Richard G. Petty, MD

A Missing Link: Serotonin, Inflammation and Psychiatric Illness

We have previously looked at the extraordinarily high rates of inflammation in psychiatric illnesses, as well as the evidence implicating disturbances in the serotonin transporter and an array of psychiatric and physical illnesses, including fibromyalgia and irritable bowel syndrome. Disturbances in serotonin homeostasis as well inflammation-promoting (pro-inflammatory) cytokines have both been implicated as causative factors in major mental illness. So the hunt has been on to see if there’s some way of uniting these two causative pathways.

There’s an exceptional important paper out this week in the journal Neuropsychopharmacology.

Investigators from the Vanderbilt University School of Medicine in Nashville, Tennessee, have established that the pro-inflammatory cytokines interleukin-1beta and tumor necrosis factor-alpha activate serotonin transporters. Using rat cells, they were able to show the precise mechanism by which these cytokines could regulate the activity of the serotonin transporter.

So why is this so important? Not only does it open up several new options for treating mental illness, but it may also explain some puzzles.

It’s recently been shown that mental illness is more common in overweight people. Large amounts of fat in the abdomen act as a kind of inflammation factory, soaking the circulation in inflammatory mediators. So here we have a link between ever expanding waistlines and the increasing rates of mental illness in the population. It’s not just stress and environmental overload; it is likely also fat causing inflammation.

Acids and Alkalis

Have you seen those books and advertisements about supplements that are supposed to “alkalinize” your body and therefore avoid the effects of nasty acids? Many have frightening titles, like “Alkalinize or Die.” Some time ago I read a whole bunch of these books while I was trying to help two people with interstitial cystitis. This is a nasty problem, and I had failed to help with conventional medicine, naturopathy, acupuncture or homeopathy. One of the many books that I read claimed that altering the acidity of the urine would cure the problem. It did not.

The basis for these claims that we need to alkalinize our bodies comes primarily from three sets of observations:

  1. That manipulating the external environment of cells in culture and isolated organs can have dramatic effects on the activity and life expectancy of these cells and organs
  2. That some of the products of exercise or metabolism are acidic, and so need to be buffered or expelled from the body
  3. A great many anecdotes about people benefiting from following an “alkalinization” protocol of some sort.

That all sounds good, but it is a big jump to go from cells in culture and perfused organs to whole human beings. Or to base medical advice on anecdotes ALONE.

There is also another origin for some of these ideas, and they derive from the work of Edgar Cayce and some oriental healing traditions: I have enormous respect for both.

I’m a card-carrying biochemist and metabolic physician, so some things about acid/base balance I know well.

Our blood is maintained at a pH of 7.42, and even the tiniest shift can cause major health and psychological problems. So there are sophisticated systems for keeping things in balance. Most of the popular books fail to mention much about the easiest way to change pH, and that is by changing your rate of breathing!

We show people how to do that every day in clinical practice. And when doing electrical recordings of the brain – electroencephalograms – hyperventilation is a good way of inducing some types of abnormal electrical activity.

We know a great deal about how changes in the pH of the blood can impact behavior and many physiological approaches. I’ve worked with hundreds if not thousands of people with disturbances in the acid/base balance of their bodies. Usually as a result of diabetes that was out control, but also scores of other illnesses. Many of them rare but educational.

The populist writers then often talk about excess acid being a stressor. So we don’t want to have acid in our systems because it depletes the alkaline buffers that are supposed to keep things in balance. An interesting idea, but one that can quickly be shown to be deeply flawed. It’s easy for a biochemist to calculate the amounts of acid in single cells, organs and the whole body. We’ve done it thousands of times when treating people with medical conditions like diabetic ketoacidosis and lactic acidosis.

Sadly some of the writers of popular books and articles on acids and alkalis have clearly not studied the literature in any detail.

There have also been some examples of what we call the “Trudeau effect:” vague comments about studies that are supposed to have been completed, but which, if they have been read at all, have never been analyzed by the writer. And often odd statements from books and from research are taken out of context and cited as the Gospel truth. There’s a legal loophole that Trudeau and some others get away with saying things about health that are not supported by any data.

Levels of Evidence
An important concept is what we refer to as levels of evidence. In the past it was often thought that the only kind of evidence to be of any value in clinical decision making had to have been obtained by randomized controlled trials. Yet we all know from experience that there are other types of evidence. A teacher or a colleague may have recommended a course of action based on experience or observation, and this can provide valuable guidance. We now recognize four types of clinical evidence:

  1. Case reports
  2. Case series and uncontrolled observational studies
  3. Retrospective database analyses
  4. Controlled analytic studies, including randomized clinical trials

You will see from this is that even single case reports go into the mix. Numbers one and two and used not as proof, but as ways to generate testable hypotheses.

