Gut Microbiota and Mental Health

Brain-Gut-Microbiota Axis: There are approximately 1013-1014 microbes in the human being. Microbial cells are 10 times more numerous than human cells in the human body such that 90% of the cells in the human body are microbes.  Approximately 500-1000 microbial species occupy the human gut. The microbes perform vital functions for the human host. Without these microbes, the gut immune system fails to develop. Harmless bacteria (called commensal bacteria) are needed to compete with harmful bacteria for space and nutrients. Commensal bacteria degrade dietary fiber into short-chain-fatty-acids which then can be absorbed. Commensals are required for the absorption of vitamin K and B (Bailey et al., 2011; Dinan &Cryan, 2012).

The composition of the microbiota community is important because some species are highly inflammatory whereas other species are anti-inflammatory. In almost all human cells there are pattern recognition receptors that recognize “foreign” molecules. Some foreign molecules belonging to bad bacteria will result in inflammation which gets communicated by the vagus nerve to the brain resulting in negative moods (anxiety and depression as discussed in the next section). Other foreign molecules associated with good commensal bacteria activate alternative pattern recognition receptors that lead to the release of white-blood-cell hormones (such as interleukin-10) that counter inflammation (Dinan, Stanton, & Cryan, 2013: Smits, et al., 2005), although the mechanism for how this is accomplished are still being worked out (Geuking, McCoy, & Macpherson, 2011). The IL-10 (white-blood cell hormone) protects the human gut from any aggressive inflammatory response that might be evoked by a bad bacteria.

The Composition of the Gut Microbiota Influences Behavior. Biologists who work with mice know that there are major strain differences in innate anxiety levels. Some mice strains are very wary of the novel and readily freeze. The skittish strains are prone to trepidations and rarely venture forth. Other strains are fearless and outgoing. While a good guess might have been that the mice differ in some aspect of the nervous system, turns out that what accounted for the difference between the species was the bacteria that they harbor in their guts. When researchers transferred the bacteria of the skittish mice into the intrepid mice, the intrepid mice exhibited anxious behavior and showed a decrease in BDNF, a protein required for optimal brain health, in their hippocampi. When researchers did the reverse fecal transplant experiment, transferring the intrepid mice microbiota into the skittish mice, the skittish mice became daring and showed an increase in BDNF in their hippocampi (Collins, Kassam, & Bercik, 2013). There were genetic differences between the skittish and intrepid mice driving behavioral differences.   But, the genes had to do with differences in the immune systems not the neurotransmitters. Immune system differences can determine which bacterial species are eliminated and which are invited to stick around.

The composition of the gut microbiota determines more than depression and anxiety levels. Gut microbiota influence appetite, obesity levels, insulin resistance (type 2 diabetes), and memory. In a dramatic demonstration, researchers transferred the gut microbiota from the obese mice to the thin mice. The thin mice then got fat, even though they had not increased their calorie consumption (Turnbaugh et al., 2006).

Factors that Influence the Composition of the Microbiota. Not surprisingly antibiotics can drastically alter the composition of the microbial community in the gut. When antibiotics are used to eradicate pathogens in some part of the body, the friendly gut bacteria who keep the nasty bacteria in check are wiped out. A relatively common occurrence these days is that after a course of antibiotic treatment, Clostridium difficile, a really nasty bacteria, takes over in digestive tract; it’s hard to get rid of. These days, fecal transplants from a healthy donor are sometimes provided. The other two major influences on microbiota composition are stress and diet.

Stress Can Alter Microbiota Composition and Behavior.

Stressors will increase the release of stress hormones in the gut which will then alter the microbial colonies which will then provoke systemic inflammation (Bailey et al., 2011; Bangsgaard Bendtsen et al., 2012). (Systemic inflammation means that inflammatory, white-blood-cell hormones are increased in blood.) Beyond changing the colonies of microbiota in the gut, stress will also alter the tight connections between the cells lining the gut so the lining becomes more permeable to pathogens and to secretions from these pathogens, further contributing to systemic inflammation (Kiliaan et al., 1998).

Diet Is a Major Factor for Determining Microbiota Composition.  Eating fermented foods such as sour kraut and yogurt is good strategy for encouraging the colonization of good microbes in the gut. Fermented food substance are called probiotics.   Fermented foods contain the good bacteria. For increasing good bacteria in gut, there’s also the prebiotic strategy (which will be referred to later in reference to why eating apples is good). Rather than consuming beneficial bacteria directly, prebiotics is about consuming dietary nutrients that will promote the survival of beneficial microbes.

A number of studies have found that administration of the species of bacteria found in yogurt decrease anxiety and depressive behaviors (Bravo et al. 2011; Messaoudi et al., 2011). In animals, probiotics are also protective against the development of anxiety in responses to stressors (Cryan & O’Mahoney, 2011). In humans, probiotics narrowed the differences between high and low anxious subjects on stress hormones in the urine (Martin et al., 2009) and decreased anxiety and depression and reduced levels of the stress hormone cortisol in blood (Benton, Williams, & Brown, 2007; Messaoudi et al., 2011; Rao, et al., 2009). Consumption of probiotics decreased social anxiety in those scoring high on a measure of neuroticism (Hilimire, DeVylder, & Forestell, 2015). Additionally, Tillisch et al. (2013) showed that consumption of probiotics resulted in a reduction in activity in the insula while viewing emotionally evocative pictures and resulted in an increase in regulatory control over areas of the brain that respond to emotion.

While probiotics and prebiotics can potentially influence microbiota composition so that distress (anxiety and depressive behaviors) is reduced, other dietary factors will probably reverse the effect. Consequently attending to the entire diet is necessary if a positive effect is to be achieved.

Encouraging the wrong type of microbes. Generally, high saturated fat and refined sugar promote inflammatory microbes in the gut (Magnusson, Hauck, Jeffrey, Elias, Humphrey, Nath, Perrone, & Bermudez, 2015; Ohland et al., 2015; Trunbaugh et al., 2009).  However, the bottom line is likely to be more nuanced than merely saying that a particular molecule is good or bad. Spreadbury (2012) suggests that it is not just saturated fats or carbohydrate molecules that should be considered but rather whether these molecules are consumed in the context of high fiber. Thus, carbohydrates consumed in plant fiber might have a different impact than pure glucose. In fact, consumption of high fiber foods (apples) change microbiota composition in animal studies (Koutsos, Tuohy, Lovegrove, 2015).   Various bacteria live on fiber and thus eating fruit with fiber is a prebiotic strategy for increasing good bacteria.

Artificial sweeteners have also been shown to alter gut microbial communities in undesirable ways (Suez et al., 2014). Atypical antipsychotics also alter the microbiota in negative ways (Dinan, Stanton, & Cryan, 2010).

