Can placebos really cure diseases? | Uncovering the placebo effect (Part 2)

Studies have confirmed that the placebo effect can regulate immune response and enhance resistance to infection; "optimistic cancer patients live longer" is also true. Today we will talk about how placebos can exert their therapeutic effects by "cheating" the reward system in the brain.

Written by He Xiaosong (Retired Professor of University of California, Davis School of Medicine)

During World War II, Dr. Beecher of Harvard Medical School observed in a front-line field hospital that some people used saline instead of morphine to relieve pain in an emergency, and it was successful. Inspired by this, he and his colleagues pioneered scientific research on the placebo effect after the war, proving that the efficacy of placebo is an objective fact, not the subjective imagination of patients. The work of Beecher and others directly led to major changes in the approval standards for new drugs in the United States, as well as a major cleanup of the existing drug market in order to eliminate ineffective drugs. (For details, see: No morphine on the battlefield, saline as an anesthetic, do you believe it? | Unveiling the placebo effect (I))

Among the various symptoms of disease and trauma, pain is perhaps the most common one. Perhaps because of this, "pain" is often used as a synonym for "disease". Early placebo studies by Beecher and others also focused on its effect on pain. They found that under certain conditions, placebos can indeed reduce pain like the analgesic morphine, but they did not really answer why. In fact, although morphine has been used as an analgesic in clinical practice for many years, the medical community has no idea about its mechanism of action. It was not until the 1970s, with the development of brain neuroscience, that the answer to this question began to emerge.

The birth of placebo biology For thousands of years, humans have been using various natural products to relieve pain. The earliest and most widely used natural analgesic is opium. According to research, as early as more than 5,000 years ago, the Sumerians in the Mesopotamian plains of the Middle East began to grow opium for entertainment and medicinal purposes. Morphine is a major active ingredient in opium. It not only has a strong analgesic effect, but also can make people feel euphoric after use. That is why it is very addictive. Morphine has a strong respiratory inhibitory effect. Overdose of morphine and other opium drugs can cause death. An antidote for these drug addicts who risk their lives to take drugs is called naloxone, which is an antagonist of morphine substances.

In the early 1970s, scientists discovered that there is a receptor molecule on the surface of brain nerve cells that can recognize opioid drugs such as morphine. This receptor was therefore named "opioid receptor". Morphine blocks the pain signals received by the brain and reduces the feeling of pain by binding to this receptor. The role of naloxone is to prevent the binding of morphine molecules to receptors. In 1975, a group of researchers in Scotland discovered that the brain itself can also produce a class of substances with similar effects to morphine, called endorphins. Its original English name endorphin is the abbreviation of "endogenous morphine". Endorphins, like morphine, can bind to opioid receptors to exert analgesic effects and cause euphoria. In other words, it is an analgesic produced by our brain itself. From this point of view, the receptor that recognizes endorphins is named "opioid receptor", which is really putting the cart before the horse. This receptor was originally designed by the Creator to recognize endogenous analgesics, and morphine is just a cuckoo in the magpie's nest!

Jon Levine, a neurobiologist at the University of California, San Francisco School of Medicine, speculated that the analgesic effect of placebos may be related to endorphins. In order to confirm his conjecture, he designed an experiment. Levine found patients who had just had a tooth extracted two hours ago and were experiencing pain. He first gave them an injection of a placebo, but told them that it was a painkiller. After the injection, some patients' pain did not improve, while others had less pain. We already know that these patients whose pain was relieved are placebo responders, and the placebo effect worked on them; while patients whose pain was not relieved are placebo non-responders.

Now comes the key part of the experiment. The researchers gave all the patients another injection, this time with naloxone. After the injection, the pain of the placebo nonresponders did not worsen, indicating that naloxone itself does not cause pain; while the pain of the placebo responders increased significantly, reaching the same level as the placebo nonresponders. This result shows that the placebo effect was eliminated by naloxone.

It is known that naloxone is a specific antagonist of morphine, which can prevent morphine from binding to the opioid receptors of brain cells and block the pharmacological effects of morphine. However, these patients have not been injected with morphine, so what is the role of naloxone? The only reasonable explanation is that the placebo effect induces the brain to produce endogenous morphine - endorphins, which are the endorphins that relieve the pain of patients, and naloxone blocks the binding of endorphins to morphine receptors.

