoid systems could underlie differences in the placebo response, making this a critical area of study not just for pain management, but also for disorders associated with these systems.
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