Image by Brian D’Cruz Hypno Plus

There are two basic schools of thought in medicine: mechanism, and vitalism.

The mechanistic school of thought argues that the body can be reduced into individual systems, and each system is complete within itself. The vitalistic idea argues that each system interacts with every other. The field of psychoneuroimmunology (PNI) clearly belongs to the latter—and as such, initially it was scorned as pseudoscience.

Not anymore.


In the 1970s, psychologist Robert Ader led an experiment which fed rats a saccharin-laced solution containing a drug which both caused gut distress and also suppressed the immune system. As in the classic Pavlov’s dog experiment, the rats learned to avoid the solution—but it turned out that the saccharin alone continued to cause immune suppression in the rats, even without the drug. This implied a connection heretofore unknown: a link between psychology and immunity. Thus, the field of PNI was born.

Being Sick Can Make You Stressed, and Stress Can Make You Sick

The HPA axis (the hypothalamus, pituitary, and adrenal glands) together with our sympathetic nervous system mediate our stress responses as humans. The hypothalamus produces CRH, which triggers the pituitary release of ACTH, which triggers cortisol release. Some of this happens in a normal day—but in an acute stress response, release of adrenaline (or epinephrine) from the sympathetic nervous system will trigger additional release of these steroid hormones. Steroids, of course, are anti-inflammatory—that is, they suppress immune function, or at least the innate immune responses. This makes sense: in an acutely stressful situation, you want to marshal all your resources for fighting or fleeing. You don’t want to waste precious energy fighting off infections that might not kill you until weeks or months down the line. This study shows how healthy adults’ immune systems respond to stressful events: namely, a decrease of helper T cells, suppressor T cells, cytotoxic T-cells, B cells, and Natural Killer cells.

At the same time, being sick is a stressor. When presented with a potential foreign invader, specialized immune cells called macrophages gobble it up and present the fragments to T-cells, so that the T-cells can decide whether or not the invader is a threat. Dr Stephen Maier demonstrated that in the process, macrophages also release a cytokine, or an immune signaling molecule, called interleukin-1. This tiny molecule can’t cross the blood brain barrier to let the brain know there’s a potential problem, though—instead, the vagus nerve (one of the cranial nerves) has receptors for interleukin-1. When the cytokine binds its receptor, the vagus nerve then sends the signal of possible invasion upstairs. The brain gets the message and produces its own cytokine signaling molecules, telling the rest of the immune system to gear up for battle. In a feedback loop, inflammatory cytokines will in turn stimulate the release of ACTH and cortisol: the stress hormones. 

Emotional stress, it turns out, follows this same procedure, except it bypasses the macrophage step. Not only does stress release the hormones from the HPA Axis, but it also increases interleukin-1, even in the absence of an actual infection.

There’s also a clear connection between high levels of interleukin-1 and depression, possibly as part of the stress response associated with illness: the body needs low activity and sleep in the case of illness in order to conserve energy and recover faster. These are also two of the hallmarks of major depression.

Neuropeptides: the “Molecules of Emotion”

Neurotransmitters are the molecules commonly referred to when discussing signaling within the brain itself. Classically they communicate only within the synaptic cleft, or the space between two neurons where their receptors are found. They transmit their message and are subsequently broken down. Most psychotropic medications either slow the breakdown of neurotransmitters, so that they can send their messages longer, or affect the receptors such that the message is either stronger or else blocked.

Neuropeptides are a different type of neurotransmitter, though—there are over a hundred of these that we know of so far, and we’re discovering more of them all the time. Neuropeptides have longer lasting effects than classic neurotransmitters, they affect a broad array of behaviors, emotions, and brain functions, and they don’t send their messages via the synaptic cleft. In fact, according to Candace Pert, researcher and author of the book “Molecules of Emotion,” less than two percent of neural communication occurs at the synaptic cleft (139). This suggests that most neural communication occurs via neuropeptides, not neurotransmitters.

Here’s why we care: In 1985, Pert discovered receptors for these neuropeptides on immune molecules. Not only that, as she writes in the book, “immune cells also make, store, and secrete the neuropeptides themselves.  In other words, the immune cells are making the same chemicals that we conceive of as controlling mood in the brain.  So, immune cells not only control the tissue integrity of the body, but they also manufacture information chemicals that can regulate mood or emotion” (183).

The Upshot

So here’s what we know.

  • The immune system and the brain talk to each other.
  • Stress causes immune suppression, and illness causes stress.
  • At least one mechanism of acute illness and chronic depression may be the same (interleukin-1).
  • The molecules that are biologically responsible for emotions communicate directly with the immune system—for good or for ill.

Many, if not all, of the books I have read on PNI reference one other fascinating book, “The Anatomy of an Illness,” by Norman Cousins. It’s the true story of the editor of a scientific publication, afflicted with an inexplicable but potentially fatal illness. When diagnosis and traditional treatment failed him, he nevertheless recovered fully through self-prescribed humor therapy (that is, he rented or read comedies and “laughed his way to health”). The book was published in 1979, well before Candace Pert’s discoveries and long before the widespread acceptance of the ideas of PNI. Fortunately, we’re now developing a framework to explain why this can happen.

The mind-body connection grows clearer all the time.