Why to get your COVID bivalent booster

The COVID vaccines have saved millions of lives, and spared millions more a frightening hospital or intensive care admission.   Many people may not realize that recovery from a COVID hospitalization will often not be complete; tissue damage from COVID pneumonia may not heal completely, also the psychological effect of respiratory failure should not be underestimated.  Severe respiratory failure (a terrifying, suffocating experience) can often be a cause of PTSD that could affect you psychologically for years afterwards.   The vaccines have caused a huge reduction in such episodes of respiratory failure.  

COVID vaccinations are not perfect, and their protective effect does diminish gradually with time, though does not disappear entirely.  There are indeed rare cases of serious adverse effects, much lower than the rate of similar or worse adverse effects from COVID itself.  Also, vaccination reduces the probability of spreading to other people, thereby multiplying the beneficial effects in the whole community.  Vaccination followed by a mild case of COVID a few months later likely adds robust protection compared to vaccination or infection alone.   But the most effective and safe protection is to have an updated bivalent COVID booster, particularly if your last dose of vaccine and any episode of COVID infection has been more than 2-3 months before present.  Unfortunately, fewer people have had their boosters compared to previous vaccine doses, resulting in thousands of needless hospitalizations and deaths.  

Anti-vaccine misinformation is widespread, with testimonial accounts from people claiming that the vaccines are harmful.  It is important to know that a bivalent booster will lead to a large reduction in risk of severe disease, hospitalization, ICU admission, and death.    Evidence to support this is very, very robust, and unfortunately has not been emphasized strongly enough in current public health information campaigns.  

I encourage perusing the references below.  Aside from reading the studies and assessing the evidence for yourself, I encourage you to look up the authors and verify for yourself that these are incredibly experienced, well-educated researchers from major research centers, with no major biases or profit motives affecting their findings.    The research findings are corroborated and consistent with the  experience of ICU and infectious disease physicians, who on a daily basis in the past months have continued to see much more severe COVID disease and dangerously high hospital occupancy among those who are not up-to-date with their booster vaccinations.  

The references below are a preliminary list; I encourage you to continue checking out other references I've included in my previous COVID-related posts.  

References

Watson, O. J., Barnsley, G., Toor, J., Hogan, A. B., Winskill, P., & Ghani, A. C. (2022). Global impact of the first year of COVID-19 vaccination: A mathematical modelling study. The Lancet Infectious Diseases, 22(9), 1293–1302. https://doi.org/10.1016/S1473-3099(22)00320-6

CDC. COVID Data Tracker.  Centers for Disease Control and Prevention. 

https://covid.cdc.gov/covid-data-tracker/#vaccine-effectiveness

https://covid.cdc.gov/covid-data-tracker/#rates-by-vaccine-status

Arbel, R., Peretz, A., Sergienko, R., Friger, M., Beckenstein, T., Yaron, S., Hammerman, A., Bilenko, N., & Netzer, D. (2023). Effectiveness of the Bivalent mRNA Vaccine in Preventing Severe COVID-19 Outcomes: An Observational Cohort Study (SSRN Scholarly Paper No. 4314067). https://doi.org/10.2139/ssrn.4314067

https://www.azdhs.gov/covid19/documents/data/rates-of-cov-19-by-vaccination.pdf?v=2023010

Lin, D.-Y., Xu, Y., Gu, Y., Zeng, D., Wheeler, B., Young, H., Moore, Z., & Sunny, S. K. (2023). Effectiveness of Vaccination and Previous Infection Against Omicron Infection and Severe Outcomes in Children Under 12 Years of Age (p. 2023.01.18.23284739). medRxiv. https://doi.org/10.1101/2023.01.18.23284739

Andersson, N. W., Thiesson, E. M., Baum, U., Pihlström, N., Starrfelt, J., Faksová, K., Poukka, E., Meijerink, H., Ljung, R., & Hviid, A. (2023). Comparative effectiveness of the bivalent BA.4-5 and BA.1 mRNA-booster vaccines in the Nordic countries (p. 2023.01.19.23284764). medRxiv. https://doi.org/10.1101/2023.01.19.23284764

