Tapping into the Power of the Placebo Effect
When Wayne Jonas was in medical school 40 years ago, doctors would write out a prescription for placebos, spelling it out backwards in capital letters, O-B-E-C-A-L-P. The pharmacist would fill the prescription with a sugar pill, recalls Jonas, now director of integrative health programs at the Samueli Foundation. It fulfilled the patient's desire for the doctor to do something when perhaps no drug could help, and the sugar pills did no harm.
Today, that deception is seen as unethical. But time and time again, studies have shown that placebos can have real benefits. Now, researchers are trying to untangle the mysteries of placebo effect in an effort to better treat patients.
The use of placebos took off in the post-WWII period, when randomized controlled clinical trials became the gold standard for medical research. One group in a study would be treated with a placebo, a supposedly inert pill or procedure that would not affect normal healing and recovery, while another group in the study would receive an "active" component, most commonly a pill under investigation. Presumably, the group receiving the active treatment would have a better response and the difference from the placebo group would represent the efficacy of the drug being tested. That was the basis for drug approval by the U.S. Food and Drug Administration.
"Placebo responses were marginalized," says Ted Kaptchuk, director of the Program in Placebo Studies & Therapeutic Encounters at Harvard Medical School. "Doctors were taught they have to overcome it when they were thinking about using an effective drug."
But that began to change around the turn of the 21st century. The National Institutes of Health held a series of meetings to set a research agenda and fund studies to answer some basic questions, led by Jonas who was in charge of the office of alternative medicine at the time. "People spontaneously get better all the time," says Kaptchuk. The crucial question was, is the placebo effect real? Is it more than just spontaneous healing?
Brain mechanisms
A turning point came in 2001 in a paper in Science that showed physical evidence of the placebo effect. It used positron emission tomography (PET) scans to measure release patterns of dopamine — a chemical messenger involved in how we feel pleasure — in the brains of patients with Parkinson's disease. Surprisingly, the placebo activated the same patterns that were activated by Parkinson's drugs, such as levodopa. It proved the placebo effect was real; now the search was on to better understand and control it.
A key part of the effect can be the beliefs, expectations, context, and "rituals" of the encounter between doctor and patient. Belief by the doctor and patient that the treatment would work, and the formalized practices of administering the treatment can all contribute to a positive outcome.
Conditioning can be another important component in generating a response, as Pavlov demonstrated more than a century ago in his experiments with dogs. They were trained with a bell prior to feeding such that they would begin to salivate in anticipation at the sound of a bell even with no food present.
Translating that to humans, studies with pain medications and sleeping aids showed that patients who had a positive response with a certain dose of those medications could have the same response if the doses was reduced and a dummy pill substituted, even to the point where there was no longer any active ingredient.
Researchers think placebo treatments can work particularly well in helping people deal with pain and psychological disorders.
Those types of studies troubled Kaptchuk because they often relied on deception; patients weren't told they were receiving a placebo, or at best there was a possibility that they might be randomized to receive a placebo. He believed the placebo effect could work even if patients were told upfront that they were going to receive a placebo. More than a dozen so call "open-label placebo" studies across numerous medical conditions, by Kaptchuk and others, have shown that you don't have to lie to patients for a placebo to work.
Jonas likes to tell the story of a patient who used methotrexate, a potent immunosuppressant, to control her rheumatoid arthritis. She was planning a long trip and didn't want to be bothered with the injections and monitoring required in using the drug, So she began to drink a powerful herbal extract of anise, a licorice flavor that she hated, prior to each injection. She reduced the amount of methotrexate over a period of months and finally stopped, but continued to drink the anise. That process had conditioned her body "to alter her immune function and her autoimmunity" as if she were taking the drug, much like Pavlov's dogs had been trained. She has not taken methotrexate for more than a year.
An intriguing paper published in May 2021 found that mild, non-invasive electric stimulation to the brain could not only boost the placebo effect on pain but also reduce the "nocebo" effect — when patients report a negative effect to a sham treatment. While the work is very preliminary, it may open the door to directly manipulating these responses.