Chemicals that extend the shelf-life of foods. The food industry adds detergent-emulsifiers to many processed foods. (Most ice creams are loaded.) Several of these common emulsifiers (carboxymethylcellulose and polysorbate-80) were tested on mice in research conducted by Chassaing et al. (2015). The emulsifiers changed the composition of microbiota to less friendly species. With the change in microbiota composition, the protective mucus layer lining the gut was eroded, bacteria clung to the cells lining the gut, and the gut lining allowed invasion into the blood stream. Of course, the immune system rapidly responded to the presence of the bacteria and bacterial products. The results were low grade systemic inflammation, more insulin insensitivity, and weight gain. The authors of the study speculated that common food additives may be contributing to the rise in inflammatory bowel disease, diabetes, and obesity. The authors did not measure changes in behavior, but given the research cited here, it’s a good bet that behavioral changes might have been found.

The serotonergic, anti-panic neurons connection. The “old-friends” hypothesis has been in the literature for a while now. The idea is that formerly common dietary bacteria such as Mycobacterium vaccae (common in human feces used as fertilizer in some parts of the world) induce the production of anti-inflammatory hormones (IL-10). IL-10 tames inflammation such that allergies and inflammatory bowel diseases are less likely (Rook & Lowry, 2008). Additionally, M. vaccae induces a cluster of serotonergic neurons, in the interfasicular part of the dorsal raphe, which are anti-panic neurons (Lowry et al., 2007). Lowry et al. placed M. vaccae under the skin or into the lungs and showed that mice displayed less anxiety.   Administering M. vaccae orally also decreases anxiety associated behaviors and improves memory (Matthews & Jenks, 2013). Recently, Lowry et al. (2015) fed mice M. vaccae and then exposed them to a larger, more aggressive animal. Rather than succumbing to the aggressor, the M. vaccae pretreated mice fought back. In another test of the anti-anxiety impact of M. vaccae, Lowry showed that fearful responses are unlearned (extinguished) much more readily in mice treated with M. vaccae. Feeding with M. vaccae has been characterized as a way to vaccinate against PTSD (Reardon, 2015).

It should be noted here, that M. vaccae is an aerobic (oxygen requiring) microbe and thus could not live for very long in the gut. However, its cell membrane contains molecules that are recognized by the “pattern recognition receptors”. Signaling through the pattern recognition receptor is the mechanism for the increase in the anti-inflammatory hormone, IL-10.

Clarification on Serotonin. It is important to recognize that serotonin is just another neurotransmitter in the brain. It is used in both anxiety inducing and anxiety reducing circuits. (There are distinct sets of connecting neurons.) Thus, the above should not be interpreted to imply that increasing serotonin is necessarily good or bad, as is sometimes implied by the simplistic story that serotonin deficiency creates depression.   (The story on serotonin is reviewed in Chapter 2 of Neuroscience for Psychologists and Other Mental Health Professionals.)

The Microbiota Research Is Just Beginning. The importance of the gut microbiota for physical health, mood, and perhaps cognitive capacity is a recent discovery. There are still plenty of unknowns. Given that so much of the American diet is based on processed foods, each food addictive needs to be interrogated to determine its impact on the microbes in the gut, general inflammation, and mood and behavior. Also each probiotic in fermented foods needs to be evaluated. Preliminary research suggests they are not all the same. However, the implications of this research are apparent. In the future, those with depression might conceivably be treated with fecal transplants from happy people. But then, it just might be easier to eat lots of nut, fruits and vegetables and avoid the processed foods and artificial sweeteners and start enjoying yogurt (the stuff without the high fructose corn syrup).

Bailey, M. T., Dowd, S. E., Galley, J. D., Hufnagle, A. R., Allen, R. G., & Lyte, M. (2011). Exposure to a social stressor alters the structure of the intestinal microbiota: implications for stressor-induced immunomodulation. Brain, Behavior, & Immunity, 25(3), 397-407.

Bangsgaard, Bendtsen, K. M., Krych, L., Sorsen, D. B. et al. (2012). Gut microbiota composition is correlated to grid floor induced stress and behavior in the BALB/c mouse. PLoS One, 7, e46231.

Benton, D., Williams, C., & Brown, A. (2007). Impact of consuming a milk drink containing a probiotic on mood and cognition. European Journal of Clinical Nutrition, 61, 355-361.

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Bercik, P., Park, A. J., Sinclair, D., Khoshdel, A., Lu, J., Huang, X. et al. (2011). The anxiolytic effect of Bifidobacterium longum NCC3001 involves vagal pathways for gut-brain communication. Neurogastroenterology and Motility, 23, 1132-1139.

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Chassaing, B., Koren, O., Goodrich, J. K., Poole, A. C., Srinivasan, S., Ley, R. E., & Gewirtz, A. T. (2015). Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome. Nature.

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Koutsos, A., Tuohy, K. M., & Lovegrove, J. A. (2015). Apples and cardiovascular health—is the gut microbiota a core consideration? Nutrients, 7 (6), 3959-3998.

Magnusson, K. R., Hauck, L., Jeffrey, B. M., Elias, V., Humphrey, A., Nath, R., Perrone, A., & Bermudez, L. E. (2015). Relationship between diet-related changes in the gut microbiome and cognitive flexibility. Neuroscience, 300, 128-140.

McKeran, D. P., Fitzgerald, P., Dinan, T. G., & Cryan, J. F. (2010). The probiotic Bifidobacterium infantis 35624 displays visceral antinociceptive effects in the rat. Neurogastroenterology and Motility, 22, 1029-1035.

Messaoudi et al. (2011). Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in rats and human subjects. British Journal of Nutrition, 105, 755-764.

Ohland, C. L., Pankiv, E., Baker, G., & Madsen, K. L. (2015). Western diet-induced anxiolytic effects in mice are associated with alterations in tryptophan metabolism. Nutritional Neuroscience, doi: 10.1179/1476830515Y.0000000034

Rao, A. V., Bested, A. C., Beaulne, T. M., Katzman, M. A., Iorio, C., Berardi, H. M., & Logan, A. C. (2009). A randomized, double-blind, placebo-controlled pilot study of a probiotic in emotional symptoms of chronic fatigue syndrome. Gut Pathology, 1, 6.

Rook, G. A., & Lowry, C. A. (2008). The hygiene hypothesis and psychiatric disorders. Trends in Immunology, 29 (4), 150-158.

Reardon, S. (12 June, 2015). Vaccine hope for post-traumatic stress: development of anxiety and fear alleviated by manipulating immune system in rodents. Nature News.

