It remains to be seen how the emerging field of Placebo Studies will incorporate the tidal surge in the use and application of Large Language Models and other forms of AI. It may be that an AI can learn to stimulate the placebo effect periodically, or as the output of some kind of trigger. It may be that the AI can also be used, consciously or not, to trigger a ‘nocebo’ effect. As with all things AI, it’s a balancing act between the extraordinary potential of the technology for benefit or for harm. But the genie is certainly out of the bottle. The graphic for this post was generated by Bing Image Creator purely from a text prompt: “The placebo effect in a world of advanced technology”
Research has shown that a vast array of different conditions benefit from placebos. This includes acne, Crohn’s disease, epilepsy, ulcers, multiple sclerosis, rheumatism, Parkinsons’s disease and colitis. A recent study also found that placebos had a highly significant effect on erectile dysfunction.
But it may be that an account of the placebo (and nocebo) effect can be sought, if not found, in a science expanded beyond the simply neurological, which is to say, in a science that understands ‘mind’ as integrated in the complex web of energies interacting with the brain.
This fascinating article discusses this perspective.
Further to our most recent post about the likelihood that the frequency of adverse side effects may be attributable to the placebo effect (or more appropriately, the nocebo effect), here’s some more detail provided by reknowned placebo research Ted Kaptchuk, in an article from the Harvard Medical School, ‘Power of Placebo: Some COVID-19 vaccine reactions may result from placebo response’.
“Nonspecific symptoms like headache and fatigue—which we have shown to be particularly nocebo sensitive—are listed among the most common adverse reactions following COVID-19 vaccination in many information leaflets,” said senior author Ted Kaptchuk, HMS professor of medicine and director of the Program in Placebo Studies at Beth Israel Deaconess.
“Evidence suggests that this sort of information may cause people to misattribute common daily background sensations as arising from the vaccine or cause anxiety and worry that make people hyperalert to bodily feelings about adverse events,” he said.
Kaptchuk and colleagues are known for a large and growing body of evidence showing that full disclosure of placebo treatment, what he calls “open-label placebo,” can actually improve common chronic conditions without any nocebo effects. Kaptchuk believes it is ethically necessary to fully inform participants about the vaccines’ potential adverse reactions.
“Medicine is based on trust,” said Kaptchuk. “Our findings lead us to suggest that informing the public about the potential for nocebo responses could help reduce worries about COVID-19 vaccination, which might decrease vaccination hesitancy.”
You may be surprised to read of three ‘effects’ of placebos proposed recently by Eve M. Krakow in Psychology Today.
Dr Krakow takes pains to emphaise that the placebo effect is a physical phenomenon. There’s nothing magical about it. It will seem magical (as Isaac Asimov once wryly observed) until there’s sufficient science.
First, the placebo has a negative ‘flipside’. This is the nocebo effect, and it’s noted and discussed elsewhere on this site (check the tags column). A placebo effect can have either positive or negative outcomes.
Second, and very weirdly (if not ‘magically’) the placebo effect seems to become stronger and more proncounced over time. Placebos seem to get stronger!
Thirdly, the placebo effect does not necessarily require deception – that is, the practitioner lying to a patient that the (inert placebo) treatment is actually the ‘real’ treatment. We cover this too, on this site – look for ‘white label placebos’ in the tags.
One of the anti-vax memes in circulation is the risk of side effects from Covid vaccines.
A meta-analysis of 12 randomized, placebo-controlled clinical trials, a team of researchers at Beth Israel Deaconess Medical Center (BIDMC) in Boston found that up to 64 percent of adverse effects may be attributable to this kind of worry. See this article in Science Alert.
Interestingly, the meta-analysis engaged with the ‘placebo effect’ as a nocebo effect, with (across the 12 trials) about half of participants taking the vaccine, the other half a placebo. The nocebo effect accounted for up to 76 percent of systemic adverse events and 24 percent of local adverse events after the first vaccine dose.
We’re unsurprised to read that non-specific symptoms (think pain, mood disorder, IBS) are particularly ‘nocebo sensitive’.