In 1978, Levine published his findings in The Lancet under the title “The Mechanism of Placebo Analgesia”[1]. Levine’s results were soon confirmed by other research teams. The epoch-making significance of this work was that it revealed the material basis of the placebo effect from a neurobiological perspective for the first time. Levine’s colleagues once commented: “Placebo biology was born.”

With the development of neuroscience, especially the use of non-invasive imaging technologies such as positron emission tomography (PET) and functional magnetic resonance imaging (fMRI), the brain's reward system can observe the activities of various parts of the human cerebral cortex in real time under non-invasive conditions. Neurobiologists have been able to directly locate the areas in the brain that control different functions such as memory, emotion, and language to different parts of the cerebral cortex. These studies have found that in addition to endorphins, the brain can also produce other similar endogenous hormones with therapeutic effects, which act through related specific neural control circuits. The famous dopamine is one of these hormones.

The brain is the nerve center that controls many behaviors of animals. There are two behaviors of individual animals that are particularly important to the entire population: one is eating, and the other is mating. Only by eating can the necessary nutrients be obtained so that the individual can survive and develop; only by mating can offspring be produced so that the population can continue. In the process of evolution, a set of mechanisms has been formed in animals through natural selection: rewarding beneficial behaviors to encourage more of them. Specifically, when eating or mating, a type of hormone that can stimulate pleasure is produced in the brain, called "happy hormones", including dopamine, endorphins, 5-hydroxytryptamine, etc. The operation of this reward mechanism involves the various parts of the nervous system that are in charge of different functions. One of the functions of hormones such as dopamine is to transmit information between the various parts and play a coordinating role, so it is also called a "neurotransmitter".

This reward mechanism is no exception in humans. Confucius said long ago, "Food, sex, and love are the greatest desires of human beings." Good food, beautiful voices, beautiful women, beautiful scenery, and all beautiful things can promote the secretion of happy hormones. Moderate physical exercise, singing, and dancing make people happy, because the brain knows that engaging in these activities is good for physical and mental health, so it secretes happy hormones to reward us.

A positive mental state and a healthy physiological state complement each other under the action of the reward mechanism. On the other hand, if one lacks rational self-control and blindly pursues the morbid pleasure of ecstasy caused by drugs, the reward system will be hijacked by drugs, which will lead to a vicious cycle, drug addiction and inability to extricate oneself, and step by step fall into an abyss of no return.

Like animals, the reward mechanism of the human brain can also be triggered by previous experience, that is, the conditioned reflex learned can also trigger the reward mechanism. For example, chili peppers can irritate the tongue and cause pain. In order to suppress this pain, the brain secretes endorphins that can relieve pain in the tongue, creating a euphoric feeling while relieving the pain in the tongue - it feels good! And we associate this pleasure with chili peppers. This is why people who love spicy food will be eager to try the spicy hot pot when they see it on the menu in a Sichuan restaurant.

In addition to rewarding beneficial behaviors, the happy hormones produced by the reward system often have other important physiological functions. The lack of these endogenous hormones may cause different diseases. For example, in addition to relieving pain, endorphins are also related to activities such as eating, drinking, exercise, and sexual intercourse; too low a concentration of serotonin is closely related to depression (see: Fanpu's article "In order to invent a good drug to treat depression, researchers have been depressed a lot"). Another example is dopamine, which not only makes people happy, but also affects learning, memory, and controls muscle movement. If the nerve cells that produce dopamine are damaged and the secretion of dopamine is reduced, it will cause symptoms such as limb tremors, stiffness, slow movement, and loss of balance. This is Parkinson's disease, a degenerative disease of the nervous system. The commonly used drug for the treatment of Parkinson's disease in clinical practice is levodopa. After taking it, the drug can enter the nerve cells and convert into dopamine, thereby alleviating the symptoms.

Clinical researchers have long discovered that when Parkinson's disease is treated with drugs, patients' expectations of treatment effects can cause a strong placebo effect, but the mechanism is unclear. In 2001, Canadian neurobiologist A. Jon Stoessl conducted a double-blind controlled trial with Parkinson's patients receiving treatment. During the experiment, PET scans were used to directly observe changes in the damaged dopamine active areas in the brain. The results showed that placebos can significantly increase the level of endogenous dopamine release in the test patients.