Davydow, D. S., Gifford, J. M., Desai, S. V., Needham, D. M., & Bienvenu, O. J. (2008). Posttraumatic stress disorder in general intensive care unit survivors: A systematic review. General Hospital Psychiatry, 30(5), 421–434. https://doi.org/10.1016/j.genhosppsych.2008.05.006

Tenforde, M.W. et al. (2022). Early estimates of bivalent mRNA vaccine effectiveness in preventing COVID-19-associated emergency department or urgent care encounters and hospitalizations among immunocompetent adults. VISION Network, nine states, Sep-Nov 2022.  Morbidity and Mortality Weekly Report, 71(5152), 1616-1624. 

Tetris or sleep deprivation to treat or prevent PTSD?

Here's a reference to an interesting 2009 study showing that playing tetris for 30 minutes can interfere with memory consolidation of upsetting visual imagery:
http://www.ncbi.nlm.nih.gov/pubmed/19127289

This is an example of evolving evidence that an important period for consolidation of  memories occurs in the first 24 hours after an experience.  A consolidated implicit association between the factual components of memory and strong negative emotions may also form most strongly during this initial post-exposure period.

The same group published a 2010 study showing that a game like tetris was more effective than a quiz-type game activity for reducing visual flashbacks following exposure to upsetting imagery:
http://www.ncbi.nlm.nih.gov/pubmed/21085661

I think the message here is not that tetris in particular has some kind of unique medicinal properties, but that a non-passive activity which requires continuous, intense visual attention is most effective at reducing consolidation of intrusive visual memory.  A distracting activity lacking strong visual involvement may be less likely to interfere with this consolidation mechanism. 

Other research has suggested that propranolol, a beta-blocking drug, can reduce post-traumatic memory consolidation, particularly the troubling implicit or emotional component responsible for psychological symptoms of PTSD.  (see my other post, http://garthkroeker.blogspot.com/2009/02/beta-blockers.html)

Some of the standard psychological treatments in the immediate post-trauma period may be harmful, such as critical incident stress debriefing.  If individuals are compelled to revisit details of their trauma in a group setting,  during the sensitive 24-hour post-incident window,  this may increase rather than decrease memory consolidation.  I think this tactic is especially problematic if there is social pressure or overt prescriptive advice from professionals to do this, when the individual may not wish to talk about the trauma.   This type of pressure may feel coercive rather than freely consensual, a dynamic which could be re-traumatizing. 

In another recent study (http://www.ncbi.nlm.nih.gov/pubmed/20889142 ),  sleep deprivation following exposure to upsetting visual stimuli was shown to reduce aspects of implicit memory consolidation.  This is consistent with other evidence showing that sleeping facilitates learning, by helping to consolidate recently acquired memories.

In conclusion, I think it is useful to know some simple techniques which could reduce the harm which traumatic experience can immediately impose upon the brain's memory systems.  Immediate distraction with an absorbing visual activity, such as tetris, could be helpful.  Sleeping right away may not be helpful, and may actually increase consolidation of traumatic memory.

For consolidated symptoms of PTSD, and for longstanding troubling thoughts, memories, images, and emotions, etc.  it is clear that therapeutic dialog can be very helpful, provided the setting is safe, non-pressured, comfortable, with a strong sense of trust.    Such gentle dialog could begin the process of weakening the strong negative emotional grip that the traumatic experiences may have in daily life.  The evidence mentioned above has to do with reducing the incidence of PTSD in the first place, through specific tactics to be undertaken immediately after the trauma. 

We could infer, conversely,  that engaging in distracting activities, such as video games, after doing an activity that you would want to remember vividly (such as studying, or some other pleasurable or meaningful event), could lessen retention of these positive experiences  (so, you shouldn't distract yourself with an absorbing visual activity right after studying).  Also, having a good sleep after a pleasurable event, or after studying, would be expected to make these experiences more permanent in your factual and emotional memory. So, it's important to be conscious of what you do, during, but also after, events of significance.

