Mechanism of the effect

Because the placebo response is simply the patient response that cannot be attributed to an investigational intervention, there are multiple possible components of a measured placebo effect. These components have varying relevance depending on study design and the types of observations. [ 24 ] While there is some evidence that placebo interventions can alter levels of hormones. [ 25 ] endocannabinoids [ 26 ] or endogenous opioids. [ 27 ] other prominent components include expectancy effects. regression to the mean. [ 20 ] [ 28 ] and flawed research methodologies.

Expectancy and conditioning

The placebo effect is related to expectations

The placebo effect is related to the perceptions and expectations of the patient; if the substance is viewed as helpful, it can heal, but, if it is viewed as harmful, it can cause negative effects, which is known as the nocebo effect. In 1985, Irving Kirsch hypothesized that placebo effects are produced by the self-fulfilling effects of response expectancies, in which the belief that one will feel different leads a person to actually feel different. [ 29 ] According to this theory, the belief that one has received an active treatment can produce the subjective changes thought to be produced by the real treatment. Placebos can act similarly through classical conditioning. wherein a placebo and an actual stimulus are used simultaneously until the placebo is associated with the effect from the actual stimulus. [ 30 ] Both conditioning and expectations play a role in placebo effect, [ 31 ] and make different kinds of contribution. Conditioning has a longer-lasting effect, [ 32 ] and can affect earlier stages of information processing. [ 33 ] Those that think that a treatment will work display a stronger placebo effect than those that do not, as evidenced by a study of acupuncture. [ 34 ] [ 35 ]

A placebo presented as a stimulant will have this effect on heart rhythm. and blood pressure. but, when administered as a depressant. the opposite effect. [ 36 ] Perceived ergogenic aids can increase endurance, [ 37 ] speed [ 38 ] and weight-lifting ability, [ 39 ] leading to the question of whether placebos should be allowed in sport competition. [ 40 ]

Because placebos are dependent upon perception and expectation, various factors that change the perception can increase the magnitude of the placebo response. For example, studies have found that the color and size of the placebo pill makes a difference, with "hot-colored" pills working better as stimulants while "cool-colored" pills work better as depressants. Capsules rather than tablets seem to be more effective, and size can make a difference. [ 41 ] One researcher has found that big pills increase the effect [ 42 ] while another has argued that the effect is dependent upon cultural background. [ 43 ]

Motivation may contribute to the placebo effect. The active goals of an individual changes his/her somatic experience by altering the detection and interpretation of expectation-congruent symptoms, and by changing the behavioral strategies a person pursues. [ 44 ] [ 45 ] Motivation may link to the meaning through which people experience illness and treatment. Such meaning is derived from the culture in which they live and which informs them about the nature of illness and how it responds to treatment. Research into the placebo treatment of gastric and duodenal ulcers shows that this varies widely with society. [ 18 ] The placebo effect in treating gastric ulcers is low in Brazil, higher in northern Europe (Denmark, Netherlands), and extremely high in Germany. However, the placebo effect in treating hypertension is lower in Germany than elsewhere. [ 46 ]

Placebo effect and the brain

The higher brain works by regulating subcortical processes. High placebo responses link with enhanced dopamine and mu-opioid activity in the circuitry for reward responses and motivated behavior of the nucleus accumbens, and, on the converse, anti-analgesic nocebos responses were associated with deactivation in this part of the brain of dopamine and opioid release. [ 48 ] (It has been known that placebo analgesia depends upon the release in the brain of endogenous opioids since 1978. [ 54 ] ) Such analgesic placebos activation changes processing lower down in the brain by enhancing the descending inhibition through the periaqueductal gray [ 48 ] on spinal nociceptive reflexes. while the expectations of anti-analgesic nocebos acts in the opposite way to block this. [ 50 ]

The brain is also involved in less-studied ways upon nonanalgesic placebo effects:

Parkinson's disease. Placebo relief is associated with the release of dopamine in the brain. [ 55 ] Depression. Placebos reducing depression affect many of the same areas that are activated by antidepressants with the addition of the prefrontal cortex [ 56 ] [ 57 ] Caffeine. Placebo-caffeinated coffee causes an increase in bilateral dopamine release in the thalamus. [ 58 ] Glucose. The expectation of an intravenous injection of glucose increases the release of dopamine in the basal ganglia of men (but not women). [ 59 ] Methylphenidate. The expectation of intravenous injection of this drug in inexperienced drug users increased the release of dopamine in the ventral cingulate gyrus and nucleus accumbens, with this effect being largest in those with no prior experience of the drug. [ 60 ]

Functional imaging upon placebo analgesia has been summarized as showing that the placebo response is "mediated by "top-down" processes dependent on frontal cortical areas that generate and maintain cognitive expectancies. Dopaminergic reward pathways may underlie these expectancies". [ 61 ] "Diseases lacking major 'top-down' or cortically based regulation may be less prone to placebo-related improvement". [ 62 ]

Brain and body

The brain has control over the body processes affected by placebos.

In conditioning, a neutral stimulus saccharin is paired in a drink with an agent that produces an unconditioned response. For example, that agent might be cyclophosphamide. which causes immunosuppression. After learning this pairing, the taste of saccharin by itself is able to cause immunosuppression, as a new conditioned response via neural top-down control. [ 63 ] Such conditioning has been found to affect a diverse variety of not just basic physiological processes in the immune system but ones such as serum iron levels. oxidative DNA damage levels, and insulin secretion. Recent reviews have argued that the placebo effect is due to top-down control by the brain for immunity [ 64 ] and pain. [ 65 ] Pacheco-López and colleagues have raised the possibility of "neocortical-sympathetic-immune axis providing neuroanatomical substrates that might explain the link between placebo/conditioned and placebo/expectation responses." [ 64 ] :441

A recent fMRI study has shown that a placebo can reduce pain-related neural activity in the spinal cord, indicating that placebo effects can extend beyond the brain. [ 66 ]

Dopaminergic pathways have been implicated in the placebo response in pain and depression. [ 67 ]

Evolved health regulation

Evolutionary medicine identifies many symptoms such as fever. pain. and sickness behavior as evolved responses to protect or enhance the recovery from infection and injury. Fever. for example, is an evolved self-treatment that removes bacteria or viruses through raised body temperature. These evolved responses, however, also have a cost that depending upon circumstances can outweigh their benefit (due to this, for example, there is a reduction in fever during malnutrition or late pregnancy ). According to the health management system theory proposed by Nicholas Humphrey. the brain has been selected to ensure that evolved responses are deployed only when the cost benefit is biologically advantageous. To do this, the brain factors in a variety of information sources, including the likelihood derived from beliefs that the body will get well without deploying its costly evolved responses. One such source of information is the knowledge the body is receiving care and treatment. The placebo effect in this perspective arises when false information about medications misleads the health management system about the likelihood of getting well so that it selects not to deploy an evolved self-treatment. [ 68 ]