The Parkinson's patients who participated in the trial knew the efficacy of the drug, so they still expected their symptoms to improve even though they took the placebo, but mistakenly thought they were taking the drug. Dr. Stossel therefore concluded that this expectation can promote the production of dopamine in the brain. This important discovery was published in Science, and it was the first to link the placebo effect to the brain's reward system [2].

When we seek medical treatment, if we trust the doctor we see and the treatment he provides, we will have the expectation of recovery, which will subconsciously send a psychological hint to the brain: the disease will be cured soon. Therefore, the brain decides to reward our behavior of seeking medical treatment. As a result, specific parts of the reward system are activated, secreting hormones such as endorphins and dopamine. These happy hormones not only make us happy, but also cause various benign physiological reactions, alleviate symptoms, and promote recovery from the disease.

"Treating the symptoms" or "curing the root cause" ... Since the severity of pain mainly depends on the patient's subjective feelings and descriptions, people often raise the following question: the placebo effect can reduce the patient's pain and is indeed useful for relieving pain symptoms; but does it also have a therapeutic effect on the underlying diseases that cause pain, such as trauma and infection, or organic lesions such as cancer? In other words, in addition to "curing the symptoms", can the placebo effect also "cure the root cause"?

Pain is usually a manifestation of inflammatory response. Inflammation is a protective response made by the immune system to repair trauma and eliminate infection. Taking viral infection as an example, when the immune system detects invading viruses, various immune cells are mobilized, replicated and amplified in large quantities, migrated to the infected site, and secreted various cytokines with different functions according to their respective division of labor. Some cytokines can directly inhibit the replication of viral nucleic acids; some can regulate the gene expression of infected host cells to put them into an antiviral state; some can mobilize immune cells in other parts of the body to quickly rush to the battlefield to support the antiviral battle. Some immune cells, such as natural killer cells (NK cells), can also directly kill host cells that have been infected by viruses together with the viruses in them. This series of reactions is manifested clinically as the redness, swelling, heat and pain we observe. Through such inflammatory reactions, the immune system may be able to eliminate the virus and restore the patient to health.

However, the inflammatory response is a double-edged sword. It can kill viruses but also cause damage to the body's own tissues. If the immune system overreacts, forming a so-called "inflammatory storm" or "cytokine storm", it can cause extensive damage and functional failure of multiple organs and tissues, endangering life. This is how the severe COVID-19 disease caused by the new coronavirus that broke out in early 2020 occurred.

If the immune system is abnormal, it may mistake healthy tissues for foreign invaders and initiate an inflammatory response to destroy them, which can lead to various autoimmune diseases, such as rheumatoid arthritis and lupus erythematosus. In addition, chronic inflammatory responses are also associated with cardiovascular disease, type 2 diabetes, dementia, etc. The latest research has found that the normal function of the immune system may also help prevent depression and maintain mental health[3].

In addition to protecting the body against infection, the immune system can also monitor carcinogenic mutations occurring in normal cells, eliminate such mutated cells in a timely manner, and eliminate cancer in the bud.

Since the various organs of the immune system are controlled by the central nervous system, just like the rest of the body, it is not difficult to imagine that various psychological activities rooted in the brain, including those related to the placebo effect, may affect the function of the immune system through signals transmitted by the nervous system.

Clinical studies have long found that psychological states such as depression and anxiety increase the body's susceptibility to infectious diseases, while positive and optimistic emotions can promote physical health, including the health of the cardiovascular system and recovery after infection by pathogens. Researchers believe that this connection between mental health and physical health is achieved through the placebo effect, and positive expectations for health can accelerate the patient's recovery.

As mentioned earlier, clinical trials have confirmed that Parkinson's patients' expectations of treatment effects can activate the brain's reward system, release dopamine, and alleviate symptoms. So can the hypothesis that the placebo effect regulates the immune system and enhances resistance to infection also be verified experimentally?

Experiments have the final say! In 2016, a group of neurobiologists in Israel carefully designed an experiment using mice to artificially stimulate the reward system in the mice's brains and then examine whether the mice's immune function to resist bacterial infection changed [4].