Researchers think placebo treatments can work particularly well in helping people deal with pain and psychological disorders, areas where drugs often are of little help. Still, placebos aren't a cure and only a portion of patients experience a placebo effect.
Nocebo
If medicine were a soap opera, the nocebo would be the evil twin of the placebo. It's what happens when patients have adverse side effects because of the expectation that they will. It's commonly seem when patients claims to experience pain or gastric distress that can occur with a drug even when they've received a placebo. The side effects were either imagined or caused by something else.
"Up to 97% of reported pharmaceutical side effects are not caused by the drug itself but rather by nocebo effects and symptom misattribution," according to one 2019 paper.
One way to reduce a nocebo response is to simply not tell patients that specific side effects might occur. An example is a liver biopsy, in which a large-gauge needle is used to extract a tissue sample for examination. Those told ahead of time that they might experience some pain were more likely to report pain and greater pain than those who weren't offered this information.
Interestingly, a nocebo response plays out in the hippocampus, a part of the brain that is never activated in a placebo response. "I think what we are dealing with with nocebo is anxiety," says Kaptchuk, but he acknowledges that others disagree.
Distraction may be another way to minimize the nocebo effect. Pediatricians are using virtual reality (VR) to engage children and distract them during routine procedures such as blood draws and changing wound dressings, and burn patients of all ages have found relief with specially created VRs.
Treatment response
Jonas argues that what we commonly call the placebo effect is misnamed and leading us astray. "The fact is people heal and that inherent healing capacity is both powerful and influenced by mental, social, and contextual factors that are embedded in every medical encounter since the idea of treatment began," he wrote in a 2019 article in the journal Frontiers in Psychiatry. "Our understanding of healing and ability to enhance it will be accelerated if we stop using the term 'placebo response' and call it what it is—the meaning response, and its special application in medicine called the healing response."
He cites evidence that "only 15% to 20% of the healing of an individual or a population comes from health care. The rest—nearly 80%—comes from other factors rarely addressed in the health care system: behavioral and lifestyle choices that people make in their daily life."
To better align treatments and maximize their effectiveness, Jonas has created HOPE (Healing Oriented Practices & Environments) Note, "a patient-guided process designed to identify the patient's values and goals in their life and for healing." Essentially, it seeks to make clear to both doctor and patient what the patient's goals are in seeking treatment. In an extreme example of terminal cancer, some patients may choose to extend life despite the often brutal treatments, while others might prefer to optimize quality of life in the remaining time that they have. It builds on practices already taught in medical schools. Jonas believes doctors and patients can use tools like these to maximize the treatment response and achieve better outcomes.
Much of the medical profession has been resistant to these approaches. Part of that is simply tradition and limited data on their effectiveness, but another very real factor is the billing process for how they are reimbursed. Jonas says a new medical billing code added this year gives doctors another way to be compensated for the extra time and effort that a more holistic approach to medicine may initially require. Other moves away from fee-for-service payments to bundling and payment for outcomes, and the integrated care provided by the Veterans Affairs, Kaiser Permanente and other groups offer longer term hope for the future of approaches that might enhance the healing response.
This article was first published by Leaps.org on July 7, 2021.
Story by Big Think
We live in strange times, when the technology we depend on the most is also that which we fear the most. We celebrate cutting-edge achievements even as we recoil in fear at how they could be used to hurt us. From genetic engineering and AI to nuclear technology and nanobots, the list of awe-inspiring, fast-developing technologies is long.
However, this fear of the machine is not as new as it may seem. Technology has a longstanding alliance with power and the state. The dark side of human history can be told as a series of wars whose victors are often those with the most advanced technology. (There are exceptions, of course.) Science, and its technological offspring, follows the money.
