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By: Q. Dawson, M.B. B.A.O., M.B.B.Ch., Ph.D.
Program Director, Tulane University School of Medicine
Three other endogenous ligands for the benzodiazepine receptor were identified in the late 1970s; they are inosine anxiety kills purchase effexor xr now, hypoxanthine anxiety 2 effexor xr 150 mg amex, and nicotinamide (Asano and Spector anxiety symptoms during pregnancy buy generic effexor xr 75 mg on-line, 1979; Mohler et al. Like -carboline, they competitively bind to benzodiazepine sites, but not to other sites with similar actions, such as -adrenergic or opiate sites. Inosine and hypoxanthine increase the inhibiting ability of diazepam, and nicotinamide was shown to potentiate the anticonvulsant properties of barbiturates typically used for epilepsy (Bourgeois et al. In addition, various other factors have been proposed as endogenous ligands of the benzodiazepine receptor, such as prostaglandins and glutamate (Asano and Ogasawara, 1982; Garthwaite et al. And as mentioned, having binding properties does not mean that there is a physiological or therapeutic component. The endogenous benzodiazepine ligands appear to play a role in modulating neuronal actions, and it is my speculation that this may be the clue to their most important function (Skolnick et al. MelAtonin Melatonin (N-acetyl-5-methoxytryptamine) is the principal hormone of the pineal gland, and the pineal is our major transducer of neuroendocrine information. There is an intriguing piece of research on the benzodiazepines that I happened upon over 20 years ago. The researchers discovered that melatonin not only fits into its own receptor, but also into the benzodiazepine receptor (Marangos et al. There are noteworthy similarities between the physiological characteristics of benzodiazepines and melatonin. For example, melatonin-like the benzodiazepines-reduces anxiety, is an antidepressant, and can aid insomnia. However, melatonin often ameliorates the same symptoms with far fewer side effects (Garfinkel et al. Diazepam can suppress melatonin-binding sites in the brain, an action that can be reversed by exogenous melatonin administration (Atsmon et al. Furthermore, when test animals are administered melatonin or a benzodiazepine (temazepam), similar types and levels of effects. Consequently, melatonin has been used therapeutically to facilitate benzodiazepine discontinuation with insomnia patients and to enhance the reduction of anxiety in the preoperative period (Garfinkel et al. Clearly, there appears to be a reciprocal and interactive nature between these two molecules. We now know that melatonin has prophylactic functions, immuneenhancing properties, and ameliorates the immune-deteriorating effects of stress. It also plays a fundamental role in immune reactions to viral and bacterial infections. The prophylactic functions of melatonin are particularly effective during times of stress. Immune system suppression in mice (including reduced antibody production, resistance to virus, gastric ulceration, and lower thymus weight) caused by the exogenous administration of the stress hormone corticosterone can actually be reversed by melatonin (Khan et al. The benzodiazepine receptors present on monocytes may be the avenue through which melatonin modulates the immune system (Moingeon et al. This finding is quite stunning, as it implies that melatonin functions as an ongoing immune-system support. Reinforcing this theory are several experiments showing that the antistress effects of melatonin are only seen in mice that have been primed with antigen (Maestroni et al. Immune-enhancing functions of melatonin also have been observed in patients with various conditions that depress the immune system, including pharmacological therapies that are typically administered for cancer treatment (Maestroni, 1993, 2001). Here again we have one of those remarkable instances of systems interacting in a bidirectional manner reminiscent of the systems integration paradigms reviewed in Chapter 2 (Maestroni, 1999). So, melatonin ends up being a powerful mediator of stress that works in a subtle manner, via the immune system, perhaps synergistically with the benzodiazepines. I think that this fact alone gives us pause to suspect that it plays a part in an endogenous system of relaxation hormones. Research is just beginning to show that the stress-reducing and immune-enhancing effects of melatonin are associated with a reduction in both breast and prostate cancer (see Coker, 1999, for a review). In the chapter on the pineal gland (Chapter 10), you will read more about associations between melatonin and disease.