Salvin, J. (2013). Fiber and prebiotics: mechanisms and health benefits. Nutrients, 5, 1417-1435.

Smits, H. H., Engering, A., van der Kleij, D., de Jong, E. C., Schipper, K., van Capel, T. M. M., Zaat, B. A. J., Yazdanbakkish, M., Wierenga, E. A., van Kooyk, Y. T., & Kapsenberg, M. L. (2005). Selective probiotic bacteria induce IL-10-producing regulatory T cells in vitro by modulating dendritic cell function through dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin. Journal of Allergy and Clinical Immunology, 115, 1260-1267.

Spreadbury, I. (2012). Comparison with ancestral diets suggests dense acellular carbohydrates promote an inflammatory microbiota, and may be the primary dietary cause of leptin resistance and obesity. Diabetes, Metabolic Syndrome, and Obesity: Targets and Therapy, 5, PMC34020009

Suez, J., Korem, T., Zeevi, D., Zilberman-Schapira, G., Thaiss, C. A., Maza, O., Israeli, D., Zmora, N., Gilad, S., Weinberger, A., Kuperman, Y., Harmelin, A., Kolodkin-Gal, I., Shapiro, H., Halpem, Z., Segal, E., & Elinav, E. (2014). Artificial sweeteners induce glucose intolerance by altering the gut microbiota. Nature, 514, 181-186.

Suez, J., Korem, T., Zilberman-Schapira, E., et al. (2015). Non-caloric artificial sweetners and the microbiome: findings and challenges. Gut Microbes, 6 (2), 149-155.

Tillisch, K., Labus, J., Kilpatrick, L. (2013). Consumption of fermented milk product with probiotic modulates brain-response to emotional pictures. Gastroenterology, 144, 1394-1401.

Turnbaugh, P. J., Ley, R. E., Mahowald, M. A. et al. (2006). An obesity-associated gut microbiome with increased capacity for energy harvest. Nature, 444, 1027-1031.

Turnbaugh, P. J., Ridaura, V. K., Faith, J. J., Rey, F. E., Knight, R., & Gordon, J. I. (2009). The effect of diet on the human gut microbiome: a metagenomics analysis in humanized gnotobiotic mice. Science Translational Medicine, 1: 6ra 14.



History of Opiates in the US.  I wrote my last post on buprenorphine and methadone with some ambivalence.  I’m not against methadone maintenance clinics.  Generally, limiting access to any drug has proven to be a bad idea.  We all remember prohibition.  When there is demand for a substance, making it illegal merely empowers the gangsters, although the numbers dependent on the substance remain about the same.  (Before the drug laws in 1914, about 1/400=.25% of Americans were addicted to opiates; in 2006, 1.6% of Americans reported having used heroin, Hart, Ksir, Ray, 2009, p.63 & p. 318).  In my class on substance abuse, we review the history of the drug laws in the US.  In fact, when all drugs were legal before the Harrison Act of 1914, there was not much of a problem with drugs in this country.  (However, in the late 1800s, there were reports of infants dying from paregoric, an opiate-based treatment for diarrhea, in the emerging pharmacy literature.)

Why Was Heroin Made Illegal?  The impetus for the Harrison Act was foreign policy.  After the Spanish American War, the US acquired the Philippines.  Given a US presence in the Pacific, Teddy Roosevelt wanted to trade with the Chinese.  But the Chinese did not trust the westerners who ran opiate concessions/parlors all along the coasts.  (The Chinese emperor did not succeed in his attempt to throw out the “foreign devil” in the Boxer Rebellion.)  Roosevelt believed he could ingratiate the US with the Chinese by regulating the world traffic in opiates.  However, the US itself had no domestic policy.  To avoid a charge of hypocrisy when telling the Europeans to clean up their act, America needed to regulate opiates. In order to promote making drugs illegal in the US, the government realized that opposition would emerge from the South to any attempt to legislate morality.  (What’s next, Jim Crow?)  So, drug policies were sold with racist propaganda.  Given that the federal income tax had recently been established in 1913, the government believed that regulating drugs through taxation would be the path of least resistance.  The Harrison Act of 1914 taxed opiates and cocaine, but omitted marijuana.  Enforcement was through the Treasury Department (IRS).  The war on drugs, at least before the recent change in metaphors, has/d been vigorous.  Michele Alexander’s book, The New Jim Crow, argues that US drug laws have effectively been an excuse to disenfranchise African Americans, who are over-represented in prison largely by dint of commission of drug-related crimes.

Why is heroin so devastating:  the drug or the drug-policy?  In talking about opiate addiction so much propaganda has surrounded the topic that it’s hard to discern the truth.  The stereotype is that of the desperate addict devoting all his/her time in pursuit of a drug which compromises values and demands the sacrifice of what one would otherwise hold dear.  There is support for the stereotype but is this stereotype attributable to the opiate drug or America’s drug policy?  In terms of addictive liability, nicotine is touted as one of the most addictive chemicals in the formulary.  Yet, no one neglects his/her children or steals to obtain a cigarette.  Cigarettes are relatively cheap and available.  Cigarettes have devastating long term effects on health, but they don’t impair ability to work or start bar room fights.  So, maybe the desperate efforts to seek an addictive drug (in this case, opiates) at any cost are a function of the government’s restriction.  If opiates were widely available, would many of the social problems evaporate?

The next question is “to what extent do opiates impair job performance?”  Although there are not many data on this issue, I remember the story of William Halsted.  Halsted was a physician at Johns Hopkins during the 1900s.  He is credited with being the father of modern surgery and the physician who came up with sterile procedures.  Halstead was maintained on morphine by his friends throughout his career.  In the modern era, we also have data on methadone maintenance clients.  The justification for the harm reduction approach of methadone maintenance is that it restores peoples’ ability to work.  The data are pretty consistent with this claim.  People in methadone maintenance clinics do return to productive employment.  Methadone is about equivalent to heroin in terms of potency at a mu receptor.  So extrapolating to other opiates from methadone, opiates probably will not rob anyone’s capacity for productive behavior, although taken in excessive doses people will fall asleep.

Then there’s the issue of long term effects on health.  Perhaps surprisingly, opiates are probably the least harmful drug on the body of just about any drug in the formulary.  They don’t damage any organ system.  They do cause immune system suppression, although Sacerdote, the expert on this topic, claims that with long term exposure to opiates cells compensate becoming tolerant to this effect.  Opiates do suppress testosterone levels and sexual function, which might result in muscle and bone wasting, although again some argue that tolerance develops here too.  Whereas withdrawal from alcohol, benzodiazepines, and barbiturates can be lethal, unless an individual is otherwise in poor health, opiate withdrawal is not life threatening.

