Heather Zwickey, PhD, is the dean of research and graduate studies at the National University of Natural Medicine (NUNM), director of the Helfgott Research Institute, and professor of immunology. In 2003, Dr Zwickey launched the Helfgott Research Institute at NUNM, where she applies her immunology expertise to natural medicine. She studies the immunological mechanisms involved in nutrition, herbal medicine, acupuncture, and mind-body medicine. Her current area of focus is the inflammatory components of Parkinson’s disease. Dr Zwickey has used her expertise in program development to establish the School of Research and Graduate Studies at NCNM, and she serves as its leader. She has developed masters programs in integrative medicine research, nutrition, and global health.
Integrative Medicine: A Clinician’s Journal (IMCJ): In the description of your presentation on the Association for the Advancement of Restorative Medicine, or AARM, Web site, it says that neuroimmunomodulation is a rapidly expanding area of research. How far back does the discipline go?
Dr Zwickey: It goes back to the late 1800s. You remember Ivan Pavlov and Pavlov’s dogs? Well, Pavlov had a contemporary named Ilya Mechnikov, and Mechnikov studied psychoneuroimmunology—what today we call neuroimmunomodulation. The terms are not quite synonymous with each other, but they are pretty close. Mechnikov would study how he could get animals to control their immune system using their nervous system. For example, he could use a smell and get them to control an autoimmune reaction with the smell.
So, the field is actually quite old; however, we have not done as much with it because, of course, Descartes had us separate all of the different systems. So, we separated the nervous system from the endocrine system, from the immune system, etc. When we did that, we created separate disciplines that people study, and rarely do the disciplines overlap. You wind up with people who are very expert in their particular discipline—neurology, or endocrinology—and know nothing about the immune system, and know nothing about how the nervous system actually modulates the immune system on a regular basis, much less how you can manipulate it to modulate it more.
IMCJ: How did researchers discover that the neurological system could modulate the immune system, and vice versa?
Dr Zwickey: We have known for a long time that people would have what we call psychosomatic responses. These are the responses where people would say, “Oh, it’s all in your head.” And this might be them making themselves sick, versus making themselves well. People started becoming really interested in those psychosomatic responses, and what happened was a paradigm shift. When did that happen? The 1980s and 1990s were when we started to notice the scientific community sit up and take notice. As they started studying this, they started asking, “What’s happening with these people who have a positive attitude, and they get better? What happens to these people who are depressed and they seem to be sick? What’s going on there?”
The first thing that happens when you have a paradigm shift like this is that the public wants to know what’s going on. The next thing that happens is that a few forward-thinkers come into the field and they start studying it. And then you create a journal. The journal that was created and that I think has driven this field forward the most is called Brain Behavior and Immunity.
You start seeing papers being published that show, for example: When you are depressed, you actually have an overabundance of one of the proteins of the immune system, called interleukin 1, or IL-1. This means that there is a relationship between depression and the immune system. That was completely unheard of. Before that discovery, everybody thought that depression was coming from serotonin and dopamine levels and that there was no immunological component to it at all. Then they started describing some of these connections that were happening.
They also started looking at the vagus nerve, and the role of the vagus nerve between the immune system and the brain. What most people do not realize is that every lymph node is innervated. They started seeing that not only is the lymph node innervated, but there are actually signals being sent from the lymph node to the brain, and vice versa. Then, in the late 1980s and early 1990s, you had people demonstrating that all the cells of the immune system had neurotransmitter receptors—they were responsive to these neurotransmitters.
People‘s response was, “Oh my goodness! Now we’re starting to see the mechanism for how these things are happening, so it must be real.” That is one of the major shifts of psychoneuroimmunology, neuroimmunomodulation— the recognition that the receptors are there, so it can happen. Before that, people just assumed that the neurotransmitters were somehow suppressing the immune system or strengthening it, without knowing how it was happening.
IMCJ: When you say that this correlates to the idea of psychosomatic illness, or psychosomatic wellness, how closely does this correlate to the placebo effect?