In the next chapter anxiety symptoms 10 year old purchase 150 mg effexor xr with amex, other hormones that produce a relaxation response will be reviewed anxiety depression symptoms buy 75mg effexor xr with amex. While glucocorticoid suppression of the immune system is helpful anxiety essential oils buy effexor xr online, if not lifesaving in short-term situations, chronic stress can alter the feedback regulation and cause prolonged glucocorticoid secretion, which can be profoundly detrimental. The stress response was not designed to be a prolonged physiological event, but rather a relatively short sprint away from the buffalo or other ominous critter (angry humans not excluded). The symptoms that occur from chronic stress, of any etiology, correlate to those physiological changes that are induced by and supportive of the fight-or-flight response. McEwen realized that the concept of a static internal system maintaining a constant homeostatic steady state was entirely unrealistic. He recognized that the body is constantly fluctuating in its effort to maintain homeostasis. McEwen used the concept of allostasis, coined by researchers Sterling and Eyer in the 1980s, to express his premise. It is the ability of the body to "achieve stability through change" (McEwen, 1998). McEwen took this concept one step farther and coined the term allostatic load (graphically depicted in Figure 3. He defined allostatic load as the state of an organism in which "the strain on the body produced by repeated ups and downs of physiological response, as well as by the elevated activity of physiological systems under challenge, and the changes in metabolism and the impact of wear and tear on a number of organs and tissues, can predispose the organism to disease" (McEwen and Stellar, 1993). In other words, there comes a point at which the strain of accommodating the stress becomes too much, and the body can no longer handle the load. At that point, the person enters a state of chronic stress, with the accompanying physiological breakdown. Many of us are always feeling rushed, and it is a major cause of stress in our culture. You are handling all of the stress, and then there is just one more thing that happens, but it happens at the wrong time. Or, if you are capable of being calmer in the face of such overload, you are undoubtedly thinking thoughts that you would rather not think. Selye gave us the basics: thymic involution (reduction in size and function of the thymus), lymphopenia (decrease in proportion of blood lymphocytes), eosinopenia (decrease in eosinophils in blood), and decreased lymph node size. Yet, in contrast, the acute stress response has been shown to strengthen the immune system and provide an immunological memory (McEwen, 1998). Recent studies, however, have provided more understanding of the extensive implications of allostatic load (McEwen, 1998, 2000c, 2000d). This basic concept of allostatic load 82 the Scientific Basis of Integrative Medicine is an important one to keep in mind as we proceed to examine different issues that may be supportive during acute stress but maladaptive during chronic stress. Based on this finding, physicians decided that glucocorticoids were immune enhancing. That concept should have been dispelled in the mid-twentieth century, when glucocorticoids were shown to have antiinflammatory properties (Hench et al. Research in the latter part of the twentieth century fully established the correlation between high doses of glucocorticoids. On the heels of these studies came the work of researchers, such as Hugo Besedovsky, who looked at the actions of the glucocorticoids from a systems interaction perspective and surmised that the net effect of glucocorticoids was modulatory. Besedovsky felt that the glucocorticoids prevent immune overactivity and permit specificity. He showed that lymphocytes with lower antigen affinity are more sensitive to the effects of glucocorticoids, once again, possibly a means for controlling overresponsiveness of the immune system (Besedovsky et al. Glucocorticoids suppress the immune system by decreasing the production of many factors that facilitate B- and T-cell proliferation, including the cytokines, -endorphin, and insulin. Inhibition of these mediators reduces proper functioning of monocytes and macrophages (Guyre et al. Curiously, one experiment showed that rats, who were administered corticosterone in amounts equal to those induced by inescapable tail shock, did not have antibody suppression like the shocked animals (Fleshner et al.
