[1] Irritable bowel syndrome affects about 1 in 5 Americans. It occurs more often in women than men, and begins before the age of 35 in about half the people who get it."

https://newsinhealth.nih.gov/2012/02/grumbling-guts 

[2] While many therapies are commonly used to treat individual IBS symptoms such as constipation or diarrhea, few therapies have been shown to be effective and safe in relieving the global symptoms of IBS.

[3] The placebo pills were ablue and maroon gelatin capsules filled with avicel, a common inert excipient for pharmaceuticals (Bird's Hill Pharmacy, Needham, MA).

[4] The provider clearly explained that the placebo pill was an inactive (i.e., “inert”) substance like a sugar pill that contained no medication and then explained in an approximately fifteen minute a priori script the following “four discussion points:” 1) the placebo effect is powerful, 2) the body can automatically respond to taking placebo pills like Pavlov's dogs who salivated when they heard a bell, 3) a positive attitude helps but is not necessary, and 4) taking the pills faithfully is critical.

[5] To our knowledge, this is the first RCT comparing open-label placebo to a no-treatment control. Previous studies of the effects of open-label placebo treatment either failed to include no-treatment controls [27] or combined it with active drug treatment. [28]

[6] 80 eligible patients were randomized into the two arms (43 into no-treatment and 37 into open-label placebo). [But 39 no treatment finished, and 31 placebo arm completed]

[7] Patients were allowed to continue IBS medications (e.g., fiber, anti-spasmodics, loperamide, etc.) as long as they had been on stable doses for at least 30 days prior to entering the study and agreed not to change medications or dosages during the trial. Patients were asked to refrain from making any major life-style changes (e.g., starting a new diet or changing their exercise pattern) during the study.

[8] https://ghsm.hms.harvard.edu/person/faculty/ted-kaptchuk 

[9]  as early as the late nineteenth and early twentieth century, interest in clinical objectivity grew, spurred on not only by astounding successes in laboratory science and clinical medicine abroad (e.g. discovery of microbes, pasteurization of milk, development of anthrax and rabies vaccines) but because of the sorry state of therapeutics at the time in America. … During the 1920's, 30's and 40's medical researchers began to conduct "cooperative investigations" designed to overcome errors attributed to individual observers working in relative isolation and replace them with standardized evaluations of therapeutic research in hundreds of patients.

[10] Major shifts in the social and scientific structure of medicine in the late 19th and early 20th centuries created new opportunities and demands for more rigorous clinical research methods. Hospitals expanded, new biologic and vaccine industries emerged to confront recently identified germs, chemists developed novel therapeutic compounds, and an unregulated subeconomy of fraudulent replicas of new agents flourished. All these factors motivated clinical investigators to pursue more sophisticated approaches for evaluating experimental therapies http://sci-hub.tw/10.1056/NEJMp1604635 

[11] Throughout the 1920s and 1930s, new technologies and new science intersected as physiology led to the discovery of vitamins and to increasing knowledge of hormones and body chemistry. New drugs and new vaccines flowed from developments started in the previous decades. Sulfa drugs became the first of the anti bacterial wonder drugs promising broad-spectrum cures. Penicillin was discovered, but its development had to await new technology (and World War II, which hastened it). New instruments such as the ultracentrifuge and refined techniques of X-ray crystallography paralleled the development of virology as a science. Isoelectric precipitation and electrophoresis first became important for drug purification and analysis. Overall, the medical sciences were on a firmer footing than ever before. This was the period in which the Food and Drug Administration (FDA) gained independence as a regulatory agency. And researchers reveled in the expanding knowledge base and their new instruments. They created a fusion of medicine and machines that would ultimately be known as “molecular biology.”

[12]E.g. Epinephrine http://sci-hub.tw//10.1001/jama.1926.02680110036011 

[13] By 1937, it had become clear to regulators and to an increasing number of outside organizations,

including the AMA, that the original 1906 "Wiley" Act had become outdated. Breakthrough

drugs such as the first sulfa drug, sulfanilamide, new drugs including amphetamines and

barbiturates, and biologics such as insulin were coming onto the market and beginning to

transform medicine entirely

[14] E.g. Tofranil https://journals.sagepub.com/doi/abs/10.1177/070674375900401S09

[15] the data suggested that about half of the placebo effects could be attributed to spontaneous symptom variation and recovery, with some variation between clinical disorders. For minor depression, this effect was shown to be as high as 81%. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4370177/#R11

[16] [e.g. Warts studies from 1927 and 1934] Sulpharsphenamine and of a placebo given in the same manner appears to rule out any specific therapeutic effect of the drug in the therapy of warts…. In a series of 179 patients, by means of suggestion alone, he was able to cure 44 per cent of those with verruca vulgaris and 88.4 per cent of those with verruca plana juvenilis.