Internet, Video Games, and TV: Addictions or Cognitive Enhancers?

I'll introduce this post with my opinion on this issue:

Almost any human activity can be addictive, in a harmful way. That is, the activity could provide a mental reward which leads to the following pattern:
- the activity happens more frequently
- tolerance develops
- increased absorption with the activity develops, in order to achieve the same or greater reward
- other activities feel more boring or unrewarding
- other activities & relationships are neglected
- physical harm may result from sleep deprivation, sedentary behaviour, repetitive strain, reduced self-care, etc.
- social harm may result from relationship neglect or isolation, but also from associating with a cohort of fellow "addicts" who do the same behaviours
- the "mental reward" could probably correlate with functional brain imaging demonstrating increased activity of central dopaminergic reward circuits

Many "good" activities could lead to an addictive pattern. Here's a list of possible activities that can potentially become addictive in this sense:
1) work
2) earning money
3) studying
4) hobbies
5) house chores
6) talking or texting on phones or other electronic devices
7) being in the company of people, or of a particular person
8) sports (playing or watching)
9) reading
10) pursuing excellence


Sometimes, behaviours or thoughts associated with depression or low self-esteem can be "addictive", in that some people may feel a type of masochistic reward from them.

Individuals may not recognize the unhealthy or addictive components of their behaviours. For a person wanting to earn more money, or pursue more excellence, it may seem absurd, and contrary to that person's values, to consider backing away from these pursuits.

For the person "pursuing excellence," it may be true that pouring more time and energy into training might increase achievement in a short-term sense. But this is the addictive trap. In order to pursue excellence in the most effective way, a balanced lifestyle is necessary. In order to achieve that balanced lifestyle, that person may paradoxically need to back away from their immediate pursuit.

I think that all types of modern technology have the potential to be addictive.

Technology and technological culture are changing at an unprecedented pace. And the technologies have ever more powerful and subtle ways to capture our interest, attention, and to stimulate neural reward.

All technological inventions have become addictive for some people. Yet most of these inventions have also contributed to an evolution of modern culture, which has been positive in many ways.

The internet, TV, and video games can all be stimulating, educational activities, which could enhance brain function, intelligence, and could lead to improved social relationships. They could be devices which improve relatedness rather than foster alienation.

Some of these technologies may permit an individual with problems such as a social skills difficulty to explore social connectedness in a different way. In this way, the internet can be an expansion of human connectedness and community. It is a technology which continues the trend of increased potential connectedness through human history. Thousands of years ago, it would have been hard to meet anyone who lived any farther away than the next village. While many individuals would have thrived socially in isolated village culture, some individuals would have been alienated.

Yet technological devices can be easily addictive. And the huge availability of choice in modern technology may permit an individual to find a particular thing that absorbs attention, and disappear into that activity while general physical, social, and mental health deteriorates. There is also a lot of choice available that has violent content, or which creates only an illusion of connection, while none really exists. Facebook or other social connection applications can become preoccupations for many people. While such sites could facilitate social connection, they could also be such a preoccupation that actual social relationships are neglected. The "network" itself could become a meaningless connection of distant acquaintances, yet the preoccupied individual may believe that expanding the network further is a valid solution to this problem. This is not unlike various neurotic social behaviours that exist outside of modern technology: people have always had collections of social behaviours which they believed to be useful, but in fact caused increased social distance & loneliness (e.g. vain behaviours, talking a lot without listening, etc.).

The thing that I believe distinguishes addictions to modern technology from other types of addiction is that many individuals are unquestioningly adopting the technologies as major parts of their daily lives, without being aware of the addictive potential, and without maintaining balance in other parts of life. While everything in life can be addictive, we have a greater understanding of non-technological addiction, since these phenomena have developed more slowly over past decades or centuries. New technology is changing personal culture so rapidly that we may have little chance to understand the risks before the addictiveness is quite entrenched in many people.