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Vietnam-veteran cohort provide direct information on the health and mortality status of female military personnel who served in Vietnam anxiety when trying to sleep effexor xr 150mg low cost, the limitations of the results must be kept in mind anxiety zen youtube effexor xr 37.5 mg generic. Specifically anxiety symptoms centre cheap effexor xr 150mg with visa, female veterans likely experienced low herbicide exposure because they were not involved in applying herbicides or engaged in direct combat, and their in-country tours of duty were generally limited to 1 year and at fixed locations that were not in proximity to known defoliated areas. In summary, this analysis does not provide evidence of a higher risk of total or cause-specific mortality in female Vietnam-deployed veterans compared with non-deployed female Vietnam veterans and the U. Army veterans were identified from a list obtained by the Army and Joint Services Environmental Support Group; computerized lists were also provided by the Air Force, Navy, and Marine Corps. Of 5,230 eligible veterans, 4,390 with a documented tour of duty in Vietnam were alive on January 1, 1992. From a pool of 6,657 women whose military units did not serve in Vietnam, 4,390 veterans who were alive on January 1, 1992, were randomly selected as controls. After the research group excluded 250 veterans and 250 nonveterans who participated in a pilot study as well as those who could not be located (n = 370), who were deceased (n = 339), or who declined to participate (n = 775, 13% of Vietnam veterans and 17% of non-Vietnam veterans), 6,430 women completed a full telephone interview, and another 366 women completed only a short, written questionnaire. The information collected included demographic background, general health, lifestyle, menstrual history, pregnancy history, pregnancy outcomes, and military experience, including nursing occupation and combat exposure. Information on pregnancy risks and complications-including smoking, infections, medications, exposure to X-rays, occupational history, and exposure to anesthetic gases, ethylene oxide, herbicides, and pesticides-was collected for each pregnancy. For the comparison group, the first pregnancy after July 4, 1965, was designated as the index pregnancy. The study analyzed data on 3,392 Vietnam and 3,038 non-Vietnam veterans and on 1,665 Vietnam and 1,912 nonVietnam veteran index pregnancies. The authors attempted to "retrieve hospital records on all reported cancers as far back as 30 years. The authors did not provide specific data on diagnosis confirmation for the three sites other than the breast, but they stated that Vietnam status was not associated with a greater likelihood of finding confirmatory medical records. The legislation covers 18 birth defects, including cleft lip or palate, congenital heart disease, hypospadias, neural-tube defects, and Williams syndrome. Proportionate-Mortality Cohort Among the earliest reports on health outcomes in Vietnam veterans was a proportionate-mortality study by Breslin et al. The participants were Army and Marine Corps ground troops (all men) who served at any time from July 4, 1965, through March 1, 1973. From this list, 75,617 individuals were randomly selected for inclusion in the study. The information extracted from the selected military records included duty stations, dates of tours, branch of military service, date of birth, sex, race, military occupation specialty codes, education level, type of discharge, and confirmation of service in Vietnam. Additional information was extracted on veterans who served in Southeast Asia, including the first and last dates of service in Southeast Asia, the military unit, and the country where the veteran served. For the final sample of Army and Marine Corps veterans, the cause of death was ascertained from death certificates or Department of Defense (DoD) Report of Casualty forms for 24,235 men who served in Vietnam and 26,685 men who did not serve in Southeast Asia. Exposue to herbicides or other environmental factors was not considered in the analysis. Deaths from external causes (accidents, poisonings, and violence) were slightly eleveated among Vietnam veterans who served in the Army but not among marines who served in Vietnam. Death from any cancer was elevated among marines who served in Vietnam but not Army veterans. Deaths from external causes (accidents, poisonings, and violence) were found to be slightly eleveated among Army I Corps Vietnam veterans, particularly deaths attributed to motor vehicle accidents and accidental poisonings. An additional 11,325 deceased Army and Marine Corps Vietnam-era veterans were identified from the period and included in the study. Proportionate-mortality ratios were calculated for three referent groups: branch-specific (Army and Marine Corps) non-Vietnam veterans, all non-Vietnam veterans combined, and the U. Deaths from external causes were again statistically significantly elevated among Vietnam-deployed marines compared with non-Vietnam veterans and Army veterans who served in Vietnam compared with Army veterans who did not serve in Vietnam and all non-Vietnam veterans. Cancer of the larynx was statistically significantly higher among Vietnam-deployed Army veterans than either non-Vietnam Army veterans or all non-Vietnam veterans but lung cancer was only significantly different for Army Vietnam veterans compared with all non-Vietanm veterans. A third follow-up proportionate-mortality study (Watanabe and Kang, 1996) used the veterans from Breslin et al. The final study included 70,630 veterans-33,833 who had served in Vietnam and 36,797 who had never served in Southeast Asia. Just as in the previous analyses of mortality, Army and Marine Corps Vietnam veterans had statistically significant excesses of deaths from external causes.
