IDENTIFYING AN OPTIMAL POLICY WITH REGARD TO OPIATES

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.

 

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.