Dr Zwickey: Very strongly. In fact, researchers who study the placebo effect these days—also now called the expectation effect—many of them are also looking at neuroimmunomodulation. In fact, we had a grant with OHSU, Oregon Health and Science University, that looked at the effects of expectation on neuroimmunomodulation for a model of lupus. There was a very strong correlation. And, of course, you have to remember that the placebo effect is named placebo effect when we do not understand the mechanism. As soon as we understand the mechanism, it is no longer called the placebo effect, right? Part of it is the nomenclature.
IMCJ: Are there specific areas where clinicians have the opportunity to intervene in the system, to create or stimulate wellness?
Dr Zwickey: Sure. Here is one of the many interesting things about neuroimmunomodulation psychoneuroimmunology. We talk about the nervous system, the endocrine system, the immune system, and psychology or mood. But the other system that strongly impacts this is the microbiome. The gut is also innervated by the vagus nerve. And we know that the highest production of neurotransmitters—dopamine, serotonin, GABA—happens in your gut rather than in your brain. You also have more of your immune system in your gut than you do in the rest of your body, including your spleen and your lymph nodes. So, the place where a lot of this interaction actually happens is in your gut.
Most people think of it as happening in the lymph nodes in the brain, but it does not. It is not that it is not happening there, but it is happening more in your gut than in your lymph nodes and in your brain. Once you realize that this is all occurring in the gut, now you have lots of ways to manipulate it. You can manipulate it through the psychological aspect, using mind/body therapy. You can manipulate it through the aspect of the gut, using probiotics to affect the gut or nutrition. You can manipulate it through a hormonal perspective. We have not talked as much about the hormonal aspects, but all of the cytokines are controlled by hormones. Hormones act as the rheostat for cytokine levels. If you think about how much of a particular cytokine you make, it is dependent on testosterone, prolactin, estrogen—all those various things. As you manipulate those hormones, whether you are giving a patient a hormone replacement therapy, testosterone, or a precursor, like DHEA, you are manipulating their immune system, which is, in turn, manipulating their mood. Most people do not recognize how those things are alike. And that is one of the things that we’re going to be talking about.
IMCJ: That sounds fascinating.
Dr Zwickey: Yes, it is going to be fun.
IMCJ: The description for your presentation refers to biological responses to emotions. Specifically you called out stress and how that influences the interactions through neuroimmunomodulation.
Dr Zwickey: When considering chronic stress, one of the things that we think about is a raised level of CRH, corticotropin-releasing hormone, which raises the levels of ACTH, adrenocorticotropic hormone, and cortisol. And when you raise those hormone levels, you have raised the levels of hormones that interact with glucocorticoids. You have raised the level of hormones that interact with nuclear factor kappa B, which is a transcription factor that is highly involved in immune response. As you look at what happens in people who are in acute stress situations, and you have very sharp peaks of these hormones, you get the effect on the immune cells of them trafficking completely differently. Originally when this was described, the Nobel Prize was won for the effect of glucocorticoids on the immune system. What they showed was that it had the equivalent effect as shutting the immune system down.
Now, in a chronic stress situation, you see something a little bit differently, because you do not have the peak levels, but you have higher-than-normal levels in a chronic state. And higher-than-normal levels in a chronic state, instead of shutting down cytokine production—it tends to drive the immune response towards what is called a Th2 response, which is more like an allergic immune response, as opposed to a response that would fight bacterial disease. In a chronic stress situation, the immune system is out of balance. When the immune system is in balance, you have easy flow between Th1, Th2, and T-regulatory responses. When it is out of balance, one of those responses dominates. And when one of those responses dominates, then you wind up with disease.
IMCJ: As you are addressing that in a clinical setting, what are some of the things you look for?
Dr Zwickey: I work in a naturopathic setting, so most naturopathic physicians will recognize chronic stress in their patients. They will recognize it in symptoms that patients describe with respect to food hypersensitivities and food allergies, with respect to fatigue, and with respect to anxiety. The interesting thing about all of those symptoms is that the symptoms actually correlate very strongly with the cytokines that are being produced and the response to the hormones that are made in the chronic stress situation. Chronic stress tends to elevate one cytokine in particular, which is interleukin 6, or IL-6. IL-6 is associated with fatigue, depression, and anxiety. You might be seeing something clinically and be stuck, until as a clinician your brain starts to trigger, “Oh wait, that’s this particular immunological cytokine. Now I know how to treat that cytokine.” Even if I cannot force my patient to make their stress go away, I can treat the underlying cause of the anxiety and the depression that are associated with being in that chronically stressed state.