So, in conclusion, I do not believe that modern technology, including internet, TV, or video games, are necessarily "bad." They may in fact be wonderful, life-enhancing joys which improve happiness, culture, relationships, and connectedness. Yet they have a high risk to be addictive. I do not believe most people understand the degree of risk involved. I encourage people, in the meantime, to choose wisely when using technology, or when doing supposedly "good" activities such as those listed above, perhaps using the following questions:

1) am I doing this just out of a habit, because of boredom, or as part of procrastinating?
2) is this activity enhancing my life, or is it just gobbling up some of my time and attention?
3) is this activity improving my community, or is it distracting energy away from healthy community?
4) is this activity causing me physical harm, due to lack of exercise, or physical overuse?
5) is this activity consistent with my core values?
6) if it is consistent, is it really helping realize those core values?
7) is the activity itself causing my core values to change in an unwelcome way?
8) is the activity distracting energy or time away from other activities (such as learning, developing a talent, practicing a creative art, developing social relationships) which are important to personal culture?
9) do I have boundaries around this activity, in terms of time & energy, that protect my health?

References & Further Reading:

http://www.ncbi.nlm.nih.gov/pubmed/19818048
{this is a 2009 study by Kira Bailey et al., giving a good review of data concerning video gaming & cognitive variables; they discuss their own study, which leads to the following conclusion:
"these data may indicate that the video game experience is associated with a decrease in the efficiency of proactive cognitive control that supports one’s ability to maintain goal-directed action when the environment is not intrinsically engaging." In other words, video gaming may lead to an ADHD-like phenomenon}

http://www.ncbi.nlm.nih.gov/pubmed/18506602
{a useful review of the subject of technological advancements, in this case specifically regarding gambling technology, looking at whether these advancements constitute increased addictive risk, and if technology to reduce addictive risk is effective. The promise is that the technology itself could evolve--if it is the will of individuals and manufacturers to permit this evolution--to become safer, healthier, and less prone to foster addictive behaviour}

http://www.ncbi.nlm.nih.gov/pubmed/19805713
{this 2-year prospective study of adolescents shows that ADHD, depression, social phobia & hostility symptoms are risk factors for developing internet addiction}

http://www.ncbi.nlm.nih.gov/pubmed/19701792
{one of many associational studies correlating negative mood & internet/gaming addiction; unfortunately, associational studies are very weak, and do not really answer the question for us of how internet/gaming affects people, since we do not see the directions or strengths of causation}

http://www.ncbi.nlm.nih.gov/pubmed/19490510
{a study showing a strong association between addictive internet use and excessive daytime sleepiness}

http://www.ncbi.nlm.nih.gov/pubmed/16634979
{a study associating TV & computer use with sedentary behavior in 5-year-olds}

http://www.ncbi.nlm.nih.gov/pubmed/19428410
{one of the studies showing enhanced visual attentional skills in video gamers. But I find this a severely limited study which should not be over-interpreted--basically it shows that if you play video games, you become more skilled at a visual attention test that resembles the video games you've been playing. It says nothing about general intelligence, social skills, verbal aptitude, etc. which may well have atrophied in the video gamers}

http://www.ncbi.nlm.nih.gov/pubmed/18929349
{a more extensive analysis of cognitive skills in relation to video game playing. But, astonishingly, no cognitive tests were given to assess verbal skills, social skills, etc.; rather the tests were all related to things that seemed to me quite similar to video game tasks--so it is no surprise that the video gamers performed modestly better on some of these! No surprise that playing 1000 hours of Tetris probably will help you mentally rotate 3-d shapes more easily! But at what cost to other social, emotional, and intellectual skills? We need to have prospective studies that do very broad cognitive and psychological evaluations following prolonged exposure to different types of video games. The evaluations must include assessments of emotional state, verbal & non-verbal attention, memory, and reasoning; and they should include assessments of "social intelligence" such as establishing appropriate social communication, empathy, recognition of emotions, etc.}

http://www.ncbi.nlm.nih.gov/pubmed/19016226
{a 30-month longitudinal study showing increased aggression and hostile attribution bias in those exposed to violent video games}