The first step of the experiment was to install a switch on the nerve cells responsible for synthesizing dopamine in the mouse brain, allowing researchers to control the release of dopamine from the cells. The switch is a specially designed protein molecule that spans both sides of the cell membrane. The end exposed outside the cell is a receptor that can recognize a drug molecule called CNO. Once CNO binds to the receptor, the switch is triggered, and the other end of the switch on the inside of the cell membrane sends a stimulation signal, causing the cell to produce dopamine.

How is this switch installed? The researchers first constructed the gene encoding the protein switch molecule and inserted it into the genome of a virus that can infect nerve cells to obtain a recombinant viral vector. Then, they used microinjection to directly inject the viral vector into the ventral tegmental area (VTA) in the brain, an area in the reward system that can produce dopamine. The viral vector infected the nerve cells of the VTA, brought the switch protein gene into the cell, and guided the synthesis of the switch protein molecule. These molecules inserted themselves into the cell membrane, and the task of installing the switch was completed.

Next, the researchers injected the mice with the drug CNO and then observed changes in the mice's behavior. CNO molecules enter the VTA area of ​​the brain through the bloodstream, bind to receptors, trigger switches, and cause cells to produce dopamine. The mice used in these experiments were kept in two connected chambers and could move freely between the two chambers. Before the injection of CNO, the mice wandered back and forth between the two chambers, spending roughly the same amount of time in each chamber. After the injection of CNO, the mice stayed longer in the chamber where they received the injection than in the other chamber. Why? Because the drug activated the VTA area and activated the reward mechanism, the mice stayed there more happily wherever the drug was injected and were reluctant to leave. In addition, compared with control mice that did not receive the injection, mice with activated VTA areas also increased their social behavior with their companions because the happy hormone made them friendly!

So far, the researchers have achieved the precise activation of the reward mechanism through artificial intervention. Everything is ready, and we can start collecting the most critical experimental data. The researchers first injected CNO into the experimental mice to activate the VTA area. After 24 hours, they checked the various immune cells of the mice and found that their activity had increased. At this time, when the mice were infected with bacteria, the ability of these immune cells to kill bacteria was significantly enhanced, and the number of bacteria in the mice was significantly reduced. In addition, after the reward system was stimulated, the level of protective antibodies against bacteria also increased. These results clearly prove that activating the reward system can enhance the ability of the mouse immune system to fight pathogen infection.

Since the placebo effect is achieved by stimulating the reward system through the expectation of recovery, the results of this study indicate that the placebo effect also has a certain therapeutic effect on diseases caused by pathogenic microorganisms.

In 2018, the same group of researchers published another important article: using a similar experimental system, they activated the brain's reward system in a mouse model of lung cancer and melanoma, thereby enhancing the immune system's anti-tumor function and shrinking the tumor [5]. Although the same experiment cannot be conducted in humans, the results of this animal experiment have well explained the phenomenon observed in the clinic: an optimistic attitude helps prolong the survival time of cancer patients.

These results show that the placebo effect is based on the activation of the brain's reward system. The structure and function of the brain itself provide the necessary platform for the placebo effect. Can doctors use this condition to enhance the treatment effect in clinical practice?

(to be continued)

Main references

· Finniss DG. Placebo Effects: Historical and Modern Evaluation. Int Rev Neurobiol. 2018; 139: 1-27.

· Hashmi JA. Placebo Effect: Theory, Mechanisms and Teleological Roots. Int Rev Neurobiol. 2018; 139: 233-53.

· Evans D. Placebo: mind over matter in modern medicine. London: HarperCollins Publishers, 2004.

· Vance E. Suggestible You: The Curious Science of Your Brain's Ability to Deceive, Transform, and Heal. Washington DC: National Geographic Partners, 2016.

References

[1] Levine JD et al. The mechanism of placebo analgesia. Lancet. 1978; 2: 654-7.

[2] de la Fuente-Fernández R et al. Expectation and dopamine release: mechanism of the placebo effect in Parkinson's disease. Science. 2001; 293: 1164-6.

[3] Pappalardo JL et al. Transcriptomic and clonal characterization of T cells in the human central nervous system. Sci Immunol. 2020;5: eabb8786.

[4] Ben-Shaanan TL et al. Activation of the reward system boosts innate and adaptive immunity. Nat Med. 2016; 22: 940-4.

[5] Ben-Shaanan TL et al. Modulation of anti-tumor immunity by the brain's reward system. Nat Commun. 2018; 9: 2723.