For example, there is an herb called feverfew, and feverfew was described because it reduces fever. And the effect of IL-6 on the immune system is fever, but the effects of IL-6 on the nervous system are anxiety and depression. I can give somebody feverfew to reduce their fever, or I can give them feverfew to reduce their anxiety. It would be called, in the pharmaceutical industry, the off-label use of a drug, right?
IMCJ: Thinking in the herbal space, it sounds like an adaptogen.
Dr Zwickey: Exactly. Ashwagandha is another great example of an herb that works in that way where it is simultaneously affecting the nervous system and the immune system.
IMCJ: As the research builds in this particular discipline, do you think it has the potential of reaching a tipping point where this could hold more promise for psychiatrists than the array of pharmaceuticals?
Dr Zwickey: What I think it really holds promise for is chronic disease. Where we really struggle is that dysfunction is not limited to one pathway in chronic disease. If you look at most pharmaceuticals, pharmaceuticals target one pathway. There are individual ingredients, acting as inhibitors, and they target one pathway. Whereas, what you see with most integrative therapies is that they target multiple pathways. They simultaneously target the immune system, the endocrine system, and the nervous system. When you have a chronic disease, where there are multiple pathways that are out of balance, rather than doing polypharmacy, doing some of these therapies that simultaneously target multiple pathways seems a whole lot safer to me, and far more effective.
That is where you see some of these natural medicine doctors and integrative medicine doctors—who are having success—is in these complex cases. Things like inflammatory bowel disease, where it is not one thing that has gone wrong—it is multiple things going wrong—so a single drug that blocks TNF-alpha will calm the inflammation, but it will cause cancer as a side effect—and infections, and tuberculosis, and all these other things. Whereas if you take some of these other therapies that are simultaneously targeting the immune system, nervous system, etc, you can actually impact inflammatory bowel disease. Take vitamin D, for example. Vitamin D affects 250 different pathways. Here you have one substance that is not limited to a single pathway for its effects. And as we start to view therapeutics in this way, we address chronic conditions far better than drugs can.
IMCJ: So, in that way, it may be similar to what Dale Bredesen is doing with dementia and cognitive impairment …
Dr Zwickey: Oh yeah, I love his work.
IMCJ: … those 32 potential targets that accumulate until you find the tipping point and the impairment regresses.
Dr Zwickey: That is right. You can try to do that with multiple drugs. The problem is that the drugs start interacting with each other and causing horrible side effects. We see people in the clinic, here, who are on 12 or 15 different drugs. They are on a drug to counteract the side effects of the first drug. Then the side effect of the second drug has to be counteracted, and so on. It is not that you end up with multiple benefits at that point— you are just trying to treat all the various symptoms caused by the various drugs. Whereas what you see with a lot of the natural therapies is that they end up enhancing each other instead of canceling each other out.
IMCJ: I understand that your presentation at AARM will have part 1 and part 2 spread over 2 days.
Dr Zwickey: It does.
IMCJ: In addition to what we have covered, what more will attendees learn about neuroimmunomodulation?
Dr Zwickey: Pretty much nothing. I think I have just given away the whole farm. … No, I’m just kidding! My intention, first of all, is to get everybody to understand how the immune system, nervous system, and endocrine system interact. When we talk about various cytokines, physicians will hear about specific effects and think, “Oh, that’s that patient.”
And then we will talk about what that cytokine is doing with the nervous system and the endocrine system. Then what typically happens for a physician is they think, “Oh, that is why when I give this therapy, it works.” Or, “That means I should try this therapy instead.” I am hoping that some of those clinical pearls are going to pop out for them. And I will be giving examples of some clinical things that they may not have recognized previously based on an interaction that they have not been previously aware of. For example, not understanding that when they put a woman on HRT, or hormone replacement therapy, that there are specific downstream nervous and immune system effects in addition to the hormonal effects.