This fear of the machine seems to be misplaced. The machine has no intent: only its maker does. The fear of the machine is, in essence, the fear we have of each other — of what we are capable of doing to one another.
How AI changes things
Sure, you would reply, but AI changes everything. With artificial intelligence, the machine itself will develop some sort of autonomy, however ill-defined. It will have a will of its own. And this will, if it reflects anything that seems human, will not be benevolent. With AI, the claim goes, the machine will somehow know what it must do to get rid of us. It will threaten us as a species.
Well, this fear is also not new. Mary Shelley wrote Frankenstein in 1818 to warn us of what science could do if it served the wrong calling. In the case of her novel, Dr. Frankenstein’s call was to win the battle against death — to reverse the course of nature. Granted, any cure of an illness interferes with the normal workings of nature, yet we are justly proud of having developed cures for our ailments, prolonging life and increasing its quality. Science can achieve nothing more noble. What messes things up is when the pursuit of good is confused with that of power. In this distorted scale, the more powerful the better. The ultimate goal is to be as powerful as gods — masters of time, of life and death.
Should countries create a World Mind Organization that controls the technologies that develop AI?
Back to AI, there is no doubt the technology will help us tremendously. We will have better medical diagnostics, better traffic control, better bridge designs, and better pedagogical animations to teach in the classroom and virtually. But we will also have better winnings in the stock market, better war strategies, and better soldiers and remote ways of killing. This grants real power to those who control the best technologies. It increases the take of the winners of wars — those fought with weapons, and those fought with money.
A story as old as civilization
The question is how to move forward. This is where things get interesting and complicated. We hear over and over again that there is an urgent need for safeguards, for controls and legislation to deal with the AI revolution. Great. But if these machines are essentially functioning in a semi-black box of self-teaching neural nets, how exactly are we going to make safeguards that are sure to remain effective? How are we to ensure that the AI, with its unlimited ability to gather data, will not come up with new ways to bypass our safeguards, the same way that people break into safes?
The second question is that of global control. As I wrote before, overseeing new technology is complex. Should countries create a World Mind Organization that controls the technologies that develop AI? If so, how do we organize this planet-wide governing board? Who should be a part of its governing structure? What mechanisms will ensure that governments and private companies do not secretly break the rules, especially when to do so would put the most advanced weapons in the hands of the rule breakers? They will need those, after all, if other actors break the rules as well.
As before, the countries with the best scientists and engineers will have a great advantage. A new international détente will emerge in the molds of the nuclear détente of the Cold War. Again, we will fear destructive technology falling into the wrong hands. This can happen easily. AI machines will not need to be built at an industrial scale, as nuclear capabilities were, and AI-based terrorism will be a force to reckon with.
So here we are, afraid of our own technology all over again.
What is missing from this picture? It continues to illustrate the same destructive pattern of greed and power that has defined so much of our civilization. The failure it shows is moral, and only we can change it. We define civilization by the accumulation of wealth, and this worldview is killing us. The project of civilization we invented has become self-cannibalizing. As long as we do not see this, and we keep on following the same route we have trodden for the past 10,000 years, it will be very hard to legislate the technology to come and to ensure such legislation is followed. Unless, of course, AI helps us become better humans, perhaps by teaching us how stupid we have been for so long. This sounds far-fetched, given who this AI will be serving. But one can always hope.
Interview with Jamie Metzl: We need a global OS upgrade
In this Q&A, leading technology and healthcare futurist Jamie Metzl discusses a range of topics and trend lines that will unfold over the next several decades: whether a version of Moore's Law applies to genetic technologies, the ethics of genetic engineering, the dangers of gene hacking, the end of sex, and much more.
Metzl is a member of the WHO expert advisory committee on human genome editing and the bestselling author of Hacking Darwin.
The conversation was lightly edited by Leaps.org for style and length.
In Hacking Darwin, you describe how we may modify the human body with CRISPR technologies, initially to obtain unsurpassed sports performance and then to enhance other human characteristics. What would such power over human biology mean for the future of our civilization?