The big problem with opiates is that they are very dangerous drugs.  They block the function of the baroreceptors (which detect a lack of oxygen) so that breathing centers don’t operate properly.  Addicts using illicit drugs and pain patients treated with OxyContin regularly die from overdoses.  Additionally, methadone (but not heroin) is associated with cardiac arrhythmias (Qtc prolongation) which can be potentiated when combined with antidepressants and antipsychotics.

What concerns me about the federal government’s response to the current opiate epidemic is that they are advocating for more opiates in the form of methadone and buprenorphine.  Although physician-prescribed buprenorphine and methadone are certainly safer than street heroin, they aren’t safe.  After clients show some trustworthiness in the methadone maintenance clinic, clinics are allowed to provide clients with take-home methadone and buprenorphine.  Once this happens, accidents are more likely to occur.  We’ll probably see more accidental poisonings with little kids.  The future should inform regarding whether OD rates decline or increase once more Americans are in “Medication Assisted Treatment.”

Can another drug cure drug addiction?  Over the years, I’ve gone to many a seminar on finding a drug to treat addiction.  I remember the NIDA researcher who came up with a drug to block a cannabinoid receptor.  There was even a guy who thought amphetamines might be the way to treat cocaine addiction.  (Works in the monkeys.)  The problem here is that for most drugs of abuse, they operate on receptors for natural chemicals in the body.  The brain releases endocannabinoids which then operate on cannabinoid receptors and decrease anxiety signaling in the amygdala.  Endorphins and enkephalins are the body’s neurotransmitters at mu and delta opiate receptors.  They function in circuits for pleasure and for energizing behavior.  Do we really want to find some chemical that blocks opiates or cannabinoid receptors?  Although some magic chemical might make it so that the drug of abuse won’t work, the body’s natural chemicals won’t work either.  The cure is often more devastating than the disease.

What is addiction anyway?  There is a lot of confusion in professional journals and in lay publications on what accounts for the compulsion to find and use drugs of abuse, the now generally accepted definition of addiction.  I’ve been convinced by the work of Peter Kalivas and Kent Berridge, among others, that compulsion to use cocaine, alcohol, and opiates has little to do with seeking pleasure or avoiding the pain of withdrawal.  Rather, it’s a story about capturing the brain’s motivational system, which operates independently from seeking pleasure or avoiding pain.  (I review this story in Chapters 2 and 8 of Neuroscience for Psychologists and Other Mental Health Professionals.)  There are ways to take back the brain’s motivational system that don’t involve more chemicals.  But, it’s tricky and knowing when someone is vulnerable to relapse is important.    This story raises the question of whether anyone has free will and ways in which free will might operate.  It’s a very interesting story.  With clarity on what accounts for compulsion to use, a more targeted picture of when people are vulnerable to relapse emerges.

Barceloux, D. G.  (2012).  Medical Toxicology of Drug Abuse. New York:  John Wiley & Sons.

Courtwright, D. T.  (1982; 2001).  Dark Paradise: A History of Opiate Addiction in America.  Cambridge, MA: Harvard University Press.

Hart, C. L., Ksir, C., & Ray, O.  (2009).  Drugs, Society & Human Behavior.  New York:  McGraw Hill.

Musto, D. F.  (1973).  The American Disease:  Origins of Narcotic Control.  New York:  Oxford University Press.

Sacerdote, P., Franchi, S., Gerra, G., Leccese, V., Panerai, A. E., Somaini, L. (2008).  Buprenorphine and methadone maintenance treatment for heroin addicts preserves immune function.  Brain, Behavior, & Immunity, 22(4), 606-613.


Heroin Addiction Epidemic

Heroin Epidemic. The United States is experiencing an epidemic of heroin addiction and a sharp rise in opiate over-dose death.  Contrary to addicts being introduced to opiate addiction through street heroin, 75% of new addicts became addicted through prescription opiates (Cierco et al., 2014).  Deaths from prescription opiates exceed death from heroin (Volkow et al., 2014).  The surge in heroin addiction is explained by the ubiquity of prescriptions for pain medications.  When the prescription opiate OxyContin becomes too expensive ($80/pill), people switch to the cheaper street heroin ($5-10/hit).  In 1999, there were on average 10 opiate deaths per day.  By 2012, there was one death every half hour (Quinones, 2015 ).

How OxyContin Came to Be a Big Seller?   Back in the 1950s, physicians were very reluctant to prescribe opiates for cancer patients who were dying.  A shift in this attitude came with several publications.  A letter to the New England Journal of Medicine by Jink and Porter in 1980 reported on a review of the hospital records of patients treated with opiates finding that less than 1% became addicted.  (In fact, this letter to the editor did not specify the conditions for which patients received opiates while in the hospital nor the dosage or duration of exposure to opiates).  This was followed by a publication in the journal Pain in 1986, by Portenoy and Foley regarding low rates of addiction in 38 patients treated with opiates for diverse conditions about a quarter of whom experienced back pain.  The 38 patients were not evaluated for whether they exhibited withdrawal symptoms post discontinuation of opioid.  However, only two patients posed management problems for doctor because they requested escalation of their dosages.  In the decades to follow, these two publications were cited as the evidence for low addictive liability of the opiates in persons experiencing pain.  Pain clinics were opened throughout the country.  Jink & Porter and   Portenoy &Foley were widely cited despite the fact that these two publications were not relevant to the question of whether patients with diverse pain conditions were invulnerable to opiate addiction, defined as experiencing drug withdrawal after opiate discontinuation.  In 1989, D. E. Weismann and J. David Haddox et al. published an article in Pain suggesting that if a pain patient asks for higher levels of medication, a sign of “pseudo addiction”, this was an indication that pain was not adequately treated and that dosage should be increased.  (J. David Haddox later went to work for Purdue Pharma, the maker of OxyContin.)   (See Quinones, 2014, for full account.)

The train had left the station.  In 1996, James Campbell, president of the American Pain Society, in a speech characterized pain as the fifth vital sign.  The American Pain Society employed the slogan “Pain: the Fifth Vital Sign.”  In 1998, the VA made it mandatory for pain to be assessed right along with pulse and blood pressure.  The Joint Commission for the Accreditation of Healthcare Organizations, which certifies all major hospitals, made compliance with evaluating pain a criterion for accreditation (Quinones, 2014).