[17] E.g.”The neglected possibility that may explain the later failure of the agent is that the good results were attributable not to the pharmacological properties of the agent, but to the very real and often powerful placebo effects http://sci-hub.tw/10.1001/jama.1954.03690220013004

[18] Approximately one-half of our boys were given a placebo instead of benzedrine in order to ascertain the degree of suggestion. Both groups improved scores.

[19]  It was not to the specific medications, however, that the patient responded, but to something inherent

in the doctor-patient relationship. (See Figure 1 on placebo publications)

[20] No evidence was obtained in these experiments that the action of codeine is any greater than can be explained by the factor of suggestion

[21] In 1954, John Hampson, David Rosenthal, and Jerome Frank designed a double blind, randomised, placebo-controlled study to test the effect of a new potential tranquilliser, mephenesin in outpatient psychotherapy at the Department of Psychiatry at Johns Hopkins University in Baltimore, MD, USA. The study reported that placebo and mephenesin produced similar effects. The authors stated that “The high value which our culture places on pills and medicines may be involved in this phenomenon whereby even inert substances become endowed with physiologic potency when they are presented to the patient as therapeutic agents”

[22] It was in 1955 that Henry K. Beecher, with his famous and seminal article ‘‘The Powerful Placebo’’ was the first author to quantify the effects of placebos in a variety of diseases. “I, with Keats, Mosteller, and Lasagna,3 in 1953, administered analgesics by mouth to patients having steady, severe postoperative

wound pain, and we found that when we took all patients and all data we could not differentiate between certain combined acetylsalicylic acid data and narcotic (morphine and codeine) data.”

[23] http://sci-hub.tw//10.1001/archpsyc.1959.03590050081010 Data are presented on a controlled study comparing iproniazid with both an inert placebo and with psychotherapy. Within the limitations of this study there is no differ¬ ence in the efficacy of iproniazid, of an inert placebo, or of psychotherapy, in the treatment of depression as a symptom.

[24] New FDA regulations said that you needed a control for new drugs “Reports of all clinical tests sponsored by the applicant or received or otherwise obtained by the applicant should be attached. These reports should include adequate information concerning each subject treated with the drug or employed as a control”... An application may be refused unless it includes substantial evidence consisting of adequate and well-controlled investigations p 6378

[25] The regulations describe the five types of controls that may serve to define a clinical study as adequate and well-controlled. In almost all cases of neurologic and psychiatric drug approval, a placebo concurrent control group has been used.

[26] From as early as 1961, placebo effects in psychiatric drug research have been systematically assessed.

[27]  Fed. Reg. 7250 (May 8, 1970). The 1970 regulations recognized comparative evidence from no-treatment and treatment groups, placebo controlled trials, active treatment trials (comparing treatments), and historical controls.

[28] In the 1960s, the controlled clinical trial, in which a group of patients receiving an experimental drug is compared with another group receiving a control drug or no treatment, became the standard for doing pharmaceutical research and measuring the therapeutic benefits of new drugs.

[29] “Although several kinds of randomized controlled trial methodologies can be useful to researchers and regulators, ultimately, it was the randomized, double-blinded, placebo controlled experiment which became the standard by which most other experimental methods were judged, and it has often subsequently been referred to as the "gold" standard for clinical trial methodology”

[30] From the FDA about Phase II studies: “ Ideally such studies are double-blind placebo-controlled investigations in

which patients are randomly assigned to a drug treatment group or a placebo group and neither the patient nor the investigator knows”

[31] In the past two decades, the number of publications devoted to the placebo effect itself—ie, not on the effect of drugs (or other therapies) in comparison with a placebo treatment—has steadily increased, with an exponential rise since the early 1990s

[32] This more recent paper-- 2016-- did a meta analysis comparing means of no-treatment v. placebo to treatment v. placebo http://sci-hub.tw/https://doi.org/10.1371/journal.pone.0062599 :In trials with binary outcomes (n = 37) treatments were significantly more effective than placebos (RRR = 0.72, 95%CI = 0.61 to 0.86, P = 0.0003). ... Because the placebo effect is part of the overall treatment effect our findings do not imply that placebos – even powerful placebos – should replace treatments. Rather, this study shows that patients will benefit if doctors exploit relatively powerful placebos either alone or as part of a therapeutic regime.