http://www.ncbi.nlm.nih.gov/pubmed/19127289
{here's a description of an interesting psychotherapeutic application for a video game: in this study, those who played Tetris after watching a disturbing film had fewer flashback symptoms afterwards; it may encourage a tactic of treating those who have recently experienced a traumatic event with cognitive distraction, in order to reduce involuntary intrusive emotional memory of the trauma, and therefore to reduce the chance of developing PTSD. The deliberate, voluntary memory of the traumatic scene was unaffected.}

http://www.ncbi.nlm.nih.gov/pubmed/16972829
{an example of using video games to reduce pre-operative anxiety in young children. This sounds like a great idea, which could improve comfort while minimizing medication use in this type of situation.}

http://www.liebertpub.com/products/product.aspx?pid=10
{this is a link to a fairly new journal called "CyberPsychology & Behavior", which looks interesting and pertinent}

Increasing anxiety in recent decades...continued

This is a sequel to a previous posting (http://garthkroeker.blogspot.com/2009/06/increasing-anxiety-in-recent-decades.html)

A visitor suggested the following July 2009 article to look at regarding this subject--here's a link to the abstract:
http://www.ncbi.nlm.nih.gov/pubmed/19660164

The author, "Ian Dowbiggin, PhD", is a history professor at the University of Prince Edward Island.

I found the article quite judgmental and poorly informed.

I thought there were some good points, exploring the interaction of social dynamics, political factors, secondary gain, etc. in the evolution of diagnostic labels; and perhaps exploring the idea that we may at times over-pathologize normal human experiences, character traits, or behaviours.

But, basically the author's message seems to be that we cling to diagnostic labels to avoid taking personal responsibility for our problems--and that therapists, the self-help movement, pharmaceutical companies, etc. are all involved in perpetuating this phenomenon.

Another implied point of view was that a hundred years ago, people might well have experienced similar symptoms, but would have accepted these symptoms as part of normal life, and carried on (presumably without complaint).

To quote the author:

"The overall environment of modern day life...bestows a kind of legitimacy on the pool of
anxiety-related symptoms"

This implies that some symptoms are "legitimate" and others are not, and that it is some kind of confusing or problematic feature of modern society that anxiety symptoms are currently considered "legitimate."

I am intensely annoyed by opinion papers which do not explore the other side of the issues--

here's another side to the issue:

1) perhaps, a hundred years ago, people suffered just as much, or worse, but lacked any sort of help for what was bothering them. They therefore lived with more pain, less productivity, less enjoyment, less of a voice, more isolation, and in most cases died at a younger age.

2) The development of a vocabulary to describe psychological distress does not necessarily cause more distress. The vocabulary helps us to identify experiences that were never right in the first place. The absence of a PTSD label does not mean that symptoms secondary to trauma did not exist before the 20th century. The author somewhat mockingly suggests that some people misuse a PTSD or similar label--that perhaps only those subject to combat trauma are entitled to use it, while those subject to verbal abuse in home life are not.

The availability of financial compensation related to PTSD has undoubtedly affected the number of people describing symptoms. But the author appears to leave readers with the impression that those seeking compensation via PTSD claims are "milking the system" (this is the subtitle of the PTSD section of this paper). There is little doubt that factitious and malingered symptoms are common, particularly when there is overt secondary gain. And the issue of how therapeutic it is to have long-term financial compensation for any sort of problem, is another matter for an evidence-based and politically charged debate. But to imply that all those who make financial claims regarding PTSD are "milking the system" seems very disrespectful to me. And to imply that a system which offers such compensation is somehow problematic again seems comparable to saying that the availability of fire or theft insurance is problematic. A constructive point of view on the matter, as far as I'm concerned, would be to consider ways to make compensation systems fair and more resistant to factitious or malingered claims.

With regard to social anxiety -- it may well be that "bashfulness" has been valued and accepted in many past--and present--cultures. But I suspect that the social alienation, social frustration, loneliness, and lack of ability to start new friendships, new conversations, or to find mates, have been phenomena similarly prevalent over the centuries. Our modern terminology suggests ways for a person who is "bashful" to choose for himself or herself, whether to stoically and silently accept this set of phenomena, or to address it as a medical problem, with a variety of techniques to change the symptoms. In this way the language can be empowering, leading to the discovery and nurturance of a voice, rather than leading to a sense of "victimhood."