If you tell me that you have slept better since you started an alkalinization regimen, I’ll see if what you are doing can be applied to others (that’s a pragmatic study), and also whether there could be an explanation for your report (that will need an analytic or mechanistic study).

When we review evidence or perform meta-analyses we give each type of evidence a rating. Controlled studies are given a higher rating than case reports, because the evidence can be generalized to many individual patients. A further refinement is to factor in the source of the study. So research by a pharmaceutical company or a manufacturer of an herbal supplement tends to get a lower rating than an independent study.

Recently someone did indeed tell me that she had slept better since following a special diet. When we looked carefully at the protocol that she was following, it was probably not the alkalinization, but the hops in the diet.

There are many, many claims of health benefits from various diets. The benefits may be genuine, but we need to be very cautious about attributing the success of a diet or any other form of treatment to just one factor.

There is no question that some illnesses, for instance peptic ulcers or gastro-esophageal reflux disease can be made worse by eating an acid diet, and having acid urine can sometimes be very irritating to the bladder.

But the evidence for the benefits of alkalinizing of the whole body – even if it were possible to do it – just does not exist.

You also need to be aware of a potential consequence of "alkalinizing diets:" they can dramatically alter the absorption of some herbs, medicines and supplements.

So what should you do?

  1. The key to any diet is balance: it would be a mistake to be on a diet consisting of just one thing. Experts are always very wary of health claims based on one juice, herb or supplement. Your body is not designed that way: you need a mixture of different fruits and vegetables. When someone tells us that the key to healing is a berry that can only be found in a hidden valley in the Himalayas, we have to ask, “How could that have happened?” How could it be that we evolved or were created with a key ingredient missing?
  2. Avoid drinking carbonated drinks. The old story about a can of Pepsi Cola being a good way to remove oil from your driveway is true. In high school we did the experiment of taking a small nail and leaving it in a sealed container with some carbonated soda. The nail had largely dissolved inside a week.
  3. Keep up your intake of pure water. The current recommendations vary depending upon the time of year and where you live. In the Southern United States, during the summer time, it is currently recommended that you should drink 120 fluid ounces of pure water each day. I personally prefer pure spring water or distilled water. But also bear in mind that if you choose not to drink fluoridated water, that your chance of dental cavities increases. You can get around that problem by applying fluoride directly to your teeth and then rinsing it out. Ask you health care provider about that.
  4. Listen to you body: you should avoid anything that feels irritant, causes indigestion, diarrhea or urinary symptoms
  5. Use you intuition: the answers are within you. One of the most valuable uses of your intuition is not to help you pick lottery numbers, but to help you make wise decisions about your body, your relationships and your subtle systems. I have already written a little about some techniques for listening to and amplifying your intuition, and I shall soon be writing and recording a lot more about those essential topics.

Training Doctors to Use New Medicines

I was saddened to see a press briefing by four senior members of the British Pharmacological Society  at the Society’s 75th Anniversary meeting in London. They called for an immediate improvement in the training of medical students and doctors in pharmacology and clinical pharmacology. They lamented the reduction in the teaching of the basic and clinical principles underpinning the use of medicines, that was leading doctors to be less confident in prescribing. This at a time when medicines are becoming increasingly powerful and complex to use, and when patients are more likely to be taking a number of different drugs.

I have known all four of the people who made these statements, and none is given to hyperbole. Professor David Webb from the University of Edinburgh had this to say: “Patients are becoming ill and some are dying as a result of poor prescribing. There is no doubt about that. A substantial proportion of that is undoubtedly avoidable.”

I was in San Francisco earlier today, and I was shocked by one of the questions, “What is the P450 system?” This is one of the most important metabolic pathways for medicines in the liver and the intestines, and it was worrying that a prescriber did not know that. In my view if a student doesn’t know something, it’s the teacher’s fault, so it means that we trainers are not doing as good a job as we should, and that the problems are not confined to the United Kingdom.

The discussion soon turned to the increasing evidence that some medicines may be associated with metabolic disturbances in some people who take them. We soon started talking about the broader issues of drug side effects. My view is that we don’t need to blame doctors or pharmaceutical companies, that have no interest in bringing unsafe medicines to market: the financial and legal consequences can be devastating. And in any case, I’ve met hundreds of people working in senior position in over thirty pharmaceutical companies and the vast majority of them are deeply committed to trying to improve the lot of humanity.

