Editing Placebo (section)

==Mechanisms==
The mechanism for how placebos could have effects is uncertain. From a sociocognitive perspective, intentional placebo response is attributed to the “ritual effect” that induces anticipation for transition to a better state.<ref>{{Citation |last1=Goli |first1=Farzad |title=The Ritual Effect: The Healing Response to Forms and Performs |date=2016 |url=http://dx.doi.org/10.1007/978-3-319-35092-9_5 |work=Biosemiotic Medicine |pages=117–132 |access-date= |place=Cham |publisher=Springer International Publishing |isbn=978-3-319-35091-2 |last2=Farzanegan |first2=Mahboubeh|series=Studies in Neuroscience, Consciousness and Spirituality |volume=5 |doi=10.1007/978-3-319-35092-9_5 }}</ref> A placebo presented as a [[stimulant]] may trigger an effect on [[heart rhythm]] and [[blood pressure]], but when administered as a [[depressant]], the opposite effect.<ref>{{cite book | vauthors = Kirsch I |year=1997 |chapter=Specifying non-specifics: Psychological mechanism of the placebo effect |editor=Harrington A |title=The Placebo Effect: An Interdisciplinary Exploration |location=Cambridge |publisher=Harvard University Press |pages=166–86 |isbn=978-0-674-66986-4}}</ref>

===Psychology===
[[File:"Miracle Cure!" Health Fraud Scams (8528312890).jpg|thumb|right|The subjective effects of placebos may be related to expectations, yet similar effects have been noted in open-label studies.]]

In psychology, the two main hypotheses of the placebo effect are expectancy theory and [[classical conditioning]].<ref name="podd" />

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.<ref>{{cite journal | vauthors = Kirsch I |year=1985|title=Response expectancy as a determinant of experience and behavior|journal=American Psychologist|volume=40|issue=11|pages=1189–1202|doi=10.1037/0003-066X.40.11.1189}}</ref> 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. Similarly, the appearance of effect can result from classical conditioning, wherein a placebo and an actual stimulus are used simultaneously until the placebo is associated with the effect from the actual stimulus.<ref>{{cite journal | vauthors = Voudouris NJ, Peck CL, Coleman G | title = Conditioned response models of placebo phenomena: further support | journal = Pain | volume = 38 | issue = 1 | pages = 109–16 | date = July 1989 | pmid = 2780058 | doi = 10.1016/0304-3959(89)90080-8 | s2cid = 40356035 }}</ref> Both conditioning and expectations play a role in placebo effect,<ref name="podd">{{cite journal | vauthors = Stewart-Williams S, Podd J | title = The placebo effect: dissolving the expectancy versus conditioning debate | journal = Psychological Bulletin | volume = 130 | issue = 2 | pages = 324–40 | date = March 2004 | pmid = 14979775 | doi = 10.1037/0033-2909.130.2.324 | s2cid = 10297875 }}</ref> and make different kinds of contributions. Conditioning has a longer-lasting effect,<ref>{{cite journal | vauthors = Klinger R, Soost S, Flor H, Worm M | title = Classical conditioning and expectancy in placebo hypoalgesia: a randomized controlled study in patients with atopic dermatitis and persons with healthy skin | journal = Pain | volume = 128 | issue = 1–2 | pages = 31–9 | date = March 2007 | pmid = 17030095 | doi = 10.1016/j.pain.2006.08.025 | s2cid = 27747260 }}</ref> and can affect earlier stages of information processing.<ref name="Colloca et al 2008">{{cite journal | vauthors = Colloca L, Tinazzi M, Recchia S, Le Pera D, Fiaschi A, Benedetti F, Valeriani M | title = Learning potentiates neurophysiological and behavioral placebo analgesic responses | journal = Pain | volume = 139 | issue = 2 | pages = 306–14 | date = October 2008 | pmid = 18538928 | doi = 10.1016/j.pain.2008.04.021 | s2cid = 27342664 }}</ref> Those who think a treatment will work display a stronger placebo effect than those who do not, as evidenced by a study of acupuncture.<ref>{{cite journal | vauthors = Linde K, Witt CM, Streng A, Weidenhammer W, Wagenpfeil S, Brinkhaus B, Willich SN, Melchart D | title = The impact of patient expectations on outcomes in four randomized controlled trials of acupuncture in patients with chronic pain | journal = Pain | volume = 128 | issue = 3 | pages = 264–71 | date = April 2007 | pmid = 17257756 | doi = 10.1016/j.pain.2006.12.006 | s2cid = 25561695 }}</ref>