After nearly four billion years of evolution, our one species suddenly has the increasing ability to read, write, and hack the code of life. This will have massive implications across the board, including in human health and reproduction, plant and animal agriculture, energy and advanced materials, and data storage and computing, just to name a few. My book Hacking Darwin: Genetic Engineering and the Future of Humanity primarly explored how we are currently deploying and will increasingly use our capabilities to transform human life in novel ways. My next book, The Great Biohack: Recasting Life in an Age of Revolutionary Technology, coming out in May 2024, will examine the broader implications for all of life on Earth.
We humans will, over time, use these technologies on ourselves to solve problems and eventually to enhance our capabilities. We need to be extremely conservative, cautious, and careful in doing so, but doing so will almost certainly be part of our future as a species.
In electronics, Moore's law is an established theory that computing power doubles every 18 months. Is there any parallel to be drawn with genetic technologies?
The increase in speed and decrease in costs of genome sequencing have progressed far faster than Moore’s law. It took thirteen years and cost about a billion dollars to sequence the first human genome. Today it takes just a few hours and can cost as little as a hundred dollars to do a far better job. In 2012, Jennifer Doudna and Emmanuel Charpentier published the basic science paper outlining the CRISPR-cas9 genome editing tool that would eventually win them the Nobel prize. Only six years later, the first CRISPR babies were born in China. If it feels like technology is moving ever-faster, that’s because it is.
Let's turn to the topic of aging. Do you think that the field of genetics will advance fast enough to eventually increase maximal lifespan for a child born this year? How about for a person who is currently age 50?
The science of aging is definitely real, but that doesn’t mean we will live forever. Aging is a biological process subject to human manipulation. Decades of animal research shows that. This does not mean we will live forever, but it does me we will be able to do more to expand our healthspans, the period of our lives where we are able to live most vigorously.
The first thing we need to do is make sure everyone on earth has access to the resources necessary to live up to their potential. I live in New York City, and I can take a ten minute subway ride to a neighborhood where the average lifespan is over a decade shorter than in mine. This is true within societies and between countries as well. Secondly, we all can live more like people in the Blue Zones, parts of the world where people live longer, on average, than the rest of us. They get regular exercise, eat healthy foods, have strong social connections, etc. Finally, we will all benefit, over time, from more scientific interventions to extend our healthspan. This may include small molecule drugs like metformin, rapamycin, and NAD+ boosters, blood serum infusions, and many other things.
Science fiction has depicted a future where we will never get sick again, stay young longer or become immortal. Assuming that any of this is remotely possible, should we be afraid of such changes, even if they seem positive in some regards, because we can’t understand the full implications at this point?
Not all of these promises will be realized in full, but we will use these technologies to help us live healthier, longer lives. We will never become immortal becasue nothing lasts forever. We will always get sick, even if the balance of diseases we face shifts over time, as it has always done. It is healthy, and absolutely necessary, that we feel both hope and fear about this future. If we only feel hope, we will blind ourselves to the very real potential downsides. If we only feel fear, we will deny ourselves the very meaningful benefits these technologies have the potential to provide.
A fascinating chapter in Hacking Darwin is entitled The End of Sex. And you see that as a good thing?
We humans will always be a sexually reproducing species, it’s just that we’ll reproduce increasingly less through the physical act of sex. We’re already seeing this with IVF. As the benefits of technology assisted reproduction increase relative to reproduction through the act of sex, many people will come to see assisted reproduction as a better way to reduce risk and, over time, possibly increase benefits. We’ll still have sex for all the other wonderful reasons we have it today, just less for reproduction. There will always be a critical place in our world for Italian romantics!
What are dangers of genetic hackers, perhaps especially if everyone’s DNA is eventually transcribed for medical purposes and available on the internet and in the cloud?