I think that the problem is not with medicine itself or with doctors or companies. The problem is inadequately trained and/or bad doctors and bad companies.

And fortunately all of those are uncommon. But if these pharmacological luminaries are flagging up a problem, we all need to re-double our efforts to ensure that everyone working in medicine is trained in the basics.

Technorati tags:

Another Controller of Appetite and Weight

We recently discussed the role of cytokines in modulating appetite and energy balance. Now a study in mice has shown that animals deficient in interleukin-18 (IL-18) develop a voracious appetite, very marked obesity and insulin resistance. The insulin resistance is secondary to the obesity that was induced by increased food intake and occurred in the liver as well as muscle and fat.

When the little creatures were given recombinant IL-18 their food intake returned toward normal.

Only recently discovered, IL-18 is an important regulator of innate and acquired immune responses. The fact that a modulator or immunity and inflammation has a key role in feeding and in energy metabolism shows us once again just how closely all these systems are tied together. You lose weight when you are sick or depressed because the body is battling the illness. As you recover, the body needs to replace everything that was lost and re-establish your resilience. These systems don’t just exist in humans, they are found in all mammals and even some birds and fish. So they have evolved over millions of years and we need to be very careful about tinkering with these complex systems. Or of allowing stress or environmental toxins to compromise these protective mechanisms.

This finding may well pave the way not just for new pharmacological approaches to weight management, but also to some non-pharmacological approaches.

Technorati tags:

Cytokines and Weight

Anyone who has ever had a sick child knows that one of the surest signs that he or she is recovering is a return of appetite. From a biological perspective, this is an attempt by the body to make up for any losses that took place during the illness. The major mediator of this effect is one set of a group of chemicals known as cytokines.

Cytokines are glycoproteins that behave like hormones and neurotransmitters, serving as chemical messengers between cells. There are many families of cytokines, including leptin, that we have met before. In recent years most of the attention of researchers has been directed not at the cytokines themselves, but at their receptors, whose activity is far more subtle.

Cytokine receptors are involved in the regulation of cell growth and repair and have important roles in immune responses. Apart from their role in feeding behavior, cytokines have roles in fatigue, fever, sleep, pain and stress. Some key cytokines: interleukin (IL)-1,  IL-6 and IL-8 are dysregulated in fibromyalgia.

At a meeting of the 6th International Congress of Neuroendocrinology in Pittsburgh last month, researchers from the Centre National de la Recherche Scientifique (CNRS) at the Pasteur Institute and the University of Lille, France, presented evidence that The cytokine interleukin-7 (IL-7) is not only involved in immune function, but also prevents obesity-prone mice from getting fat. This is the converse of those cytokines that cause weight gain. IL-7 interacts with the regions of the hypothalamus involved in appetite control. This is yet another piece of evidence indicating that the immune and neuroendocrine systems are closely inter-linked.

This is not really a surprise. One of the big problems I people with many chronic illness, particularly cancer, is that they tend to lose appetite and weight. Sometimes they lose a great deal of weight even while maintaining a decent diet. The anorexia of cancer is caused by many factors working on the signaling pathways in the hypothalamus that modulate energy homeostasis. Research has shown that cytokines are major mediators of weight and appetite loss in cancer patients, by working on two systems known as melanocortin and neuropeptide-Y. It also seems likely that the weight loss that happens with stress, depression and chronic inflammation are all mediated by specific cytokines. These same cytokines increase the risk of developing heart disease. A recent study from Ireland has shown that treatment with an SSRI antidepressant reduces measures of systemic inflammation.

It may be that this new insight into the relationship between inflammation and weight will offer up some more solutions for the problems of obesity, but we are going to need to be alert to the possibility that anything that modulates cytokines may increase the risk of vascular disease.

The more that we learn, the more that we understand about the miraculous checks and balances that keep us healthy.

Technorati tags:


Fibromyalgia can be one of the most difficult of clinical problems. Sadly this illness or group of illnesses is often dismissed as no more than a series of symptoms caused by depression, and people then do not get the treatment that they need. Fortunately we are now seeing the emergence of consensus guidelines on how to diagnose the problem.

Fibromyalgia is a common syndrome of chronic pain and fatigue, but it is a great deal more than just pain. It may affect many systems of the body, and depression and cognitive symptoms are common.