[33] The enhanced message did not confer any added benefit to montelukast for improving symptom control. Importantly, although the enhanced message improved asthma control in the placebo group, it did not influence lung function measures. Asthma: a large study of 600 patients found that placebos made people feel better, but didn’t objectively reduce their symptoms [NB: This old review paper found that suggestion could lead to bronchoconstriction]

[34] … So for example, in a recent review of the placebo effect on Urinary Tract Infection…. people said it helped with incontinence and needing to pee at night, but when researchers measured how much pee they actually peed out -- it didn’t change. 

[35] Artemisinin-based combination therapies are the first-line defense to treat malaria. See figure 1, shows ACT studies measured against placebos.

[36] E.g. Median progression-free survival was 5·3 months (4·6–6·4) in the selumetinib group and 2·1 months (95% CI 1·4–3·7) in the placebo group (HR for progression 0·58, 80% CI 0·42–0·79; one-sided p=0·014). 16 (37%) patients in the selumetinib group and none in the placebo group had an objective response (p<0·0001

[37]  In randomized double-blinded, placebo-controlled trials, presumably with minimum sources of bias, placebos are sometimes associated with improved control of symptoms such as pain and appetite but rarely with positive tumor response.

[38] Exercise https://www.researchgate.net/profile/Christopher_Beedie/publication/215748564_Placebo_effect_of_caffeine_in_cycling_performance/links/580a2f1e08ae74852b52f5b1/Placebo-effect-of-caffeine-in-cycling-performance.pdf 

[39] In the last decade, with the revolutionary discovery of effective pharmacotherapy for ED and in addition to an aggressive marketing, oral phosphodiesterase type-5 inhibitor (iPDE5) has become one of the most common prescribed drugs for men….https://www.ncbi.nlm.nih.gov/pubmed/19758285 

[40] https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/1748829?= Our results suggest that the response to sham acupuncture and sham surgery can be as great as the mean response to active drugs-  meta analysis

[41] We found an effect on patient-reported outcomes, especially on pain.

[42] OLP may reduce fatigue symptom severity and fatigue-related quality of life disruption in cancer survivors.

[43] Our Review of present knowledge of placebo responses in psychiatry across different clinical disorders in children and adults shows that although the placebo response is evident and effective in all disorders—both in RCTs and in laboratory testing—its predictors are still widely unknown.

[44] Migraine https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5495100/pdf/nihms868685.pdf 

[45] https://www.nejm.org/doi/full/10.1056/NEJMoa0900429 

[46] “At no point did either of the intervention groups report less pain or better function than the placebo group.”

[47] Arthroscopic (Knee) Surgery: Although marked improvement from baseline to 12 months was seen in the three primary outcomes in both study groups (Fig. 2 and Table 2), there were no significant between-group differences in the change from baseline to 12 months in any of these measures.

[48]  Alterations in brain activity are accompanied by changes in brain neurochemistry, particularly in the endogenous opioid and the endogenous cannabinoid systems that, intriguingly, seem to differentially contribute to different types of placebo analgesia

[49] There are a collection of brain studies that show placebos for different conditions pain, anxiety, Parkinson’s and depression light up different areas of the brain…

[50] Look at Box 1 for a list. “In Parkinson’s disease, placebos trigger endogenous dopamine release in the basal ganglia17,18, which leads to improvements in motor function”

[51] Mayberg and colleagues12 described changes in brain metabolism (as measured by PET) in response to a 6 week double-blind treatment with fluoxetine or placebo in patients with unipolar depression. Placebo responses were associated with regional metabolic increases in some areas of the brain and decreases in others that mimicked some of the effects of fluoxetine. 

[52] https://www.ncbi.nlm.nih.gov/pubmed/18250260 Found placebo and nocebo acting on dopamine and opioid system.