It may be that the placebo effect is ‘not all in your head’. Findings from a new study indicate distinct physiological effects related to the perception of pain, according to a patient’s belief that a cream applied to their arm was either generating heat (the ‘nocebo’ option), numbness (the ‘placebo’ option) or no change (the ‘control’). All of the ‘creams’ were actually Vaseline. (Ref. Brainstem mechanisms of pain modulation: a within-subjects 7T fMRI study of Placebo Analgesic and Nocebo Hyperalgesic Responses, The Journal of Neuroscience)
The Australian researchers measured brainstem activity with high-resolution functional MRI (fMRI) in participants as they rated the pain of a hot stimulus applied to their arm.
From this article: “Over two successive days, through blinded application of altered thermal stimuli, participants were deceptively conditioned to believe that two inert creams labeled ‘lidocaine’ (placebo) and ‘capsaicin’ (nocebo) were acting to modulate their pain relative to a third ‘Vaseline’ (control) cream.”
Placebo and nocebo effects influenced activity in the same brainstem circuit but in opposite ways. The strength of the placebo effect was linked to increased activity in an area called the rostral ventromedial medulla and decreased activity in a nucleus called the periaqueductal gray; the nocebo effect induced the opposite change. These results reveal the role of the brainstem in pain modulation and may offer a route for future treatments of chronic pain.
“Placebo and nocebo effects influenced activity in the same brainstem circuit but in opposite ways. The strength of the placebo effect was linked to increased activity in an area called the rostral ventromedial medulla and decreased activity in a nucleus called the periaqueductal gray; the nocebo effect induced the opposite change. These results reveal the role of the brainstem in pain modulation and may offer a route for future treatments of chronic pain.”
When is a placebo not a placebo? It seems that placebos are no as ‘unreactive’ as the literature would suggest. Research hastened and made more urgent by the rushed efforts to develop a Covid-19 vaccine have revealed the need to create a standard for the actual content/ingredients of the placebo used in a given trial.
This article claims that:
“Some researchers conducting clinical trials on a COVID-19 vaccine have not revealed to the public what the placebo contains, but they should. This is because the placebo ingredients influence how effective or harmful the active treatment, with which the placebo is compared, appears.”
Later, the article continues:
“Placebo controls are rightly the gold standard against which new treatments are measured. If a new treatment proves to be better than a placebo, it is taken to be effective. Otherwise, it isn’t. The problem is that until today, there has been no standard for placebos, which made estimates of side-effects confusing. Our new guideline fixes this problem by encouraging rigorous reporting of placebo ingredients.
We’ve known about the failure – and need – to report what’s in placebos for 15 years. By following the new guideline, we can get more accurate information about how beneficial and harmful treatments tested in placebo-controlled trials are.”
Here’s a study on ‘A guide and checklist for reporting placebo and sham controls’
We all know about the ‘nocebo’ effect by now – the dark twin of the beneficial placebo effect. For example, a study showed that the pharmacological efficacy of remifentanil (a pain medication) was significantly decreased after patients were told the infusion was stopped during a heat-pain modulation test. Although the infusion had not actually been halted, participants experienced a significant exacerbation of pain even while still receiving remifentanil.
To counter undesirable ‘nocebo’ effects, this article suggests to health practitioners that ‘pragmatic strategies related to patient–practitioner interaction, clinical setting, and context may be implemented to help minimize and prevent the consolidation of negative expectations’.
There is some evidence – for example, in this study – that simply receiving the results of DNA tests can have a physical impact. Why? Well, once more the Placebo Effect is mentioned (as well as its dark twin, the Nocebo Effect, also covered on this website.
DNA tests are becoming quicker, cheaper and more reliable, so this is an issue we’ll hear more about.
We’ve posted elsewhere about the placebo’s dark twin, the nocebo, the phenomenon of the mind provoking negative and damaging effects through the same mechanism that accounts for the positive effects of a placebo.
This paper brings focus to ‘nocebo algesia and hyperalgesia (ie, the occurrence and worsening of nocebo-induced pain, respectively)’ and makes practical suggestions for reducing the incidence of this. As always, these relate to the patient-practitioner relationships and interactions, and strongly reinforce the ‘subjective’ and ‘negotiated’ nature of the experience of pain.
‘In general, the literature shows that uncaring interactions that convey a message of invalidation and lack of warmth may trigger nocebo effects. Avoiding negative communication and interactions with a patient may help to shape a safe and positive environment that not only promotes placebo effects but that also reduces nocebo effects.’