For instance anxiety symptoms getting worse purchase effexor xr 37.5mg on line, a study of Caucasian male and female twins demonstrated that telomere length of leukocytes is increased when leisure time is spent in physical activity- possibly by as much as 88 nucleotide repeats (Cherkas et al anxiety symptoms tinnitus purchase effexor xr 150mg with mastercard. Similarly anxiety tattoos purchase 37.5mg effexor xr with mastercard, a study in Lancet Oncology supports our contention that lifestyle changes can impact the Stress System 95 telomere viability. The study, which was led by Dean Ornish (see Chapters 4 and 5) and included Epel, Blackburn, and Liu of the 2004 Epel et al. Appropriately, the investigators described the finding as "a significant association rather than inferring causation. They lived with the feeling of being more than themselves, a feeling of being connected, a feeling of identity, and with the security that they had a place, an inherent place in life. What Wolf found in Roseto was that the incidence of heart disease and mortality was lower when compared with neighboring towns. Some of the people did well with their lives, and instead of living on Gabriel Avenue in the center of town, they moved to a big house on top of the hill. Soon, the woman who lived in the nice house on top of the hill started complaining that nobody comes around to visit anymore. But, for so many years, these people had dietary habits that were absolutely horrific by most conventional standards, yet the incidence of myocardial infarction and cardiovascular disease was incredibly low (Wolf, 1992). Humans experience unpleasant emotions as unpleasant bodily sensations, and thus they feel physically distressed when emotionally distressed. Shen resides in various organs, correlating to the primary emotion that one is experiencing. When you are feeling grief, you feel it in the lungs, and sadness is felt in the heart. So, for example, when someone is very fearful for a long period of time, often that person may go to the doctor complaining of low back pain, prostate, or menstrual disorders. If you are a physician or healthcare practitioner of any sort, you might want to pick up a book on the five Chinese elements and learn how emotions affect the different organ systems. I should not have been surprised, but I was, which was my scientific skepticism showing. The effects of stress are numerous: physical, emotional, behavioral, and cognitive. Repression of anger, fear, and grief may lead to chronic disease, helplessness, depression, and alexithymia. In the next section, we will discuss memory and trauma, and the engrams that crystallize in our personalities. According to Chinese tradition, when you repress an emotion, it creates an energetic imbalance. This imbalance, over a long period of time, will be translated into functional pathology, like back pain. An actor was instructed to depict various emotions through facial distortions and to poignantly express an emotion: anger, fear, sadness, happiness, surprise, and disgust. The technician in the other room could guess what emotion he was showing by the physiological response seen on the monitors. For example, if he had a high skin temperature and pulse rate, the technician knew that he was angry. If his skin temperature went up, but his pulse rate was low, he was either fearful or sad, and so on. This landmark study showed a direct physiological correlation to an emotion simply performed by an actor. Just as with our actor, something so simple as contracting a few muscles may actually alter your mood. Embodiment theory exerts that the relationship between mind and body in processing emotional information is neither a direct nor a linear event. Studies have shown a reciprocal relationship between how the body expresses an emotion and how that emotion is interpreted. For instance, if an individual receives positive news while the body is in a posture that is upright/shoulders back, he or she experiences more pride the Stress System 97 than if the very same piece of news is delivered while in a slumped posture.