The Marketers Take Over for Promotion of Pharmaceuticals.  Quinones characterizes Arthur Sackler, a physician who directed the Creedmoor Institute of psychiatry in New York in the 1950s, as playing a big role in medicine becoming a consumer product.  Sackler opened an advertising firm for pharmaceutical companies, William Douglas McAdams.  Sackler and his brothers established medical journals which were effectively advertising devices for pharmaceutical houses.  In the 1960s, Sackler was influential in marketing efforts for valium.  Sackler recommended the direct marketing to physicians with drug reps visiting individual physician offices.  This became the model for Purdue Pharmacy, the makers of OxyContin.

In 1995, the FDA approved Purdue Pharmacy’s claim that OxyContin, because of its extended duration release, had lower addictive potential.  Curtis Wright headed the FDA committee approving this claim, although he did add notes of caution.  (Curtis Wright later went to work for Purdue.)  William Douglas McAdams, the firm founded by Sackler, became the advertising firm for Purdue.  Purdue Pharma sponsored physician CME events all over the country.  They all cited the landmark Porter and Jink’s work as evidence supporting the low vulnerability of patients with pain to opiate addiction.  They all referred to the low risk of addiction with extended release OxyContin.  Sales reps offered OxyContin coupons to physicians who distributed them to patients.  OxyContin coupons could be exchanged at pharmacies for an initial free OxyContin prescription.  This initiated the opiate epidemic associated with the wide-spread prescriptions for OxyContin (Quinones, 2014).

In recent times, more notes of caution have appeared in the literature.  In 2007, Purdue Pharmacy pled guilty to misbranding OxyContin (Quinones, 2014, 75%; Meier, 2007). Portenoy characterized his promotion of the idea that opiates would not be addictive for those in pain as misguided on the website Physician’s for Responsible Opiate Prescribing (see the five minute video, Addiction is NOT rare in pain patients).

US Government’s Response to Heroin Epidemic. Nora Volkow of NIDA, Tom Frieden of the CDC, and Michael Botticelli of the White House’s Office of Drug Control Policy have advocated the expansion of methadone programs and buprenorphine treatment to respond to the epidemic.  SAMSHA, the federal agency which regulates methadone maintenance programs, suggests that we call these interventions “Medication Assisted Treatment” (MAT) rather than opiate substitution programs so as not to stigmatize persons.

SAMSHA’s New Rules.  Methadone programs have been around since the mid-1950s in New York State.  Under the Narcotic Treatment Act of 1974, methadone maintenance clinics became legal in the United States, although states vary in state regulations.  What is new is that SAMSHA has effectively rewritten the rules on how methadone maintenance clinics are run.  Whereas the law of 1974 limited methadone to those who had been addicted for a year, the SAMSHA (2012, Tip 43) guidelines allow for those who are not physically dependent on opiates to receive methadone.  While initially the goal was to wean patients off, SAMSHA (2012) advises directors of clinics that when a patient requests a dosage reduction that they should “educate” the patients on the importance of staying on their Medication Assisted Treatment.  There is no duration limit on MAT.  Moreover, there is no longer a limit on dosage.  Given that stress is a reliable precipitant to relapse in drug abusers, SAMSHA discusses increasing dosage during stressful times (see page 77, in SAMSHA’s Tip 43, Medication-Assisted Treatment).

Buprenoprhine is a partial agonist?  The newcomer on the scene for treatment of opiate addiction is buprenorphine.  The drug company characterizes buprenorphine as a “partial agonist” at a mu-receptor and an antagonist at a kappa receptor.  In the body, there are 3 types of receptors for opiates: mu receptors, kappa receptors, and delta receptors.  Mu receptors produce the pleasurable effects and the compulsion to use opiates.  Kappa receptors counter the mu-effects.  Upon hearing that buprenorphine is a partial agonist, I wondered “how?”  I’m always amazed at the amount of information available to biologists.  For almost all receptors, someone knows the shape of the receptor, the amino acids in the receptor that a ligand (neurotransmitter or drug) interacts with, the proteins in the body of the neuron that are influenced when the ligand binds, and the downstream effects on the ligand/receptor binding.  So what is making buprenorphine different from methadone, morphine, and OxyContin?  It did not take long to find out.

Turns out that buprenorphine not only interacts with the mu-receptor but also another protein called a “Regulator of G-protein Signaling” which turns off activity at the mu-receptor.  The problem is that tissues and brain areas vary in terms of whether the neuron contains the “Regulator of G-protein Signaling”.  As such, buprenorphine will only demonstrate this effect on some outcome measures but not on others.  Thus it will be a “partial agonist” on some measures but not on others. The case has been made that buprenorphine is less likely to produce an overdose via respiratory depression than other opiates.  However, all bets are off if buprenorphine is used with another drug.  Many people on buprenorphine die when they combine “bup” with alcohol.

Opiate Agonists Are Very Dangerous Drugs: Lack of Guidelines on Safe Dosing.  Deaths of opiate patients being treated in pain clinics began to escalate around 1999.  This correlated with a switch from low potency to high potency opiate prescribing according to a study by Franklin, Mai et al. (2005) in American Journal of Industrial Medicine (Quinones, 2015, 58%).  Mai and Franklin had noted these trends in the statistics for those persons receiving Workman’s Compensation.  Mai contacted to Jennifer Sabel, an epidemiologists, to ascertain whether their findings reflected a more general phenomenon. According to Quinones (2015, 66%), Sabel queried pain specialists regarding a maximum safe dosage.  Purdue Pharma responded with outrage suggesting that limiting dosing represented prejudice and ignorance.  The absence of a ceiling dose was noted in the pain field.  Interestingly, at the present time, SAMSHA has no maximum dose limit for methadone and buprenorphine for those physicians in MAT clinics.

A problem with establishing safe dosing is the opponent process phenomenon.  Psychologists have recognized that for any process imposed on the body, the body will respond in the opposite direction, i.e., with an opponent process.   The opponent process is triggered by environmental cues.  For example, if a person exercises in the same gym, the environmental cues at the gym will trigger an opponent process so that the workout feels less exhausting.  However, if the person exercises in a new environment, where the opponent process has not been conditioned, then the same workout will feel much more exhausting.  The same phenomenon is relevant to opiate drugs.  A safe dose in the customary environment may not be safe in a new environment.

Increased Risk When Opiates Are Combined with Other Drugs.  Methadone and buprenorphine compete for the same enzymes as many antibiotics, antidepressants, and antipsychotics for their metabolism (removal from the body). As such the effective dose of methadone is much higher than when people are not on these other medications.  In addition, methadone can result in cardiac arrhythmias because of a change in electrical conduction in the heart (QTc prolongation), although buprenorphine is supposed to be a little safer on this outcome.  However, many antidepressants and antipsychotics can also increase QTc prolongation.  With regard to danger associated with cardiac arrhythmias, the probability of an adverse event increments with each additional drug.  Studies of opiate overdoses find that antidepressants, benzodiazepines, and antipsychotic drugs are associated with lethal overdoses.  The SAMSHA guidelines recommend screening for co-occurring disorders.  The Tip 43 guidelines do mention those medications which compete for the same enzymes as methadone but don’t discuss risks associated with multiple medications that increase risk of cardiac arrhythmias.  The drug interactions increase the lethality of opiate drugs.