[53] The patients were randomly given morphine, placebo, or naloxone (the combination of morphine followed by naloxone being excluded) so that patients could expect a powerful analgesic as well as something which might make pain worse.  http://sci-hub.tw//10.1016/S0140-6736(78)92762-9 

[54] http://science.sciencemag.org/content/293/5532/1164 

[55] 2010 Review https://jamanetwork.com/journals/jamapsychiatry/fullarticle/210854 

[56] Review paper, critical of placebo, acknowledges this: Several laboratory studies indicate a neurobiological mechanism for the analgesic effect of placebo (Sauro 2005). These studies are often small, mostly based on healthy volunteers, and of short duration. The findings cannot easily be extrapolated to a clinical context, but they do elucidate the probable importance of, for example, endorphins in the analgesic response to placebo, and indicate that it is unlikely that response bias can account for all of the analgesic effect

[57] http://www.jneurosci.org/content/19/1/484.long  The administration of a placebo can trigger both cognitive (expectation) and conditioning mechanisms. Expectation activates endogenous opioid systems, whereas conditioning is mediated by specific mechanisms.

[58] https://pdfs.semanticscholar.org/83cd/1823af2ba26ce3c3e7f8e1b78daa74cc530b.pdf Placebo analgesia represents the best-studied placebo response (4) and is mediated by an activation of the opioid-dependent endogenous pain modulatory system (5–7).

[59] For instance, placebo analgesia — one of the most robust and best studied placebo responses — is mediated by changes in neural activity in the dorsolateral prefrontal cortex, the anterior cingulate cortex, the amygdala and the periaqueductal grey. All of these regions of the brain are key players in the so-called ‘descending pain modulatory network’7,8 that amplifies or inhibit incoming pain signals, even at the level of the spinal cord

[60] When both groups were compared in fMRI analyses of brain activity, only the group receiving the verbal suggestion showed large reductions in brain activity related to processing pain (7). IBS patients who received the verbal suggestion also had increases in neural activity in brain structures involved in endogenous analgesia, such as prefrontal cortical areas, rostral anterior cingulate, and right amygdala. [Actual study here] [Described in this commentary]

[61] “We found a significant decrease in striatal RAC binding potential [17% for the caudate nucleus (range, 8 to 25%); 19% for the putamen (range, 8 to 28%); P , 0.005 for both, two-tailed paired t test] when the patients received placebo compared with open baseline observations

….These observations indicate that there is placebo-induced release of endogenous dopamine in the striatum” that was similar to what the active drug would have done. [RR: But this was only 6 patients.]

[62] Study found that when they were told “you have a 75% chance of getting the drug” but got a placebo, it release dopamine. BUT not when told there’s a 25%, 50% or 100% http://sci-hub.tw/10.1001/archgenpsychiatry.2010.88 

[63] A study which found just telling house cleaners their work was healthy - could lower their blood pressure! https://dash.harvard.edu/bitstream/handle/1/3196007/langer_excersiseplaceboeffect.pdf?sequence=1

[64] When told a milkshake is fattening it released more of a “full” hormone… than someone who was told it was skinny … We argue that, much like placebo effects, alterations in mindset—what one believes and expects to be eating— have the potential to elicit a seemingly inappropriate sense of satiation.

[65] if you tell people a pill will affect their heart rate… it literally constricts blood vessels,...  

[66] http://europepmc.org/articles/pmc4817362#R8 placebo-related factors inflate Diet/Lifestyle intervention outcomes

[67] http://sci-hub.tw//10.1016/j.jpsychores.2008.09.004 And one small study found that telling people a pill will make their tummy stimulated… actually recorded more EEG activity in the stomach of people who got the stimulated pill.

