I was wandering around the internet last night, looking for scholarly articles on something called ‘methylation pathways’, when I came across a very disturbing article on the potentially quite toxic interaction between nitrous oxide (NO2) and certain states of B12 deficiency. Before getting into the nitty gritty, bottom line, let me give you some background.

Nitrous Oxide (NO2)-commonly referred to as ‘laughing gas’ was used for years in the practice of dentistry.  It is used currently as part of general anesthesia, and recently has been gaining popularity as a ‘recreational drug’.  An article in Popular Science in the late 1940’s demonstrates how easy it is to make NO2 with an at ‘home laboratory’.

The methylation pathway I refer to above is a fundamental biochemical pathway occurring billions of times per second in the human body.  It’s like the dollar bill of our economy-it keeps things moving.  Methylation plays a key role in the building up and breaking down of molecules.  For example, methylation helps make and break down neurotransmitters (serotonin, dopamine, norepinephrine), estrogens, and histamine (think allergy); methylation helps turn certain genes on and others off, and methylation is involved in protecting nerve cells, making blood cells, strengthening collagen (fewer wrinkles), etc.

The methylation pathways work well when we get enough B12 in our diet (vegans are very vulnerable to B12 deficiencies), enough folic acid (spinach, kale, Swiss chard), and B6.  Additionally selenium (nuts), vitamin B2 (riboflavin), magnesium (Brazil nuts and almonds), and some amino acids (methionine, cysteine, serine, glycine, taurine) are needed to keep the methylation cycle running smoothly.

In addition to these nutrients, we must have genes that can make the enzymes that ‘grease the wheels’ of these pathways.  These enzymes allow things to flow smoothly, and allow methylation to meet the demands of the body and environment.  There are several genes involved in the methylation pathways, and abnormalities of one or more of these genes are quite common (e.g., MTHFR C677T).  These abnormalities slow down the methylation pathways, and connected detoxification and free-radical pathways.

So here is the punch line:

Laughing gas (N02)―nitrous oxide―stops the methylation pathway in its tracks by deactivating B12, and stopping the activity of a certain enzyme for days to weeks. When someone is already deficient in B12/folate (e.g., due to diet, medications such as proton pump inhibitors or Metformin),  or has genes that are not functioning properly, the B12 deficiency is suddenly worsened, and weeks later neurological and psychiatric problems develop. They can be subtle (e.g., trouble with balance) or they can be severe (cognitive problems); any psychiatric syndrome (e.g., panic, depression) can develop.  It is unlikely that anyone will make a correlation of cause and effect between the NO2 and the symptoms, because of the delayed toxicity, and the fact that not every one is effected. Symptoms can be subtle.

NO2 is a very serious danger to your health. The risk is unappreciated by college students who are using NO2 as a recreational drug, and the risk needs to be assessed before use of anesthesia (by testing homocysteine and methionine in the blood, looking for risk factors for B12 deficiency such as a vegan diet or the use of certain medications, as well as the genetic MTHFR test) when possible.  Please raise people awareness of this risk by passing this information along.

Many people would be surprised that the immune system, the gastro-intestinal tract and stress interact, but that is what the most recent of a number of studies shows. In this study on mice, (Brain, Behavior, and Immunity Volume 25, Issue 3, March 2011, Pages 397-407. http://www.ncbi.nlm.nih.gov/pubmed/21040780)  researchers demonstrated that  psychological stress causes almost immediate changes to the gut bacterial population, and that some of these affected sub-populations strongly influence the effect that stress has on immunity. In the study, the researchers exposed mice to social disruption, which is known to cause increases in circulating cytokines ('hormones of the immune system), which themselves induce enhanced reactivity in the immune system.  The researchers found that social disruption altered bacterial counts of some gut bacteria sub-populations, particularly when the bacteria were assessed immediately after stress exposure. Stress exposure  increased the relative abundance of bacteria in the genus Clostridium, which often causes prolonged and severe diarrhea (generally after antibiotc use). The stressor also increased circulating levels of IL-6  which was significantly correlated with stressor-induced changes to certain other sub-populations. In a second experiment, these researchers found that a combination of antbiotics prevented the stress induced increase IL-6. This means that certain gut bacteria are necessary for stressor-induced increases in circulating cytokines.So, not only does stress affect the gut bacterial population, but these organisms are also required for  activation of the immune system.