Dilemma of Other Addictive Drugs in Methadone Maintenance.   It has been known for a long time that most heroin addicts do not limit their drug consumption to heroin.  When people are in methadone maintenance, they often don’t quit using cocaine, marijuana, or alcohol.  (In terms of drug interactions, there is some suggestion in the literature that concurrent use of marijuana actually decreases the opiate dosage required to curtail cravings.)  While SAMSHA does suggest that Opiate Treatment Programs screen for other drugs, SAMSHA is unclear about what should happen if the urine tests positive.  (According to SAMSHA instructions, we are to use the language ‘tests positive’ rather than ‘dirty urines.’)  SAMSHA is clear that patients should not be dis-enrolled from the program.  Sanctions can include limiting take-home dosages of methadone.  They also suggest switching the patient to long-acting naloxone.

Naloxone, seriously?  When I read the suggestion to switch to Naloxone, I was really confused.  SAMSHA seems to want to avoid an addict’s use of street heroin at all costs.  Naloxone will displace all opiates (buprenorphine, heroin, morphine, methadone) from the mu-receptor but won’t induce any signaling in the neuron.  In fact, naloxone will displace natural opiates (endorphins) from the receptor as well such that even any placebo effect on pain suppression is lost.  In terms of listed side effects, naloxone causes lethargy, anxiety, a decrease in pain tolerance, joint and muscle pain, and induces immediate withdrawal signs if taken by someone who is dependent on opiates.  There’s a history of poor compliance among addicts with naloxone.  SAMSHA knows this.  Why would they introduce a drug option that could undermine all their efforts to set up a self-sustaining high compliance program?

To be fair here, long-acting naloxone does decrease relapses in alcoholics who are trying to maintain sobriety.  So we can call it “evidence-based treatment”.  Drug addicts are not going to crave their drug(s) of choice when taking naloxone.  The problem is that with naloxone patients aren’t going to want anything else either, such as food, going to work, etc.  (Yes, naloxone has been considered as a potential treatment for obesity.)  Of course the drug companies don’t include measures such as lethargy and apathy when they are doing the drug trials, but the impact is clear in the animal literature.

The Staff in Methadone Maintenance Clinics.  So we’re back to the real problem of what to do about methadone and “bup” patients that use other drugs.  Especially when used in combination with alcohol, methadone and buprenorphine can induce overdose.  Another complicating factor with the SAMSHA’s goal of increasing the numbers on MAT is the paucity of knowledgeable clinicians who approve of MAT in America.  About 45% of the non-physician clinicians in substance abuse treatment in this country are persons in recovery.  They generally are strong adherents to Twelve Step Principles.  The goal for Twelve Steppers is freedom from all mood and mind altering drugs.  They don’t generally approve of MAT.  Historically, physicians in Addiction Medicine often are recovering people as well.  So where are all these substance abuse professionals to staff methadone maintenance clinics going to come from?  The danger in by-passing the current work force and developing a new work-force is that it will take some time for the new recruits to develop expertise in detecting when a client is abusing alcohol and knowing the population.

Ironically, while the government’s response to the opiate epidemic is to increase MAT with more liberal dosing practices, they are also more closely monitoring pain clinic doctors.  At a recent International Opioid Conference I attended in Boston, most of the presenters were doctors working in hospice or pain clinics.  The lawyers talked about pain-management doctors being entrapped by clients working for the DEA and then facing criminal charges and fines.  (The director of prestigious Stanford pain-management clinic was recently visited by the DEA.)  At the conference, the director of the Stanford clinic talked about his clinic’s response to the DEA scrutiny.  They have developed very rigorous screening batteries to detect those pain clinic patients most likely to become addicts; they have developed elaborate informed consent procedures entailing a 20 minute video presentation for all prospective patients; they implemented drug screening procedures with point of care methods followed by laboratory screening involving very expensive assays.  The bottom line is that costs have increased dramatically, further contributing to the cost of medical care, which presently is already the most expensive system in the world.  This all seemed ironic to me, because if given a pain patient is indeed an addict, then the protocol is to refer to methadone or buprenorphine.  Once the patient becomes a methadone or buprenorphine patient, doctors are to “educate” the patient about the dangers of ever trying to become abstinent.  Moreover, the rationale for methadone is that the dosage is to be sufficiently high so that tolerance develops such that heroin, at any dose, will fail to produce an effect (opiate blockade).

We’re Off to Another Epidemic?  Given that buprenorphine is now in a clinical trial to treat medication resistant depression, we’re probably going to have a lot of people taking opiates.  Then we’ll have many dilemmas over what to do if the patient escalates the “bup” dose without permission or uses an unapproved medication.  Physician may wonder whether they need parole officer training. But, whatever the outcome for the patient, more money will be spent on drugs, monitoring, and auxiliary personnel.  With more opiate drugs circulating in the general population there will probably continue to be many opiate related deaths.   Thus, the U.S. is embarking on another big experiment with the drug companies and another big increase in the cost of medical care in this country.

Cicero T. J., Ellis, M. S., Surratt, H. L., & Kurtz, S. P.   (2014).  The changing face of heroin use in the United States:  a retrospective analysis of the past 50 years.  JAMA Psychiatry, 71(7), 821-826.

Franklin, G. M., Mai, J., Wickizer, T., Turner, J. A., Fulton-Kehoe, D., & Grant, L.  (2005).  Opioid dosing trends and mortality in Washington State workers’ compensation, 1996-2002.  American Journal of Industrial Medicine, 48 (2), 91-99.

Leece, P., Cavacuiti, C., Macdonald, e. M., Gomes, T., Kahan, M., Srivastava, A., Steele, L., Luo, H., Mamdani, M. M., & Juurlink, D. N.  (2015).  Predictors of opioid-related death during methadone therapy.  Journal of Substance Abuse Treatment, in press.

McCance-Katz, E. F., Sullivan, L., Nallani, S.  (2010).  Drug interactions of clinical importance among the opioids, methadone and buprenorphine, and other frequently prescribed medications: a review.  American Journal of the Addictions, 19(1), 4-16.

Meier, B.  (May 10, 2007).  In guilty plea, OxyContin maker to pay $600 million.  New York Times,

Portenoy, R. K., & Foley, K. M.  (1986).  Chronic use of opioid analgesics in non-malignant pain: report of 38 cases.  Pain, 25(2), 171-186.