One of the key difficulties in people with fibromyalgia is a disturbance in pain thresholds. There has also been a lot of interest in the idea that people with fibromyalgia are “hypervigilant,” as a result of disturbance in the serotonin pathways in the brain. Something similar happens in many people with other types of chronic pain, particularly low back pain. The problem with all of this research has always been the chicken and egg problem: how many of these abnormalities are due to having chronic pain, and how many might be the cause of the problem?

As an example, I was treating someone with fibromyalgia, and as part of the package of treatments, she was to have acupuncture. If practiced by a professional, acupuncture is usually painless. I had not seen anyone experience pain from the treatment in many years; however, this person was so sensitive that even gentle tapping was excruciatingly painful for her. I have colleagues who take this to be evidence that the whole thing is psychological. But I am sure that they are not correct. To a neurologist this is wrong on three counts:
1.    There is a lot of data indicating metabolic disturbances in people with fibromyalgia that is quite different from anything seen in anxiety or depression. These include reductions in the activity of the cellular powerhouses – the mitochondria – as well as subtle effects in blood flow.

2.    A number of other illnesses, like migraine, are associated with changes in pain threshold, indicating a disturbance in the mechanisms that control pain sensation, either in the brain stem on the thalamus.

3.    This notion that “it’s psychological rather than physical,” harks back to the kind of dualism that is not very helpful.

Recent research  indicates that although fibromyalgia is a little more common in women, the old view that it is predominantly a female illness is not correct. There are also some strong associations with other illnesses, including depression, anxiety, headache, irritable bowel syndrome, chronic fatigue syndrome, systemic lupus erythematosus, and rheumatoid arthritis.

In the days that I treated a great many individuals myself, I always found that fibromyalgia and chronic fatigue syndrome were amongst the most difficult.

I’ve long been interested in the links between sleep disturbances and fibromyalgia as well as the modest improvement in people with a meditation program.  There is also another factor that is often not much talked about: people with chronic pain, from whatever cause can develop pain cycles: pain begins in some part of the body, but is then maintained by neurological circuits in the spinal cord and brain. Interfering with these pain cycles for even a day or two can sometimes be very helpful.

Fibromyalgia is one of the groups of conditions in which combinations are key. Trying just to use a medicine or just a diet is rarely likely to be crowned with success. The most helpful strategies that we have found have been combinations of:

  1. Physical care:
    1. Appropriate medications to help with pain transmission and symptoms of depression
    2. Sleep hygiene, and some of the other approaches that I’ve suggested for dealing with disrupted sleep.
    3. Low intensity exercise
    4. Nutrition: this one of the clinical conditions that first persuaded  me that there are some people who have genuine food and environmental sensitivities, and, in some rare cases Candida overgrowth. There are quite a number of foods that may be very helpful, depending upon the individual’s likes and dislikes.   
    5. I’ve had colleagues who’ve had some great results with herbal remedies and supplements, but there is little published  evidence that these work.      
    6. Some people seem to have biochemical disturbances that can be  helped with some of the Schussler tissue salts.
  2. Psychological support: there is some good evidence that some personality types and temperaments may be at increase risk of developing fibromyalgia, so any thing that helps build resilience and cope with negative cognitions can be very helpful. Some of the  tapping therapies can be very helpful adjunctive treatments, as can music therapy.
  3. People with fibromyalgia are often very sensitive to the people around them, and their nearest and dearest often need help in understanding how best to support the person with the illness.
  4. The subtle systems of the body are invariably compromised in people with fibromyalgia, and acupuncture – if people can tolerate it – as well as homeopathy can be very helpful. We have often used both together, though this is anathema to many classical homeopaths or acupuncturists. Perhaps they could not have been used in combination 50 years ago, but people have changed physically, psychologically, socially and energetically, and the rules have changed.
  5. As with most people struggling with chronic illness, many people with fibromyalgia lose contact with their Source. And this is why – in my books and recordings – I spend so much time helping people  re-establish meaning and purpose in their lives, and help them use the illness not simply  as a barrier to be overcome, but as a stimulus for internal growth. I have also seen a number of indivudals in whom fibromyalgia was symptommatic of a spiritual awakening.       

One of my biggest worries with fibromyalgia, as with so many chronic illnesses, is that many desperate sufferers and their families can become victims of the unscrupulous. I have seen countless people selling advice and treatments that have no basis in fact.

Not everything that I have discussed here is evidence based: there is so little research on things like acupuncture and homeopathy. But those are treatments to be used in combination with more conventional approaches. Using all together is usually the best way forward. And everything that I’ve discussed here has been used in working with hundreds of people around the world.