The sky is really the limit for how we can use gentic technologies to do things we may want, and the sky is also the limit for potential harms. It’s quite easy to imagine scenarios in which malevolent actors create synthetic pathogens designed to wreak havoc, or where people steal and abuse other people’s genetic information. It wouldn’t even need to be malevolent actors. Even well-intentioned researchers making unintended mistakes could cause real harm, as we may have seen with COVID-19 if, as appears likely to me, the pandemic stems for a research related incident]. That’s why we need strong governance and regulatory systems to optimize benefits and minimize potential harms. I was honored to have served on the World Health Organization Expert Advisory Committee on Human Genome Editing, were we developed a proposed framework for how this might best be achieved.
You foresee the equivalent of a genetic arms race between the world's most powerful countries. In what sense are genetic technologies similar to weapons?
Genetic technologies could be used to create incredibly powerful bioweapons or to build gene drives with the potential to crash entire ecosystems. That’s why thoughtful regulation is in order. Because the benefits of mastering and deploying these technologies are so great, there’s also a real danger of a genetics arms race. This could be extremely dangerous and will need to be prevented.
In your book, you express concern that states lacking Western conceptions of human rights are especially prone to misusing the science of genetics. Does this same concern apply to private companies? How much can we trust them to control and wield these technologies?
This is a conversation about science and technology but it’s really a conversation about values. If we don’t agree on what core values should be promoted, it will be nearly impossible to agree on what actions do and do not make sense. We need norms, laws, and values frameworks that apply to everyone, including governments, corporations, researchers, healthcare providers, DiY bio hobbyists, and everyone else.
We have co-evolved with our technology for a very long time. Many of our deepest beliefs have formed in that context and will continue to do so. But as we take for ourselves the powers we have attributed to our various gods, many of these beliefs will be challenged. We can not and must not jettison our beliefs in the face of technology, and must instead make sure our most cherished values guide the application of our most powerful technologies.
A conversation on international norms is in full swing in the field of AI, prompted by the release of ChatGPT4 earlier this year. Are there ways in which it’s inefficient, shortsighted or otherwise problematic for these discussions on gene technologies, AI and other advances to be occurring in silos? In addition to more specific guidelines, is there something to be gained from developing a universal set of norms and values that applies more broadly to all innovation?
AI is yet another technology where the potential to do great good is tied to the potential to inflict signifcant harm. It makes no sense that we tend to treat each technology on its own rather than looking at the entire category of challenges. For sure, we need to very rapidly ramp up our efforts with regard to AI norm-setting, regulations, and governance at all levels. But just doing that will be kind of like generating a flu vaccine for each individual flu strain. Far better to build a universal flu vaccine addressing common elements of all flu viruses of concern.
That’s why we also need to be far more deliberate in both building a global operating systems based around the mutual responsibilities of our global interdependence and, under that umbrella, a broader system for helping us govern and regulate revolutionary technologies. Such a process might begin with a large international conference, the equivalent of Rio 1992 for climate change, but then quickly work to establish and share best practices, help build parallel institutions in all countries so people and governamts can talk with each other, and do everything possible to maximize benefits and minimize risks at all levels in an ongoing and dynamic way.
At what point might genetic enhancements lead to a reclassfication of modified humans as another species?
We’ll still all be fellow humans for a very, very long time. We already have lots of variation between us. That is the essence of biology. Will some humans, at some point in the future, leave Earth and spend generations elsewhere? I believe so. In those new environments, humans will evolve, over time, differently than those if us who remain on this planet? This may sound like science fiction, but the sci-fi future is coming at us faster than most people realize.
Is the concept of human being changing?
Yes. It always has and always will.
Another big question raised in your book: what limits should we impose on the freedom to manipulate genetics?
Different societies will come to different conclusion on this critical question. I am sympathetic to the argument that people should have lots of say over their own bodies, which why I support abortion rights even though I recognize that an abortion can be a violent procedure. But it would be insane and self-defeating to say that individuals have an unlimited right to manipulate their own or their future children’s heritable genetics. The future of human life is all of our concern and must be regulated, albeit wisely.