[68] https://www.sciencedirect.com/science/article/pii/S0304395902003457 

[69] The principal underlying mechanisms that are best supported by empirical evidence are as follows: expectancy (that is, patients’ expectations of the benefit of a treatment) (FIG. 1a); behavioural conditioning (FIG. 1b); and the quality of the patient–physician relationship

[70] Placebos also work better when a doctor gives them to you rather than being part of a clinical trial…  “t. On the other hand, 12 of the 14 studies that investigated placebo analgesia mechanisms gave suggestions to subjects to the effect that they would receive a powerful painkiller (c.f. Table 3). Consequently, they were likely to have much higher expectations of efficacy than that of subjects in clinical trial studies. A recent study by Pollo et al. (2001) supports this interpretation of our data. They found that the instruction influences the magnitude of placebo analgesia.”And a study that Ted did…  found that placebo effects get stronger when a doctor gives the drug with “warmth, attention, and confidence”

[71] Invasive procedures are thought to incorporate many factors that may contribute to the placebo responses including use of a hospital-like setting; multiple, authoritative providers; frequent and repeated suggestions about expected outcomes; a physical invasion of the body; and an elaborate ritual of treatment delivery and recovery

[72] So for example, studies found that you could change how much pain someone was feeling by just telling them “this cream will make your pain better”, “this cream will make it worse” -- when really it was the same stuff https://pdfs.semanticscholar.org/83cd/1823af2ba26ce3c3e7f8e1b78daa74cc530b.pdf

[73] E.g. Fabrizio, Manfred, Dr Cynthia McCrae, Prof Jon Stoesel

[74] Recently, five non-deceptive open-label placebo (OLP) studies (i.e., where participants were told they were receiving placebo pills) demonstrated significant improvement for patients with Irritable Bowel Syndrome (IBS), episodic acute migraine attacks, chronic low back pain, allergic rhinitis and depression

[75] https://www.jpain.org/article/S1526-5900(15)00033-4/fulltext 

[76] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5113234/pdf/jop1-157-2766.pdf Compared to Treatment As Usual, Open Label Placebo elicited greater pain reduction

[77] Open‐label placebos appear to have positive clinical effects compared to no treatment. Caution is warranted when interpreting these results due to the limited number of trials identified, lack of blinding, and the fact that positive messages were included alongside open‐label placebos https://onlinelibrary.wiley.com/doi/full/10.1111/jebm.12251 

[78] https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0140967&type=printable The experiments were performed in our laboratories at the Plateau Rosa Research Station in the Matterhorn area at the Italian-Swiss border (Breuil-Cervinia area on the Italian side and Zermatt on the Swiss side) at an altitude of 3500 meters, that can be reached through three cableways in 30 minutes, starting from an altitude of 2050 m in Breuil-Cervinia

[79] https://sites.tufts.edu/prep/tag/fabrizio-benedetti/ 

[80]https://neuroen.campusnet.unito.it/do/gruppi.pl/ShowFile?_id=c95y;field=allegato;key=jOVKYhuiGMI7MU2Dh9E9NI5LeLiT5LCXA;t=4506 Center for Hypoxia

[81] At 3500 m air pressure is about 490 mmHg (760 mmHg at sea level) and oxygen pressure about 102 mmHg (159 mmHg at sea level). This corresponds to a blood oxygen saturation in the range of 83-90% (98-99% at sea level), depending on different individuals

[82]  Acute mountain sickness (AMS)  - an unacclimatized person who has recently reached an altitude above 2500 m along with one or more of such symptoms as gastrointestinal disturbances (anorexia, nausea, or vomiting), shortness of breath, dizziness, light headedness, insomnia, or fatigue

[83] 7 in this study did the oxygen conditioning procedure… https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0140967#pone-0140967-t001 and in this study 7 did the oxygen conditioning procedure.

[84] In two different published studies we tested 63 subjects, but in unpublished pilot studies (aimed at better defining the experimental protocol) we tested more than 50 subjects. Therefore, you can say that we tested more than 100 subjects. [Email with Fabrizio]

[85] In each of these tests, the subjects had to complete 3000 steps on a stepper

[86] http://sci-hub.tw/10.1097/j.pain.0000000000000288 /   Also described here:  Exercise consisted in subjects completing 3000 steps on a stepper. Oxygen placebo was given to participants via an oxygen mask connected to an oxygen supply with no real oxygen inside. Results from this study highlighted that placebo oxygen alone was effective in reducing fatigue; however no significant changes were reported in relation to headache at rest, post-exercise headache, HR, PGE2, and SO2

[87] One important factor triggering high-altitude headache is represented by the acute effects of hypoxia on prostaglandin (PG) synthesis through the cyclooxygenase (COX) enzyme, with the formation first of PGH2, and then of PGF2, PGD2, PGE2, PGI2 (prostacyclin), and TXA2. 4

[88]  A saliva sample (about 1 mL) was taken just before and right after exercise for PGE2 measurement.