Additionally, [[motivation]] may contribute to the placebo effect. The active goals of an individual changes their somatic experience by altering the detection and interpretation of expectation-congruent symptoms, and by changing the behavioral strategies a person pursues.<ref name="Geers et al">{{cite journal | vauthors = Geers AL, Weiland PE, Kosbab K, Landry SJ, Helfer SG | title = Goal activation, expectations, and the placebo effect | journal = Journal of Personality and Social Psychology | volume = 89 | issue = 2 | pages = 143–59 | date = August 2005 | pmid = 16162050 | doi = 10.1037/0022-3514.89.2.143 }}</ref> 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.{{cn|date=November 2023}}

===Placebo analgesia===
[[Functional imaging]] upon [[placebo analgesia]] suggests links to the activation, and increased functional correlation between this activation, in the [[anterior cingulate]], [[prefrontal cortex|prefrontal]], [[orbitofrontal cortex|orbitofrontal]] and [[insular cortex|insular]] cortices, [[nucleus accumbens]], [[amygdala]], the [[brainstem]]'s [[periaqueductal gray matter]],<ref>{{cite journal | vauthors = Oken BS | title = Placebo effects: clinical aspects and neurobiology | journal = Brain | volume = 131 | issue = Pt 11 | pages = 2812–23 | date = November 2008 | pmid = 18567924 | pmc = 2725026 | doi = 10.1093/brain/awn116 }}</ref><ref>{{cite journal | vauthors = Lidstone SC, Stoessl AJ | title = Understanding the placebo effect: contributions from neuroimaging | journal = Molecular Imaging and Biology | volume = 9 | issue = 4 | pages = 176–85 | year = 2007 | pmid = 17334853 | doi = 10.1007/s11307-007-0086-3 | s2cid = 28735246 }}</ref> and the [[spinal cord]].<ref name="autogenerated2007">{{cite journal | vauthors = Goffaux P, Redmond WJ, Rainville P, Marchand S | title = Descending analgesia--when the spine echoes what the brain expects | journal = Pain | volume = 130 | issue = 1–2 | pages = 137–43 | date = July 2007 | pmid = 17215080 | doi = 10.1016/j.pain.2006.11.011 | s2cid = 20841668 }}</ref><ref>{{cite journal | vauthors = Qiu YH, Wu XY, Xu H, Sackett D | title = Neuroimaging study of placebo analgesia in humans | journal = Neuroscience Bulletin | volume = 25 | issue = 5 | pages = 277–82 | date = October 2009 | pmid = 19784082 | pmc = 5552608 | doi = 10.1007/s12264-009-0907-2 }}</ref><ref>{{cite journal | vauthors = Zubieta JK, Stohler CS | title = Neurobiological mechanisms of placebo responses | journal = Annals of the New York Academy of Sciences | volume = 1156 | issue = 1 | pages = 198–210 | date = March 2009 | pmid = 19338509 | pmc = 3073412 | doi = 10.1111/j.1749-6632.2009.04424.x | bibcode = 2009NYASA1156..198Z }}</ref>