Perhaps the lack of a vocabulary to articulate distress causes a spurious impression that the distress does not exist, or is not worthy of consideration. A historical analogy might be something along the lines of this: terms such as "molecule", "Uranium", or "electromagnetic field," may not have been used before 1701, 1797, or 1820, but this was merely a product of ignorance, not evidence of the non-existence of these phenomena in the 1600's and prior.

It may well be true that many individuals misuse the vocabulary, or may exploit it for secondary gain. And it may well be true that some diagnostic labels introduce an iatrogenic or factitious illness (the multiple personality disorder issue could be debated along these lines). But to imply that the vocabulary itself is harmful to society is akin to saying that fire insurance is harmful, since some people misuse it by deliberately burning their houses down.


3) Similarly, the so-called self-help movement may be part of some individuals fleeing into self-pathologizing language, while ironically neglecting a healthy engagement with their lives. But in most cases, it has actually helped people to recognize, label, and improve their problems. For a start on some evidence to look at regarding this, see the following reference to a meta-analysis on self-help for anxiety disorders: http://www.ncbi.nlm.nih.gov/pubmed/16942965).

---
So, in conclusion, it is interesting to hear a different point of view. But I would expect a distinguished scholar to provide a much more balanced and insightful debate in such a paper, especially when it is published in a journal which is supposed to have high standards.

And I would certainly expect a much more thorough exploration of research evidence. The presence of 35 references in this paper may fool some readers into thinking that a reasonable survey of the research has been undertaken. Almost all of the references are themselves opinion pieces which merely support the author's point of view.

Prazosin and other treatments for PTSD-related nightmares

Nightmares are a common symptom of post-traumatic stress disorder (PTSD).

Various psychotherapeutic approaches can help people to deal with nightmares, both to be more psychologically prepared for them, and to be able to let them pass with a smaller amount of distress. Techniques include simply keeping a written record of the nightmares, with or without doing some cognitive therapy exercises based on this record; practicing relaxation techniques; exposure therapy during the daytime (by evoking the imagery of the nightmares, possibly "rescripting" the sequence of events); or by planning for a "rescripting" of the nightmare during the nightmare itself. Here is a reference to a review article about psychotherapy for nightmares: http://www.ncbi.nlm.nih.gov/pubmed/18853707

Sedative drugs can change dreaming activity, but often times these medications are problematic: tolerance or oversedation may develop, or sometimes the nightmares continue despite other types of sleep improvement.

Prazosin is a cardiovascular drug which blocks alpha-receptors, and is commonly used to treat high blood pressure. Alpha receptors are stimulated by adrenaline, which causes constriction of blood vessels, therefore increased blood pressure. In the brain, increased stimulation of alpha-receptors may be one of the mechanisms driving PTSD-related sleep disturbances such as nightmares. Prazosin has been shown to help reduce PTSD-related nightmares. Here are a few references:

http://www.ncbi.nlm.nih.gov/pubmed/18447662 {a good review article}

http://www.ncbi.nlm.nih.gov/pubmed/17069768 {a 2007 randomized, controlled, crossover study published in Biological Psychiatry, showing pronounced reduction in PTSD-related nightmares with 10-15 mg bedtime doses of prazosin}

http://www.ncbi.nlm.nih.gov/pubmed/12562588 {a 2003 randomized study published in The American Journal of Psychiatry showing substantial benefit in PTSD-related sleep symptoms with prazosin at an average of 10 mg/d}

There is the suggestion in these studies that prazosin, if dosed in the daytime as well, could help treat other PTSD symptoms.

Prazosin has been used for over 35 years in the treatment of hypertension. Interestingly, it is also one of the treatments of choice in the medical management of severe scorpion stings. It may also be a promising option in the treatment of alcoholism (reference: http://www.ncbi.nlm.nih.gov/pubmed/18945226).