[89] When little oxygen is available in the air, a condition called hypoxia, several body functions counterbalance the oxygen shortage by triggering at least three fundamental compensatory responses: increase in ventilation (hyperventilation) through the activation of chemoreceptors; increase in circulation through increased cardiac output, e.g., heart rate increase; and increase in perfusion through vasodilation, e.g., cerebral vasodilation, whereby prostaglandins (PG) such as PGE2 have been found to be involved.

[90] Differently, when placebo administration was preceded by oxygen preconditioning, whereby real oxygen was administered for several sessions in a row and then replaced by sham (placebo) oxygen on the last test session, not only fatigue was found to be reduced but also post-exercise headache, HR, and PGE2.

[91] Brogden: three groups of four dogs, each with a different type of CR, were tested. Each type of response was conditioned to bell, the animals being placed in a light-shielded, sound-proofed test-chamber with the experimenter observing through a one-way glass screen

[92] http://s-f-walker.org.uk/pubsebooks/pdfs/Condditioned%20Reflexes%20And%20Psychiatry.pdf 

[93] The placebo effect in animals: “Empirical support for the conditioning model of the placebo effect comes primarily from animal studies. Classical conditioning was first described by Pavlov, who observed that dogs that salivated when fed began to salivate in response to certain nonfood stimuli that were always evident at the time of feeding, such as the sound of attendants’ footsteps or the sight of a feeding dish. … He tested his theory by rising a bell prior to each feeding; after several trials, the dogs salivated at the sound of the bell alone.”

[94] https://www.uk-essen.de/medpsychologie/index.php/en/institute/team/director 

[95] Peripheral physiological functions such as secretion of growth hormone and cortisol were not affected through mere manipulation of expectancy but through behavioral conditioning [11]; https://www.uk-essen.de/medpsychologie/index.php/en/institute/team/director

[96] Based on these data, it can be hypothesized that paradigms of conditioned immunosuppression might be utilized as a supplement or complement to drug regimes aiming the reduction of medication dosage required, and thus possibly limiting unwanted drug side effects 

[97] Thirty-four healthy male volunteers were tested during a 2 wk period (Fig. 1A). Starting on day 1 at 1800, the experimental group (n18) received 4 doses of cyclosporin A (CsA, 2.5 mg/kg) every 12 h in capsule form (Sandimmun®, Novartis, Basel, Switzerland) together with a green-colored, novel-tasting drink (150 mL strawberry milk aromatized with 1 drop lavender oil). Five days later, subjects were re-exposed to the drink but received identical looking placebo capsules.

[98] Email Manfred: WE TESTED AROUND N=150 HEALTHY SUBJECTS WITH CSA; AROUND N=60 PATIENS WITH HOUSE DUST MITE EMPLOYING ANTI-HISTMINIC DRUGS AS UNCONDITIONED STIMULI; 30 RENAL TRANSPLANT PATIENTS WITH CSA

[99] Cyclosporine is still commonly used as first-line immunosuppression after pediatric liver transplantation in many parts of the world. https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/ciclosporin

[100] https://www.mayoclinic.org/drugs-supplements/cyclosporine-oral-route/description/drg-20075815 

[101]https://www.fasebj.org/doi/abs/10.1096/fj.02-0389com?rfr_dat=cr_pub%3Dpubmed&url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&journalCode=fasebj 

[102] Just telling someone they’re getting an immune suppressing pill… doesn’t mean their immune system will go down… “Furthermore, the data reveal that mere verbally induced expectation of receiving the immunosuppressive drug CsA did not significantly decrease IL-2 secretion of activated PBMC, regardless of the declared probability of receiving active medication.”

[103] Thus, re-exposure to the conditioned stimulus (novel drink) induced a suppression of IL-2 and IFN- mRNA expression in peripheral blood lymphocytes in conditioned subjects

… These data for the first time demonstrate in humans that after repetitive pairings of an immunosuppressant drug (UCS) with a novel and distinctively flavored drink (CS), re-exposition to the novel drink alone is sufficient to elicit an immune suppression that mirrors the actual drug effect

[104] https://www.pnas.org/content/pnas/115/16/4223.full.pdf 

[105] Coughing https://www.researchgate.net/profile/Michael_Farrell13/publication/225095544_The_Effect_of_Placebo_Conditioning_on_Capsaicin-Evoked_Urge_to_Cough/links/54530cb70cf2cf51647a566d.pdf

[106] ADHD https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2902360/ Pairing placebos with stimulant medication elicits a placebo response that allows children with ADHD to be effectively treated on 50% of their optimal stimulant dose.