This information becomes even more relevant for psychiatric disorders such as OCD, and depression, as activation of IL-6 has clearly been associated with depression. In fact blockers of IL-6 (eg etanercept) have been shown to reduce depression scores. Furthermore, we can now see, that stress, via its effect on gut bacteria, and hence the immune system (IL-6) can change brain function. We know this because IL-6 activates a certain enzyme (IDO), which actually 'steals' or syphons-off  tryptophan from its normal metabolic pathway ( ie conversion into serotonin and then melatonin) and instead converts it into chemicals that increase activity of glutamate (in depression) at an excitatory-and some times toxic- receptor (NMDA) in the brain. The result of all of this is increased depression, anxiety, and reduced memory. In mice this effect can take moths to reverse. The upshot of all of this, is that stress, the gut, the brain and the immune system are really intimately linked, and inseparable. While this might be news to most psychiatrists, it is not news when one understands the Whole Psychiatry model.

The Spectrum of Disorders Associated with Panic

      Panic attacks are among the most terrifying experiences a person can have. Panic disorders include panic with and without agoraphobia, simple phobia, posttraumatic stress disorder, and perhaps social phobias. The controversy over whether these disorders are closely related, and in what way is not addressed, since the research in this area is inconsistent and inconclusive. The focus here is on the current understanding of the biological underpinnings of the panic attack itself, as well as the psychosocial aspects of panic disorder.

Diagnostic Considerations

     Symptoms of panic disorder, according to the DSM IV, include two broad categories. First, a subjective sense of  terror, going crazy, losing control, or dying must be present. Second, accompanying the subjective criteria, are a host of symptoms of  hyperarousal of various body systems including cardiovascular (rapid pulse, palpitations, lightheadedness), respiratory (sighing, hyperventilation, shortness of breath, subjective sense of difficulty breathing or breathlessness), gastrointestinal (dry mouth, nausea, vomiting, diarrhea) urogenital (urge to urinate), cognitive (trouble thinking clearly), dermatologic (sweating, clamminess, flushing) and neurological (tremulousness, tingling, trouble with speech, dizziness, dissociation). Panic attacks may be spontaneous (ie without provocation of a situation or thought) or triggered.

Associated Features of Panic Disorders

     Once a person has developed panic attacks a series of consequences may follow. He or she is likely to try to avoid situations that either would trigger panic (as in phobic panic) or place themselves in a situation where help might not be available. Since the patients with spontaneous panic would feel shortness of breath and suffocation feelings as a first symptom, they would be fearful of being in any situation that would impair their ability to either get help (if they felt they were suffocating) or to get fresh air. Eventually, perhaps thru a kindling mechanism caused by repetitive firing of the involved nuclei, a sense of anticipatory anxiety (fear of the possibility of a panic attack) would lead to constant over activity of parts of the brain involved in anticipatory fear (the raphe nucleus in the brain stem). This anticipatory anxiety component is not treatable by older medications such as imipramine (which was one of the first medications effective for panic). It requires other medications such as buspirone (Buspar) which act on the serotonin receptors of raphe nucleus neurons, or benzodiazepines, such as clonazepam (Klonopin) which act on other brain regions that mediate general levels of anxiety via the GABA (inhibitory) neurons and receptors. Some people with a triggered panic attack take a counter-phobic response, so for example, someone who has a panic attack when speaking in public, joins Toastmasters. In my case, when I was young (around 19) I needed to earn some money, so I took a job that involved climbing up 20 foot ladders (they seemed like they were 50 feet tall). At first I felt panicky (not a full panic), and so I desensitized myself by slowly going up the ladder, bit by bit. By the end of the first day, I was able to climb the ladder in a relaxed state of mind. Desensitization works only when there is a sense of control, ie, that one way or another, if you need to, you can terminate the panic.

Medical Conditions Associated with Panic Disorder

     Patients with panic disorder have a higher likelihood of having mitral valve prolapse (MVP). MVP is a weakness of one of the valves of the heart. It is relatively benign, but does occasionally produce abnormal sensations including pounding heart, rapid heart rate, lightheadedness, dizziness, fainting, fatigue, difficulty breathing and chest pain. In one study, 34% of panic disorder patients had MVP.  One of my first patients had a panic disorder which did not respond at all to any of the usual treatments (cognitive behavioral therapy, and various medication trials) and it turned out that she had a severe B12 deficiency. Her panic cleared completely with the first B12 injection. Other patients may have an underlying have seizure disorder (e.g., temporal lobe syndrome), adrenal or thyroid dysfunctions, with PMS, post-partum, post -menopausal, and with significant inflammation or infection (which alters brain production of serotonin, dopamine and glutamate).  I recall one woman who had chronic inflammation as a result of both a chronic sinus condition and work in a very moldy environment.

