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A Question of Mind over Immunity

By: Robert Fuhlbrigge, MD, PhD | April 14, 2016 | What Caught Our Eye

As pediatric rheumatologists, we are familiar with issues of anticipatory nausea in patients taking methotrexate and potent placebo effects that influence the interpretation of clinical trials in our field.

The power of the mind to influence physiologic symptoms is impressive. But what if we could harness this power for good? What if you could teach your patients to respond as if they were exposed to a medicine even if they were not?

Have you have ever gotten sick after eating a specific food, and for weeks or months afterward, you found you couldn’t face eating it again? This is called learned or conditioned taste aversion, which seems to make teleological sense (i.e., avoiding foods that have poisoned you in the past protects you from getting ill again), and can be both potent and long-lasting. In the 1970s, Robert Ader, a psychologist at the University of Rochester, was studying taste aversion in rats and stumbled across a most unusual result. Ader conditioned animals by providing a saccharin solution, a sweet taste rats love, with small doses of cyclophosphamide, which made them feel sick. After several cycles of training, the rats would refuse to drink the saccharin water, just as he expected. As a control, he force-fed conditioned rats a small amount of saccharine water to see if it caused a change in behavior. Instead, they died, succumbing to infection as if they had received a dose of cyclophosphamide. He followed this up by showing conditioned animals exposed to saccharine at the time of vaccination also produced markedly lower specific antibody responses, similar to mice who were treated with cyclophosphamide during the immunization period (Ader and Cohen, Psychosom Med., 1975).

The phenomenon in which contextual cues are associated with a physiological response is well known. As we all recall from Psych 101, behavioral conditioning was first described by the Russian physiologist Ivan Pavlov in the 1890s, who noticed that dogs learned to associate his presence with being fed so that his arrival caused them to salivate even if he had no food. He showed that different signals – such as a buzzer or electric shock – could be used to trigger the same automatic response.

Learned associations are an important part of our daily lives. Cues prepare our bodies for important biological events and trigger responses that help us avoid danger. For example, I fall asleep as soon as a lecture starts so that I am not exposed to any dangerous new ideas. While this effect was well-known for responses known to be associated with the brain – such as nausea, heart rate, and salivation – Ader’s results were revolutionary because they showed that learned associations could influence immune responses too.

Ader and his colleagues, followed by a series of other investigators, went on to describe similar effects of conditioning on cell proliferation and DTH responses, in addition to both thymus-dependent and -independent antibody production, and graft vs. host disease. Subsequent exploration of the signaling pathways involved has demonstrated both direct sympathetic nerve innervation of spleen and lymph node and involvement of both endogenous opioid and adrenergic signaling pathways.

In 1982, Ader extended the impact of this concept by showing that behavioral conditioning could be used to prevent disease in lupus-prone mice. He trained mice to associate cyclophosphamide with saccharin solution, just as in his original experiments, and showed that conditioned mice given saccharine water along with half the usual drug dose used to prevent development of nephritis experienced slower disease progression and lived longer than either conditioned mice on half dose who did not receive the stimulus or control mice on full dose cyclophosphamide.

Extending his work to humans, Ader conducted a study in 1996 in which 10 patients with multiple sclerosis were conditioned with cyclophosphamide and a bitter flavored syrup. When later given the syrup along with a placebo pill, eight of the ten showed a degree of leukopenia similar to treatment with a dose of cyclophosphamide. Ader also reported that control of psoriasis could be achieved with a quarter to half the dose of corticosteroid ointment when used in conjunction with conditioned responses compared to controls.

Manfred Schedlowski, a medical psychologist at the University of Essen in Germany, has shown in a pilot trial that lupus patients conditioned with taste aversion and cyclosporine A showed 20-40% greater suppression cell proliferation and reduction of IL-2 production than patients treated with drug alone. A larger trial is ongoing to try and demonstrate if disease control can be accomplished with lower drug doses over an extended period of time. Schedlowski and colleagues have also reported that conditioning with an antihistamine can reduce immune responses and symptoms in allergic rhinitis, and, by a report of unpublished studies, that conditioned responses can augment drug responses in both animal models and human patients with arthritis.

So, while the phenomenon of behavioral modification of immune responses has been around for 40+ years, it is just now coming into its own as a defined biological mechanism and as a legitimate method for manipulation of disease and drug effects in humans. The potential, to achieve disease control with no or substantially lower drug doses, could be transformative, resulting in reduced costs, fewer off-target drug effects, improved quality of life, etc. across a broad spectrum of diseases ranging from allergy to autoimmunity to cancer.

Key questions remaining include pinning down the precise mechanisms controlling conditioned immune responses and why some individuals respond more strongly to conditioning than others. Interestingly, people with high levels of anxiety appear to respond better to conditioning, possibly because they have a more active sympathetic nervous system.

Equally important will be the exploration of how to best employ this effect in broad populations.

Paul Enck, a medical psychologist at the University of Tübingen, Germany, has suggested a method that he calls “placebo-controlled dose reduction.” In a 2010 trial, children with attention deficit hyperactivity disorder (ADHD) were given a distinctive green-and-white placebo pill alongside their regularly prescribed drugs. The children knew these pills were placebos, but those who went through this conditioning process later did just as well on the placebo and half their normal drug dose as a control group without conditioning did on full drug dose, and significantly better than children with ADHD who received the placebo and a half-dose without conditioning. If used widely, the cost effects could be dramatic. In the US, for example, drugs for ADHD are reported to total more than $5.3 billion of medical expenditure each year.

Unfortunately, the novelty of the concept and the prospect of dramatically reduced drug use may also be the primary barriers to exploration. To most doctors and scientists, the concept of immunomodulatory treatments with no pharmaceutical component is hard to grasp. Using placebos in open-label treatment trials is certainly innovative, but getting reviewers to understand and clinicians to support this sort of paradigm shift may take substantial time and effort. And it goes without saying that drug manufacturers, which drive most of the applied research into dosing and development of new therapies, might have a hard time finding incentive to fund studies that would reduce the amount of medication used.

Finally, it is interesting to consider what this means for our understanding of the placebo and ‘nocebo’ effects in both clinical trials and daily clinical management. Perhaps more on that another day.

There is still a long way to go, but the ride only gets more interesting.

This story includes material from an article by Jo Marchant that first appeared on, and is republished here under a Creative Commons license CC-BY 4.0.