In some cases, such as when we have the ability to prevent a deadly genetic disroder, it might be highly ethical to manipulate other human beings. In other circumstances, the genetic engineering of humans might be highly unethical. The key point is to avoid asking this question in a binary manner. We need to weigh the costs and benefits of each type of intervention. We need societal and global infrastrucutres to do that well. We don’t yet have those but we need them badly.
Can you tell us more about your next book?
The Great Biohack: Recasting Lifee in an Age of Revolutionary Technology, will come out in May 2024. It explores what the intersecting AI, genetics, and biotechnology revolutions will mean for the future of life on earth, including our healthcare, agriculture, industry, computing, and everything else. We are at a transitional moment for life on earth, equivalent to the dawn of agriculture, electricity, and industrialization. The key differentiator between better and worse outcomes is what we do today, at this early stage of this new transformation. The book describes what’s happening, what’s at stake, and what we each and all can and, frankly, must do to build the type of future we’d like to inhabit.
You’ve been a leader of international efforts calling for a full investigation into COVID-19 origins and are the founder of the global movement OneShared.World. What problem are you trying to solve through OneShared.World?
The biggest challenge we face today is the mismatch between the nature of our biggest problems, global and common, and the absence of a sufficient framework for addressing that entire category of challenges. The totally avoidable COVID-19 pandemic is one example of the extremet costs of the status quo. OneShared.World is our effort to fight for an upgrade in our world’s global operating system, based around the mutual responsibilities of interdependence. We’ve had global OS upgrades before after the Thirty Years War and after World War II, but wouldn’t it be better to make the necessary changes now to prevent a crisis of that level stemming from a nuclear war, ecosystem collapse, or deadlier synthetic biology pandemic rather than waiting until after? Revolutionary science is a global issue that must be wisely managed at every level if it is to be wisely managed at all.
How do we ensure that revolutionary technologies benefit humanity instead of undermining it?
That is the essential question. It’s why I’ve written Hacking Darwin, am writing The Great Biohack, and doing the rest of my work. If we want scietific revolutions to help, rather than hurt, us, we must all play a role building that future. This isn’t just a conversation about science, it’s about how we can draw on our most cherished values to guide the optimal development of science and technology for the common good. That must be everyone’s business.
Portions of this interview were first published in Grassia (Italy) and Zen Portugal.
Jamie Metzl is one of the world’s leading technology and healthcare futurists and author of the bestselling book, Hacking Darwin: Genetic Engineering and the Future of Humanity, which has been translated into 15 languages. In 2019, he was appointed to the World Health Organization expert advisory committee on human genome editing. Jamie is a faculty member of Singularity University and NextMed Health, a Senior Fellow of the Atlantic Council, and Founder and Chair of the global social movement, OneShared.World.
Called “the original COVID-19 whistleblower,” his pioneering role advocating for a full investigation into the origins of the COVID-19 pandemic has been featured in 60 Minutes, the New York Times, and most major media across the globe, and he was the lead witness in the first congressional hearings on this topic. Jamie previously served in the U.S. National Security Council, State Department, and Senate Foreign Relations Committee and with the United Nations in Cambodia. Jamie appears regularly on national and international media and his syndicated columns and other writing in science, technology, and global affairs are featured in publications around the world.
Jamie sits on advisory boards for multiple biotechnology and other companies and is Special Strategist to the WisdomTree BioRevolution Exchange Traded Fund. In addition to Hacking Darwin, he is author of a history of the Cambodian genocide, the historical novel The Depths of the Sea, and the genetics sci-fi thrillers Genesis Code and Eternal Sonata. His next book, The Great Biohack: Recasting Life in an age of Revolutionary Technology, will be published by Hachette in May 2024. Jamie holds a Ph.D. from Oxford, a law degree from Harvard, and an undergraduate degree from Brown and is an avid ironman triathlete and ultramarathon runner.