Quinones, S.  (2014).  Dreamland: The True Tale of America’s Opiate Epidemic.  New York:  Bloomsbury Press.

Volkow, N. D., Frieden, T. R., Hyde, P. S., Cha, S. S.  (2014).  Medication-assisted therapies—tackling the opioid-overdose epidemic.  New England Journal of Medicine, 370, 2063-2066.

Weissman, D. E., & Haddox, J. D.  (1989).  Opioid pseudoaddiction—an iatrogenic syndrome.  Pain, 36 (3), 363-366.

Zedler, B., Xie, L., Wang, L., Joyce, A., Vick, C., Brigham, J., Kariburyo, F., Baser, O., Murrelle, L.  (2015).  Development of a risk index for serious prescription opioid-induced respiratory depression or overdose in Veterans’ Health Administration patients.  Pain Medicine, in press.

Zedler, B., Xie, L., Wang, L. Joyce, A., Vick, C., Kariburyo, F., Rajan, P., Baser, O., & Murrelle, L.  (2014).  Risk factors for serious prescription opioid-related toxicity or overdose among Veterans Health Administration patients.  Pain Medicine, 15, 1911-1929.

Why Antidepressants Cause Cognitive Dysfunction

Neuroscientists have long been focused on the mystery of how learning (the formation of memories) is encoded in the brain.  Following the maxim of Donald Hebb, that neurons that fire together wire together, neuroscientists have focused on the relationship between two types of receptors for the neurotransmitter glutamate: AMPA receptors and NMDA receptors.  The story on long term potentiation (the term for memory formation) has pretty much been worked out.  It involves coordinated activity of the AMPA and NMDA receptors.

With the knowledge of the particular mechanism for learning, Joe Tsien began making modifications of the relevant proteins involved in the process and ended up with the “Doggie Howser” mouse: a super-smart mouse that out performed all of the other mice on memory tasks.  What Tsien did was to over-express a particular version of a subunit of the NMDA receptor: the NR2B subunit.  (Tsien manipulated the neuron’s DNA so that more of the NR2B protein was produced.)

Elsewhere other researchers have paid attention to the impact of antidepressants (Selective Serotonin Reuptake Inhibitors) on which versions of the NMDA receptor subunits are used to create the NMDA receptor.  Turns out long term use of antidepressants decreases the supply of these NR2B subunits so that NMDA receptors rely on NR2A instead of NR2B version of the protein at least in the amygdala.  With aging, the brain does increase its use of NR2A subunits, but antidepressants (Selective Serotonin Reuptake Inhibitors) accelerate this effect.

The impact of long term antidepressants on decreasing NR2B subunits does have functional consequences.  Joe LeDoux is the neuroscientist who has worked out the particulars in the amygdala on how a rat learns to associate a light with shock when the two stimuli are repeatedly paired.  (This is called fear conditioning.)  Initially, LeDoux and colleagues showed that antidepressants impair the acquisition of fear memories.  (Perhaps a positive outcome.)  It is also known that unlearning the association between the light and the shock, called extinction, also involves new learning.  According to a study by LeDoux and colleagues, long term exposure to antidepressants makes it harder to unlearn fear memories as well.  Moreover, in their study, the deficit capacity to unlearn the association was correlated with deficit amounts of NR2B subunits.  LeDoux and colleagues concluded that the addition of antidepressants to exposure therapy, for extinguishing fear memories, is counter-productive.

LeDoux et al. did not examine whether similar reliance on NR2A rather than NR2B subunits is happening elsewhere in the brain when an organism is exposed to antidepressants.  However, others have examined the impact of long term exposure to antidepressants and found NR2B deficits in other brain areas besides the amygdala.  Both studies by Ampuero et al. and Boyer et al. suggest that a decrease in NR2B proteins is found in the cortex as well after long term exposure to antidepressants.  However, there are not many studies.  Future work promises to identify those areas of the brain and those types of learning where the composition of the NMDA receptor units matter.

Naturally, with aging, more NR2A subunits replace the NR2B subunits.  Perhaps accelerated aging in cognitive capacity should be added to the list of antidepressant side effects.  This area of research has yielded some useful findings as well.  Dietary consumption of Magnesium threonate can increase NR2B subunits.  For brain health and optimal functioning, we’re once again back to the topic of diet.


Abumaria, N., Yin, B., Zhang, L., Li, X. Y., Chen, T., et al. (2011).  Effect of elevation of brain magnesium on fear conditioning, fear extinction, and synaptic plasticity in the infralimbic prefrontal cortex and lateral amygdala.  Journal of Neuroscience, 31, 14871-14881.

Abumaria, N., Luo, L., Ahn, M., & Liu, G.  (2013).  Magnesium supplement enhances spatial-context pattern separation and prevents fear overgeneralization.  Behavioral Pharmacology, 24, 255-263.

Ampuero, E., Rubio, F. J., Falcon, R., Sandoval, M., Diaz-Veliz, G., Gonzalez, R. E., Earle, D., Dagnino-Subiabre, A., Aboitiz, F., Orrego, F., & Wyneken, U.  (2010).  Chronic fluoxetine treatment induces structural plasticity and selective changes in glutamate receptor subunits in the rat cerebral cortex.  Neuroscience, 169 (1), 98-108.

Boyer, P. A., Skolnick, P., & Fossom, L. H.  (1998).  Chronic administration of imipramine and citalopram alters the expression of NMDA receptor subunit mRNA in mouse brain: a quantitative in situ hybridization study.  Journal of Molecular Neuroscience, 10, 219-233.

Burghardt, N. S., Sigurdsson, T., Gorman, J. M., McEwen, B. S.  & LeDoux, J. E. (2013).  Chronic antidepressant treatment impairs the acquisition of fear extinction.  Biological Psychiatry, 73(11), 1078-1086.

Jacobs, S., Cui, Z., Feng, R. Wang, H., Wang, D. & Tsien, J. Z.  (2014).  Molecular and genetic determinants of the NMDA receptor for superior learning and memory functions.  PLOS One, 9 (10), e111865

Wang, D., Jacobs, S. A., & Tsien, J. Z.  (2015).  Targeting the NMDA receptor subunit NR2B for treating or preventing age-related memory decline.  Expert Opinion and Targeted Therapeutics, 18 (10), 1121-1130.