[107] The possibility of utilizing conditioning responses to improve or maintain immunosuppressive efficacies while reducing toxicities is certainly exciting!

[108] 2004: To conclude, the effects of exogenously applied insulin can be conditioned in a reliable way. In correspondence with the lower intensity of the unconditioned stimulus (US), conditioning effects with glucose—and, thus, endogenously produced insulin—are weaker but also reflect the actions of central insulin http://sci-hub.tw/10.1016/j.physbeh.2003.12.019

2000: Together, our results demonstrate the conditionability mainly of insulin, but also of glucose effects in healthy humans. The clinical relevance and future research perspectives are

outlined with an emphasis on insulin in the brain and its role in learning and memory. http://sci-hub.tw/10.1016/S0166-4328(99)00192-8

[109] Theories of placebo analgesia have posited that placebo responses are the result of top-down expectations and predictions of pain (relief), integrated with bottom-up sensory signals at multiple levels of the neural hierarchy (23, 25, 26). Here we demonstrate, for the first time to our knowledge, not only that the reflection of top-down predictions is manifested at lower levels of the neural axis but also that new associative learning of pain responses can take place in the absence of conscious awareness.

[110] In its most simple form, our experiment would be as if Pavlov would ring his bell (or more correctly he might have used tones or buzzers) at a consciously undetectable frequency (conditioned stimulus) to test the effects of conditioned pain responses. Nonetheless, all 3 studies, taken together, support the conclusion that “conditioning procedures and other sources of information sometimes shape conscious expectancies and that these expectancies mediate some placebo effects; https://www.ncbi.nlm.nih.gov/pubmed/25452576 

[111]Significant placebo and nocebo effects were found in both experiment 1 (using clearly visible stimuli) and experiment 2 (using nonconscious stimuli), indicating that the mechanisms responsible for placebo and nocebo effects can operate without conscious awareness of the triggering cues. https://www.ncbi.nlm.nih.gov/pubmed/23019380 

[112] [Commentary on Ted’s study] Some of these studies show that changes in pain are preceded by reduced ratings of expected pain in instances wherein analgesia is produced. However, expectation does not seem to act alone but is combined with other conscious parameters. … expectation could still be a critical mediator of changes in pain even during unconscious conditioning. Participants may have expectations despite no awareness of the cues that lead to them

[113]Didn’t work here https://link.springer.com/article/10.1007/s00213-017-4718-2 

[114] In contrast, in the context of learned immunosuppression the major issues are 1) how can learned immunosuppression (or activation) be protected from extinction and 2) how can it be reactivated on demand by CS re-exposure (Schedlowski and Pacheco-Lopez 2010). There are no data available on this topic and it has never been systematically investigated before. [As of 2013]

[115] See Figure 1 B https://www.researchgate.net/profile/Ali_Canbay/publication/11003964_Behavioral_conditioning_of_immunosuppression_is_possible_in_humans/links/54ae76e60cf24aca1c70550c.pdf 

[116] In a first experiment, using an established taste–immune conditioning paradigm in humans, we observed extinction of the learned immune response after 14 unreinforced CS reexposures

[117] We first determined the “subtherapeutic” dosage of CsA in our model and observed that 10% (0.25mg/kg) of the CsA dosage used as the US during acquisition was barely detectable in blood and did not affect the IL-2 production of activated T cells.. p. More importantly, when using “subtherapeutic” CsA dosages together with the CS, we still detected a significantly reduced IL-2 production in the conditioned-sub group after 14 CS reexposures (t = 3.0; P < 0.01), indicating inhibited extinction of the learned immunosuppression

[118] The principal underlying mechanisms that are best supported by empirical evidence are as follows: expectancy (that is, patients’ expectations of the benefit of a treatment) (FIG. 1a); behavioural conditioning (FIG. 1b); and the quality of the patient–physician relationship

[119]  If so, then expectation could still be a critical mediator of changes in pain even during unconscious conditioning. Participants may have expectations despite no awareness of the cues that lead to them.