Prazosin is well-tolerated by the majority of people taking it. It appears to have minimal psychiatric side-effects. Sedation does not seem to be common. If the dose is too high, too soon, it can cause excessive postural blood pressure drops, with dizziness and a risk of fainting (syncope). It may cause nasal congestion or headache. Priapism (a medically dangerous sexual side-effect) is possible but very rare.

MDMA (ecstasy): risks and benefits

"Ecstasy" is a common recreational drug. Chemically, it is known as MDMA, or 3,4-methylenedioxymethamphetamine. It is a type of chemically modified amphetamine compound which causes a release of serotonin and other transmitters from brain cells. It probably has a variety of other pharmacological effects.

MDMA has been shown in many studies to be neurotoxic, particularly causing harm to the cells in the brain which produce serotonin. There is evidence that MDMA can cause permanent harm or cell death. These studies have been done using rodents, monkeys, and using laboratory cell cultures. The neurotoxicity seems to be associated with, or magnified by, the increase in body temperature caused by ecstasy ingestion. Here are a few of the many references about this:
http://www.ncbi.nlm.nih.gov/pubmed/1379014
http://www.ncbi.nlm.nih.gov/pubmed/18991870
http://www.ncbi.nlm.nih.gov/pubmed/16884865
http://www.ncbi.nlm.nih.gov/pubmed/12464456

But here is a paper describing long-term MDMA exposure in monkeys, which did not lead to chemical evidence of neurotoxicity:
http://www.ncbi.nlm.nih.gov/pubmed/15039771

An important body of research is the Netherlands XTC Toxicity (NeXT) study. This 2008 paper from the NeXT study describes a prospective follow-up of new low-dose ecstasy users, and found evidence through functional brain imaging of neurotoxicity in the ecstasy-using group:
http://www.ncbi.nlm.nih.gov/pubmed/18842607

Here is another similar 2007 paper published in Archives of General Psychiatry describing a slight reduction in verbal memory performance in individuals who had used even just a few doses of ecstasy, compared to individuals who had not used any:
http://www.ncbi.nlm.nih.gov/pubmed/17548754

However, this paper gave rise to a good debate in subsequent issues of this journal. Basically, neither group in the study declined in memory performance, it's just that the non-ecstasy group improved more than the ecstasy group on re-testing. The ecstasy group included some people who had used much more than others. Also, the ecstasy-using group may have been more anxious about negative memory effects, since they had been warned about this possibility in advance. Such anxiety can impare test performance. The ecstasy-using group may have taken drugs tainted with impurities. A very important point I would add is that most people who use ecstasy recreationally do so in a chaotic, loud environment such as a rave--the drug may act as an emotional or interpersonal "amplifier", which in the case of a rave, could give rise to an amplification of social chaos. Also such an environment might lead to a higher degree of hyperthermia, which is associated with worse neurotoxicity. Use of ecstasy in a controlled, gentle, intimate environment might be much safer.


Here's a reference to a 2009 British Journal of Psychiatry study showing no difference in serotonin transporter binding between groups of former MDMA users, other drug users, and controls with no history of street drug use:
http://www.ncbi.nlm.nih.gov/pubmed/19336788?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum


This is a randomized, double-blind study looking at physical and emotional effects of acute MDMA ingestion, at low (1 mg/kg) and high (1.6 mg/kg) doses. It did not demonstrate hyperthermia as an effect of the drug, rather it implies that hyperthermia is caused by the environmental situation in conjunction with the drug (e.g. vigorous activity dancing indoors in a crowd).
http://www.ncbi.nlm.nih.gov/pubmed/18626271

There may be therapeutic applications for MDMA. The subjective effects of the drug can be to dramatically increase a feeling of openness, empathy or connectedness with other people, both on an emotional level and also sensually or physically.