The Critical Mind-Body Connection: The Correlation between Stress and Inflammation

Links among depression, stress and inflammation.  An explosion of research has documented the link between the experience of stressful conditions, markers of inflammation in the blood, and the experience of depressive feelings and behaviors.  Inflammatory hormones (called cytokines) are elevated in persons diagnosed with depression (Raison, Capuron, & Miller, 2006).  Persons undergoing the stress of caring for a loved one with Alzheimer’s disease show elevations in inflammatory markers (Kiecolt-Glaser, et al., 2003).  In the Whitehall studies of employees in the British Civil Service system, those who were paid less and had less control over their work schedules, as a group, were higher on inflammatory markers even after controlling for possible differences in diet and smoking (Steptoe et al., 2003). Most recently, Setiawan et al. (2015), using brain imaging strategies, measured the level of activated white blood cells in brain and found a correlation between level of depression and activation of microglia, the brain’s major type of white blood cell.  About 1/3 of persons diagnosed with major depressive disorder exhibit elevations in inflammatory white blood cell hormones (cytokines) in blood (Tartter, Hammen, Bower, Brennan, & Cole, 2015).

Showing Causal Association between Stress and Inflammation.  Beyond the correlational studies, there is research in which animals have been manipulated in some way and then inflammation has been measured.  Animals have been subjected to bouts of foot shock that they were unable to control.  Subsequently, these animals displayed depressed behavior (not eating sweet foods, avoiding other animals, moving less).  They also had higher amounts of inflammatory cytokines in brain and when the researchers put in a molecular sponge to bind up the inflammatory cytokine in brain, the animals reverted to normal behavior (Maier & Watkins, 1998). These studies showed that stressing the animal results in more depressive behaviors and that these depressive behaviors are caused by the brain inflammatory factors.

Showing a causal link between infection and depression.  Researchers also know that another way to cause inflammatory factors to rise in the brain is by inducing infection in the periphery.  A number of experimenters have placed the wall of a bacterium into the paw of a rodent.  Subsequently, inflammatory cytokines increase in brain and the animal loses preference for sweet liquids, avoids other animals and moves less.  Again, if the researcher puts in a molecular sponge to bind up the inflammatory factor, the behavior reverts to normal (Maier & Watkins, 1998).

Showing causal link between inflammation and distress in people.  The accumulation of the animal findings has prompted similar studies in people.  Researchers have placed the wall of a bacterium into the periphery.  The wall of the bacterium in the body results in activation of areas of the brain associated with alarm, less response to money in reward areas, and stronger activation in the amygdala (an anxiety center) in response to scary images (Eisenberger et al., 2009, 2011; Inagaki et al., 2012).  In another approach, researchers arranged for research-participants to feel bad.  They had their research-participants play a computer game with others tossing a frisbee type object around.  Then suddenly the research-participant gets excluded.  Again, activation in the brain’s alarm area is noted.  However, if the research-participant had taken acetaminophen (Tylenol), an anti-inflammatory, prior to the study, then the alarm area remained quiet and people reported less distress (Dewall et al., 2010).

The causal role that inflammation plays in producing depression and anxiety has many implications.   Many reports of depression preceding dementia, heart disease, strokes, cancer have been published in samples of persons who were not taking antidepressants.  The common factor in all of these conditions is inflammatory processes.

A flood of new information on the immune system has emerged in the last several decades.  New fields, such as psychoneuroimmunology and psychoneuroendocrinology, have initiated research into how various systems, once thought to operate somewhat independently, are linked.   I cover topics in these fast-changing areas of research in Neuroscience for Psychologists and Other Mental Health Professionals.  Chapters 6 and 7 also covers disorders associated with hearing voices and how inflammation plays a role here as well.  On this web-site, I will be updating the latest findings in the research areas covered in Neuroscience for Psychologists and Other Mental Health Professionals.  We’ll examine the impact of psychiatric medications on inflammation.  We’ll also examine how dietary factors, exercise, salubrious social relationships, yoga and meditation can tame inflammation.   A picture of how the various systems in the body are coordinated is emerging in various literatures.  Integrating these diverse findings is the objective of this website.

Dewall, C. N, Macdonald, G., Webster, G. D., Masten, C. L., Baumeister, R. F., Powell, C., . . . Eisenberger, N. I.  (2010).  Acetaminophen reduces social pain:  behavioral and neural evidence.  Psychological Science, 21 (7), 931-947

Eistenberger, N. L., Berkman, E. T., Inagaki, T. K., Rameson, L. T., Mashal, N. M., & Irwin, M. R.  (2100)  Inflammation-induced anhedonia:  endotoxin reduces ventral striatum responses to reward.  Biological Psychiatry, 68(8), 748-754.

Eisenberg, N., Inagaki, T. K., Rameson, L. T., Marshal, N. M., & Irwin, M. R.  (2009).  An fMRI study of cytokine-induced depressed mood and social pain:  the role of sex differences.  Neuroimage, 47(3), 881-890.

Inagki, T. K., Muscatell, K. A., Irwin, M. R., Cole, S. W., & Eisenberger, N. I. (2012).  Inflammation selectively enhances amygdala activity to socially threatening images.  Neuroimage 59(4), 3222-3226.

Kiecolt-Glaser, J. K., Preacher, K. J., MacCallum, R. C., Atkinson, C., Marlarkey, W. B., Emery, C. F., & Glaser, r.  (2003).  Chronic stress and age-related increases in proinflammatory cytokine IL-6.  PNAS, 100(15), 9090-9095.

Maier, S. F., & Watkins, L. R.  (1998).  Cytokines for psychologists:  implications of bidirectional immune-to-brain communication for understanding behavior, mood, and cognition.  Psychological Review, 105(1), 83-107.

Raison, C. L., Capuron, L., & Miller, A. H.  (2006).  Cytokine sing the blues: inflammation and the pathogenesis of depression.  Trends in Immunology, 27(1), 24-31.

Setiawan, E., Wilson, A. A., Mizrahi, R., Rusjan, P. J., Miller, L., Rajkowska, G., Suridjan, I., Kennedy, J. L., Rekkas, P. V., Houle, S., & Meyer, J. H.  (2015).  Role of translocator protein density, a marker of neuroinflammation in the rain during major depressive episodes.  JAMA Psychiatry, 72 (3), 268-275.

Steptoe, A., Kunz-Ebrecht, S., Owen, N., Feldman, P. J., Rumley, A., Lowe, G. D., & Marmot, M.  (2003).  Influence of socioeconomic status and job control of plasma fibrinogen responses to acute mental stress.  Psychosomatic Medicine, 65(1), 137-144.

Tartter, M., Hamman, C., Bower, J. E., Brennan, P. A., & Cole, S.  (2015).  Effects of chronic interpersonal stress exposure on depressive symptoms are moderated by genetic variation at IL6 and Il1β in youth.  Brain, Behavior, and Immunity, 46, 104-111.