     Patients with bipolar disorder have a 20% chance of having a panic disorder and panic disorder is associated with increased risk of suicide, major depression and other anxiety disorders. Patients with panic disorder have a significantly higher rate of gastrointestinal complaints, such as irritable bowel syndrome . In general most panic disorder patients tend to describe themselves as always having been fearful and shy as children, have discomfort with aggression, and low self esteem. This description is reminiscent of the discussion on temperament.

Lyme disease is the result of infection with the spirochete Borrelia Burgdorferi. It is generally thought that the infection is the result of a tick bite, which about 50% of the time results in a rash, often described as a ‘bulls eye’ rash, but which can vary in appearance.

Symptoms of untreated Lyme disease typically include joint aches which seem to migrate from one joint to another over days), flu-like symptoms (fever, chills, body aches, headache), neuro-psychiatric problems (e.g., Bell’s palsy-paralysis of one side of the face; numbness, weakness, mood disorders, psychosis, cognitive impairment, even seizures). Some people report abnormal heartbeats (conduction abnormalities), or gastrointestinal problems.

There is an extreme polarization around the twin questions of diagnosis and treatment for those with Lyme disease. The highly charged and politicized conflict between the Infectious Disease Society of America (IDSA) and International Lyme and Associated Diseases Society (ILADS)  is well described in Pamela Weintraub’s excellent book, Cure Unknown.

On the one side, is the position of the IDSA, which has a strict requirement for diagnosis and treatment (http://www.idsociety.org), and has concluded that long term antibiotic therapy (greater than one month) is not indicated in those who continue to have symptoms despite the normal treatment regimen (2-4 weeks of oral or IV antibiotics, depending on the symptoms and laboratory data). The ILADS organization (which is a conglomeration of “Lyme literate” physicians, non-physician health care practitioners and patient’s and their families), believes that scientific data has proven that residual symptoms are the result of either co-infections (the tick often contains many bacterial and parasitic organisms, such as Bartonella species, Babesia, Ehrlichia etc), or Borrelia Burgdorferi infections that are intracellular, and therefore not detectible using routine testing. Furthermore, standard Lyme disease testing (a Western Blot) is believed to highly insensitive, by ILADS, giving rise to many false negatives.

My Position

Having followed this debate for several years now, I have come to the following ‘conclusions’, none of which are written in stone:

1.     Standard Western Blot testing is very insensitive, leading to many false negatives. To understand this, one must understand the way the typical Western blot is done. First a drop of blood is applied to a gel. An electric current is applied and this separates the different proteins from each other, based on different characteristics of the proteins. The proteins are then transferred to a membrane where they are allowed to react to antibodies.  A chemical reaction produces light (called chemo-luminescent detection) which is then detected by photographic film. The image is analyzed by densitometry, which evaluates the relative amount of protein staining and quantifies the results in terms of optical density (OD).

The key issue here is that if one protein band has an OD of less than 100, the test is negative, but if it is 100 or greater, it is positive. So an OD of 99 is read as negative, and an OD of 100 is read as positive, yet the difference between the two is so marginal that it is literally absurd to make the distinction or diagnosis based on such criteria. (In fact the Centers for Disease Control established these guidelines in the 70’s when Lyme disease was first recognized as a way of making clear diagnoses for research and tracking purposes.).

By analogy, it would be the equivalent of diagnosing a person with diabetes if their blood sugar is over 100, but diabetes-free, if the blood sugar is 99. That simply is not how the body (nor the world for that matter) works. The best Western Blot test is that which shows the clinician the picture of the bands, with a specific optical density for each, i.e., “ OD 63% in Band 28”. Using this grey scale, along with symptoms and signs, as well as exposure, one can more easily make a diagnosis with higher reliability.