Technorati tags:

Systemic Psychiatry

“Once a disease has entered the body, all parts which are healthy must fight it: not one alone, but all. Because a disease might mean their common death. Nature knows this; and Nature attacks the disease with whatever help she can muster.”
–Paracelsus (a.k.a. Theophrastus Phillippus Aureolus Bombastus von Hohenheim, Swiss Physician and Alchemist, 1493-1541)

It is usually a mistake to try and look at an illness in isolation.

We are all human beings, and physical challenges affect the whole organism, as well as our mind, our relationships and our spiritual connections.

There is currently a very hot area of research that is still unknown to most people: even to most people working in psychology and psychiatry. This hot new area proposes that schizophrenia, bipolar disorder, major depressive disorder and autistic spectrum disorders, are disturbances affecting the whole body, but with prominent effects in the brain and on emotion and behavior. This may help provide one part of the explanation for why people struggling with chronic mental illness – and their relatives – suffer from an array of physical illnesses that cannot be explained by stress or poor lifestyle choices alone.

You can find a brief review with a stack of references here.

This idea of psychiatric problems being generalized systemic disturbances that have their primary effects on the brain and on behavior is important to the general themes of this blog. We are always interested in looking beyond the obvious causes, to a dynamic integrated vision of a person that includes every part and every dimension of his or her being. If we want to help people recover from illness, to triumph over adversity, and to use challenges as springboards to transcend themselves and the limits placed upon them, it is only possible if we take account of the whole person.

Perhaps we can reduce mental illnesses to disturbances in cell membranes or a few chemicals in the brain. But I do not think so. It is more accurate for us to be thinking about a perturbation or disturbance in the Informational Matrix that underlies the subtle systems of the body, that in turn support the biochemical reactions that provide the structure for the external expression of life itself.

We live in very interesting times.

“Good timber does not grow with ease. The stronger the wind the stronger the trees.”

–Willard J. Marriott (American Businessman and Founder of Marriott Hotels, 1900-1985)

Technorati tags:  

Predicting Responses to Supplements

The other day I was being asked about the use of S-adenosyl methionine (S-AME) for depression and the same day somebody was asking me about some of the supplements – mainly creatine – being taken by body builders.

The research data for each of these is patchy. When S-AME is injected, it seems to help with mild to moderate depression. But oral S-AME is a different issue, because the compound is about a soluble as sand. Not that much is absorbed, which is why we give fairly large amounts so that some gets into the body. Some research has been positive and some not. Similarly, when we look at creatine, there is a limit to how much can be taken up into the intestines or into muscles.

These are not nit-picky observations: When we take a supplement, it is good to know the chances that it will help. You don’t want to waste money on something that has little chance of getting into your body. It is always possible that a supplement works by some unknown mechanism, and we don’t want to dismiss that possibility: if you take a large dose of Vitamin C, most of it will be out of your body and into the plumbing within two hours. But that does not exclude the possibility that during those two hours it is doing something useful inside your body.

This is why we look at five things:
1.The research data, and also who did the research? With pharmacological agents as well as herbs and supplements, there have been countless examples of research funded by the manufacturer, generating glowing testimonials that don’t hold up to independent scrutiny
2. Individual accounts of benefit. Though they don’t carry the same weight as controlled studies, they can’t be minimized
3.The origin, purity, dose, concentration and expiration of the supplement. With many herbs and supplements there is a great deal of variability in quality control from one company to another and sometimes even from one batch to another
4.The plausibility that a treatment could be helpful. If a medicine cannot get into the body, it is not that likely to be helpful.
5.The possibility that a herb or supplement may be acting by some entirely novel mechanism

Rest assured that when we write our articles, we always check out all of these five things, as well as analyzing all the data in the reports of the research. I have mentioned before that when I read a paper, I sit down with a notepad and calculator so that I can check everything in the study. Many journals now post all the raw data online, and we check through that as well.

There are countless magazines and websites that try to bring you all the latest and greatest information. When you read their material it is a great idea to see if they have checked all of these five points as well as analyzing the data in the studies. Many of them do, but not always.

Some of us have been pulling our hair out every time that we see a well-known marketer present more of his infomercials. He is one of that band of people who quote research without really understanding it, perhaps in the hope that nobody will check up on them!

If you are interested in some herb or supplement, let me know and I shall see if I can help you. And if I do not know, I promise that I shall tell you!

Technorati tags:

logo logo logo logo logo logo