The placebo cure

What happens when a control group mimics a drug response?

Five round pills lined up with smiley faces drawn on the front

Hope and expectation and the sense of being cared for are constructs, but those constructs are also states in our brains. When our brains are active, a tangible, measurable response arises. This is neither coincidence nor magic: It is the science behind placebos. 

The “placebo effect” refers to a non-medicated reaction to an inert drug treatment, and is used colloquially to infer a physical response to a stimulus that is arguably imaginary. While operating primarily as controls in a study, placebos themselves can play a role in the treatment.

Randomized double-blind placebo control studies are considered the “gold standard” of epidemiologic studies. Neither the patients nor doctors are aware of who is in the active drug group, and who is in the placebo group. 

A placebo is medically inert, but it is administered like a drug. This is key, for the quantifiable, measurable effects reported in placebo control groups are a result of the placebos’ mimicry of a drug. The ritual of swallowing a drug, the setting, even the level of faith or esteem a control subject has in the doctor involved has a marked, quantifiable effect—i.e., the placebo effect. 

In a brain scan of pain relief elicited by a placebo, part of the frontal lobe is activated. Expectation of relief activates the reward center of the brain and releases endorphins. Endorphins work to alleviate pain, hence the placebo has created a desired effect to reduce pain. In drug treatment, if symptoms are modulated by the brain, a placebo effect can have quantifiable results, and in one study, the same results as a drug. 

In one example, Carsten Skarke, a research assistant professor of medicine, sought to understand the relationship of fish oil and alcohol. “How do they have good effects? People in the Mediterranean, the South of France, Italy etc., have lower cardiovascular morbidity than northern areas of Europe.” 

Skarke addressed that query in a study using prescription fish oil caps and supplemented healthy volunteers for four weeks. Fish oil is an omega-3 fatty acid, and an active placebo—omega-6 caps—was the control, delivering similar amounts of fats but with a distinct effect on the composition of cell membranes where the fatty acids are built in. Healthy volunteers were randomized and looked at for parameters. 

“We were interested in cardiovascular effects of fish oil, specifically the long chain fatty acid DHA and EPA. For that research, fish oil and alcohol were studied for their effects on markers of cardiovascular health,” Skarke says. “Omega-3 subjects, in comparison to omega-6, gave us a signal of improved metabolic effects associated with DHA and EPA. We used grain alcohol dosed to body weights and mixed in lemonade. The control in that study was just lemonade. This design helped us to understand that circulating levels of a certain peptide increases due to the alcoholic drink.” 

The findings, according to Skarke, provide important leads to understand the underlying mechanisms. Here, the use of placebo conditions increases the credibility of the findings and provides a new angle to look into the relationship between the fish oil and alcohol.

In order to successfully come to that conclusion, other mitigating factors need to be eliminated. By controlling the outside environment, the “noise,” cause-and-effect is distilled. 

“If you run a study there are always certain conditions associated with control trials,” explains Skarke. “Patients come to a dedicated study room. Personnel is trained. It’s always the question of whether your findings are initiated through treatments or through other factors or other elements. That’s why you always need a placebo integrated.”

The combination of patient expectancy with the conditioning in the brain, the placebo induces an effect elicited by a placebo capsule alone. When trying to reduce a drug dosage over time, the use of a placebo on non-medication days extends the level of therapeutic effect more than intermittent dosing. 

“If you look at a drug and how it cures a certain disease, you start treating patients with them,” says psychiatry professor Michael Thase. “Then look six months later: In some cases, with certain diseases, some people will get better and some will get sicker. If you add a randomized control group to that, the placebo group will give you a sense of order.”

There are other aspects of a placebo response—being active and engaged with solving the problem, and the whole process of care involved. “If you were just given a box of pills you wouldn’t be so engaged. Much of the response is the expectation—you feel more confident going to a prestigious doctor or hospital, or if the doctor is kindly, it builds and fosters hope,” Thase says.

The role of the placebo is to provide a baseline with which to compare the treatment group. In some areas of research, randomized double blind placebo control studies are not always an option. “In cancer care, it’s unethical to do placebo control unless there is no other treatment available, so most of the clinical trials in cancer, you test the new treatment against an existing treatment or a standard of care,” explains Patricia Corby, associate dean of translational research at the School of Dental Medicine

In drug research, the placebo also functions as the hurdle past which new drugs have to outperform in two independent studies in order to receive FDA approval. However, the effects of the drug are measured above the placebo effect, meaning the drug has to work a percentage higher than the placebo measures. 

The FDA recently approved esketamine as an effective adjunct to standard antidepressants for patients with clinical depression who have not responded to other treatments. The randomized control studies with esketamine were funded by Janssen Lab, with Thase serving as a principal investigator for the clinical trials that were conducted at Penn. He explains: “At the outset of our research, the placebo response rate was about 20 percent, which is low for studies of antidepressants. As has happened with some other new medicines, the placebo response rates increased as the level of hope and expectation about esketamine increased. Today, just as esketamine is about to be marketed, there was a tidal wave of expectations and enthusiasm, so you might expect to find a 40-50 percent placebo response rate. So, if esketamine is observed to deliver a 60 or 70 percent response rate, the actual drug only offers about a 10-20 percent response over the placebo effect.”

For new drugs, a pilot study is the first step. That is where researchers get a preliminary understanding of how effective the new treatment may be and just how many outliers they might have. 

In other words, the “noise” of conducting the study, including the number of outliers (i.e., people with results that are much different than the average patients), will help determine the number of studies that may be needed to be done and how many people should be enrolled in each study. With this information, researchers can maximize the chances that the studies will produce adequate tests of the drug’s utility. Usually, a drug company will plan to conduct at least three or four large scale studies of a new antidepressant to ensure that at least two of the studies are statistically significant (i.e., the drug has the predicted advantage compared to the placebo).

However, interesting things are happening on the placebo side, including some changes in brain physiology. Patients in a control group can become better on their own. Researchers can factor that the more patients get better with placebos, the greater number of subjects are needed. 

“The placebo condition also provides a reference for side effects,” says Thase. “It normalizes non-drug related factors to help tease out how much the drug has made a result.”

The promise of relief is a powerful remedy in itself. People claim measurable effects to wildly varying doses of non-FDA approved and unregulated self-medication protocols. CBD oil is an example of a hugely popular drug that has had virtually no randomized double-blind placebo control studies, save for Epidiolex, a pediatric anti-seizure medicine. Not only is the unregulated CBD oil marketed as potent and effective at varying doses, numerous people lay claim to measured, marked efficacy in depression, insomnia, and even seizures. 

Without the studies and FDA approval, there is no way to know whether the power of the CBD oil is eliciting a response, or if the placebo effect itself is providing therapeutic relief. With a neurological response akin to relief, what exactly is the difference?