2.      The terrain must be ‘fixed’.  Louis Pasteur, the founder of the Germ Theory of Disease, is reported to have acknowledged, just before his death that the terrain (i.e. the host’s condition physically and mentally) is more important than the ‘germ’.  I would say that like all things, it is neither all the germ nor is it all the terrain, rather it is the interaction of the bacteria/virus/parasite with the terrain. Therefore as part of the treatment for those with any chronic illness, including Lyme, the terrain must be assessed and corrected in order for the immune system to recover, with the help of antibiotics where appropriate.

3.      All that is claimed to be Lyme is not Lyme. I have a close friend who was diagnosed with a tick borne disease. She was on antibiotics for six months, and was not improving much at all. It turned out that the convector system at work was quite toxic, and once replaced, her symptoms (e.g., extreme fatigue, cognitive difficulties, achiness) cleared within days. Clearing gluten from her diet, made further improvement. The clinician must be treating much more than Lyme, to keep their mind open to other diagnostic possibilities.

4.      I am far from convinced about the general usefulness of long term antibiotics, as I have not seen clear-cut improvement in many patients at all.

5.      Chronic Lyme disease symptoms are frequently the result of a failure to deal with other problems (e.g. the functional medicine systems model, which includes nutrition, gluten, mold, psychological, toxic, hormonal factors, etc) as well as a likely disturbance in the immune system itself, which is in a feed forward pro-inflammatory state. 

As I mentioned in part I of this blog, there is a strong association between insulin resistance, diabetes and mental health.

Caught and treated early, insulin resistance is reversible in >90% of patients, and there is a clear improvement in well-being associated with this reversal.  To get to the foundation of the problem, you must do a diagnostic work-up, to identify and deal with the layered factors which promote insulin resistance and diabetes. Factors to be assessed include:

a)     Cortisol-levels which are too high, (as might be the case in anxiety disorders, mood disorders, and psychotic disorders) cause insulin to be elevated, and increase appetite. Cortisol can be reduced easily enough by either supplements or medications, as well as psychotherapeutic methods (e.g., biofeedback, certain therapies, body work etc)

b)     Female and male hormones-low levels of testosterone result in lowered lean body mass (therefore lower metabolic rate), lower energy and vitality. High levels of estrogens (e.g. with potent birth control pills) can also cause weigh gain, albeit in a different pattern of distribution.

c)      Stress-many people over eat when tired, angry, frustrated, bored, lonely; Becoming mindful of your sense of hunger before eating, can, over time, reduce unconscious habitual stress eating. Identifying the situations which make you stressed and problem solving them when possible can help reduce stress eating. Keeping a daily log  (what you ate, when you ate it, and situations in which you over-ate) will definitely raise consciousness

d)     Lifestyle-getting adequate sleep (7-9 hours for most people), moderate exercise 4-5 times per week will reduce the tendency to eat highly processed foods in an out of control manner when you are tired.

e)     Inflammation and toxins: inflammation due to infection, or toxins in your environment can cause weight gain, as a hormone called Leptin can rise to unusual levels. Irvingia Gabonensis has been shown to help reverse leptin elevation and therefore help with appetite reduction and weight loss.

f)       Nutritional deficiencies (e.g., chromium, vanadium, thiamine) can lead to trouble handling carbohydrates in the body.

g)     Caloric restriction-the hardest part of the program is to reduce calories, but with the above measures, perhaps a support group (e.g. weight watchers, over-eaters anonymous, food addicts anonymous), you can do it.

Yours in Health,

Dr. Hedaya

Insulin resistance is a fully reversible condition in which the cells of the body become insensitive to the insulin signal, which itself is designed to take glucose (sugar) out of the blood and into the cells (for energy). If insulin resistance becomes severe enough, it progresses into type II diabetes. Diabetes is more difficult to reverse, and is associated with frequent urination, increased weight, increased thirst, and a host of other problems.

The connection between obesity, insulin resistance, diabetes and mental health problems is no longer questioned. There are number of reasons for the association, including the use of psychotropic medications which cause weight gain, and promote the metabolic syndrome; the social stigma associated with obesity and the lifestyle changes associated with diabetes; and inflammatory activation due to poor diet, high insulin and glucose levels, which in turn changes brain neurochemistry.