Since 1978, it has been known that placebo analgesia depends upon the release of [[endogenous opioids]] in the brain.<ref>{{cite journal | vauthors = Levine JD, Gordon NC, Fields HL | title = The mechanism of placebo analgesia | journal = Lancet | volume = 2 | issue = 8091 | pages = 654–7 | date = September 1978 | pmid = 80579 | doi = 10.1016/s0140-6736(78)92762-9 | s2cid = 45403755 }}</ref> Such analgesic placebos activation changes processing lower down in the brain by enhancing the descending inhibition through the periaqueductal gray on spinal [[Withdrawal reflex|nociceptive reflexes]], while the expectations of anti-analgesic nocebos acts in the opposite way to block this.<ref name="autogenerated2007"/>

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. [[Dopamine pathways|Dopaminergic reward pathways]] may underlie these expectancies".<ref>{{cite journal | vauthors = Faria V, Fredrikson M, Furmark T | title = Imaging the placebo response: a neurofunctional review | journal = European Neuropsychopharmacology | volume = 18 | issue = 7 | pages = 473–85 | date = July 2008 | pmid = 18495442 | doi = 10.1016/j.euroneuro.2008.03.002 | s2cid = 40020867 }}</ref> "Diseases lacking major 'top-down' or cortically based regulation may be less prone to placebo-related improvement".<ref>{{cite journal | vauthors = Diederich NJ, Goetz CG | title = The placebo treatments in neurosciences: New insights from clinical and neuroimaging studies | journal = Neurology | volume = 71 | issue = 9 | pages = 677–84 | date = August 2008 | pmid = 18725593 | doi = 10.1212/01.wnl.0000324635.49971.3d | s2cid = 29547923 }}</ref>

===Brain and body===
{{Further|Neural top–down control of physiology}}

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 [[immunosuppressive|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.<ref>{{cite journal | vauthors = Ader R, Cohen N | title = Behaviorally conditioned immunosuppression | journal = Psychosomatic Medicine | volume = 37 | issue = 4 | pages = 333–40 | year = 1975 | pmid = 1162023 | doi = 10.1097/00006842-197507000-00007 | s2cid = 15306042 }}</ref> 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|serum iron levels]], [[DNA oxidation|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<ref name="Pacheco">{{cite journal | vauthors = Pacheco-López G, Engler H, Niemi MB, Schedlowski M | title = Expectations and associations that heal: Immunomodulatory placebo effects and its neurobiology | journal = Brain, Behavior, and Immunity | volume = 20 | issue = 5 | pages = 430–46 | date = September 2006 | pmid = 16887325 | doi = 10.1016/j.bbi.2006.05.003 | s2cid = 11897104 }}</ref> and pain.<ref>{{cite journal | vauthors = Colloca L, Benedetti F | title = Placebos and painkillers: is mind as real as matter? | journal = Nature Reviews. Neuroscience | volume = 6 | issue = 7 | pages = 545–52 | date = July 2005 | pmid = 15995725 | doi = 10.1038/nrn1705 | s2cid = 9353193 }}</ref> 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".<ref name="Pacheco"/>{{rp|441}} There has also been research aiming to understand underlying neurobiological mechanisms of action in pain relief, [[immunosuppression]], [[Parkinson's disease]] and [[Depression (mood)|depression]].<ref name=Neurobiology2005>{{cite journal | vauthors = Benedetti F, Mayberg HS, Wager TD, Stohler CS, Zubieta JK | title = Neurobiological mechanisms of the placebo effect | journal = The Journal of Neuroscience | volume = 25 | issue = 45 | pages = 10390–402 | date = November 2005 | pmid = 16280578 | doi = 10.1523/JNEUROSCI.3458-05.2005 | pmc = 6725834 }}</ref>

Dopaminergic pathways have been implicated in the placebo response in pain and depression.<ref>{{cite journal | vauthors = Murray D, Stoessl AJ | title = Mechanisms and therapeutic implications of the placebo effect in neurological and psychiatric conditions | journal = Pharmacology & Therapeutics | volume = 140 | issue = 3 | pages = 306–18 | date = December 2013 | pmid = 23880289 | doi = 10.1016/j.pharmthera.2013.07.009 }}</ref>