A recent study (McIntyre et al.  brain volume abnormalities and neurocognitive deficits in diabetes mellitus: points of pathophysiological commonality with mood disorders?: Adv. Ther. 2010 Feb;27(2):63-80. ) reviewed the literature on brain changes in type one and two diabetes, and concluded that the brain areas which are affected in mood disorders and DM diabetes mellitus, significantly overlap. The association is so compelling that one article in 2007 (Ann. Clin. Psychiatry; 2007 Oct-Dec;1994):257-64) was titled: “Should Depressive Syndromes Be Reclassified as “Metabolic Syndrome Type II”. The association with diabetes (and obesity and insulin resistance) extends beyond just mood disorders, to anxiety disorders, and major psychiatric syndromes such as bipolar disorder and schizophrenia.

Women have twice the frequency of depression as men, and are more vulnerable to many psychiatric disorders between puberty and menopause. Menopause and the post partum are time of high vulnerability for women. Women are more likely to be hospitalized or jailed in the days just before menstruation begins. Transdermal estrogen has been proven in three studies to have antidepressant effects (as opposed to oral estradiol). These facts, and others, beg for our attention to the role of female hormones in mental health. When one adds the concerns raised by the woman’s health initiative study of over 160,000 women on synthetic estrogens, one can easily be left in a state of confusion.
What to do?

First, write down a complete history of your mental health and hormonal events. This means looking at mental health symptoms just before and during puberty, in the days before your period, in response to pregnancy and birth control pills, after any female surgeries, and around menopause. What were your symptoms, did they get better or did some get worse? Include your family history of female (ovarian, uterine, breast) cancers, male cancers (prostate), and cardiovascular disease.

Next if you are still menstruating, track your symptoms and your cycle for three months. Some studies suggest that 50% of women who think they have PMS, do not. Whether that statistic is correct or not, you need to make an accurate correlation.

Finally, work with your doctor to check your FSH, LH, estradiol and progesterone in both the follicular (first 10-12 days) and luteal (days 18-24) parts of your cycle. If you can arrange for continuous salivary monitoring of estradiol and progesterone (less reliable) during that same cycle, you will get a very nice picture of what your hormones are doing in relation to your symptoms. In a simplistic way–estrogen tends to be activating, and progesterone is like the drug Valium—calming in small doses, sedating and depressing in large doses. If you want to be really comprehensive, you can test your genetics (CYP450 1B1 and COMT) and estrogen metabolism to determine whether you can improve your protection against female cancers by eating crucifers, or whether these veggies might increase your risk for making ‘bad’ estrogens.

In addition, look at other hormones (adrenal and thyroid) that influence the female hormone cycle to round out the picture.

All this and more will be discussed in my upcoming complimentary Lunch and Learn teleconference May 5th, at 12:00.

A recent study known as the Colorado Thyroid Disease Prevalence Study, found that 13 million Americans may have undiagnosed thyroid conditions, and suggested that more widespread thyroid testing is needed. Among their findings are the fact that 9.9 percent of the population had a thyroid abnormality that had gone unrecognized. An underactive thyroid -- hypothyroidism -- affects more women than men, and the risk increases with age for both men and women. Clearly, there is a need for more widespread thyroid stimulating hormone (TSH) testing and more aggressive treatment, especially for subclinical patients. Additionally, another study, called the NHANES study, showed that the reference ranges (for TSH) in most laboratories are too wide. Furthermore, relying on the TSH (being in the normal range) as the only way to define hypothyroidism may mean that still more millions are hypothyroid, but undiagnosed and overlooked.

A thorough workup of the thyroid axis should include an assessment of the adrenal axis as well. Of course a history (dry skin, hair loss, constipation, weight gain, brittle nails, irregular menses, muscle weakness, sensitivity to cold, recurrent upper respiratory tract infections, depression, low energy, hoarseness, elevated cholesterol), physical exam, body temperatures, and lab testing (TSH, free T4 , Free T3, reverse T3) are part of a complete evaluation.

Finally, another new study (of 17, 684 people) showed that when one is on thyroid hormone, an optimal dose is one that keeps the TSH very low, but not completely suppressed. This reduces risks of cardiovascular complications and fractures. These results are surprising, but the study was quite strong in design. (J. Clin Endocrinology Metab, Jan 2010, 951(1):185-193).

We will be hosting a workshop webinar on the effects of thyroid function and mental health on April 7th at 12:00 noon EST - 12:30pm. Registration is free, sign up today.