Here are some references about this:
http://www.ncbi.nlm.nih.gov/pubmed/19273493
{this is a brief 2009 review of the subject of possible psychotherapeutic uses of MDMA, such as in anxiety disorders and PTSD}

http://www.ncbi.nlm.nih.gov/pubmed/19004414
{this 2008 study from Madrid showed that 50-75 mg doses of MDMA used in conjunction with psychotherapy for PTSD appeared to be physiologically and emotionally safe for 6 subjects. The study apparently had to be ended due to political pressures, before more subjects could be treated. Clearly, this is a controversial issue}

A psychiatrist by the name of Michael Mithoefer is trying to do research about using MDMA for treating PTSD. Here are some related sites:
http://scienceblogs.com/neurophilosophy/2007/11/mdma_for_ptsd.php
http://www.maps.org/mdma/protocol/
http://www.maps.org/mdma/

I think it is important to be open-minded about things outside the mainstream, and to recognize that mainstream research may sometimes dismiss ideas considered too controversial. Yet I recognize that the above sites have a biased agenda of their own which may undervalue important risk analyses published in the mainstream literature.

Answering questions relating to controversial issues, such as the potential use of MDMA as a therapeutic agent, requires a very neutral, unbiased research environment.

Aside from therapeutic possibilities in PTSD, it seems to me that MDMA might be worth investigating as an adjunct for couples' therapy, particularly for couples who feel inhibited or disconnected with each other. MDMA can foster a sense of connectedness, sensuality, and empathy. These three domains are often major weaknesses in troubled relationships. Apparently MDMA has been used in relationship therapy in the past, but the results have been poorly documented.

I have seen patients for whom MDMA use appears to have been part of a destructive long-term drug abuse pattern, which has most likely exacerbated mood, anxiety, and interpersonal problems. I have also seen a few patients for whom isolated experiences with MDMA have led to strong, memorable experiences of openness and intimacy with friends or partners.

In conclusion, I emphasize that MDMA is clearly a dangerous drug. It is most definitely neurotoxic. The risk of neurotoxicity is most likely higher with frequent, regular, or long-term use. Most "ecstasy" obtained on the street is tainted with numerous impurities--both deliberately, to reduce production costs, and as by-products of crude synthetic techniques; the impurities are likely to add to potential toxicity. I think that the setting in which MDMA is used most frequently (e.g. as a "dance drug") is likely to magnify its toxicity, in that hyperthermia is more likely, and any intimate emotional benefit is less likely. Many MDMA users are taking this drug frequently, over a period of years--I think this pattern has a very high risk of causing permanent neuropsychiatric harm.

We do not know yet if MDMA could have a positive therapeutic role for some people, but if it did, it would most likely have to be used only a very small number of times, in a carefully controlled, socially supported, comfortable, quiet, cool setting, by individuals who are already in a state of relative emotional calm. I suspect that a history of psychotic or bipolar illness, or a history of other street drug use or dependence, would greatly magnify the psychiatric risks of MDMA use. In the meantime, the existing research shows that any possible benefits would have to be weighed against very substantial risks. It remains an illegal drug in most jurisdictions.

Trazodone

Trazodone is another antidepressant introduced in the early 80's. Once again, its use was fashionable for a time, gradually faded, and at this point it is mainly used adjunctively to treat insomnia.

It is notable among antidepressant choices in not causing sexual side effects (other than the rare incidence of priapism, which is a medically dangerous, painful, abnormally sustained penile erection, which occurs in probably less than 1 in 1000).

The trouble with trazodone is that for many people, it causes too much daytime sedation. However, it can be worth a try, to treat insomnia associated with depression or antidepressant therapy, or possibly as an augmentation to treat depression or OCD.

In my experience, about 50% of people find trazodone a helpful adjuct, but the other 50% find it causes too much tiredness or dizziness the next day to be worth continuing.

Here is a literature review:


http://www.ncbi.nlm.nih.gov/pubmed/19112384
{in this 2008 study from a minor journal, trazodone was shown to increase the amount of slow-wave sleep in treating chronic insomnia}

http://www.ncbi.nlm.nih.gov/pubmed/12930437
{a 2003 urology article showing evidence that trazodone may help treat erectile dysfunction, especially at higher doses}

http://www.ncbi.nlm.nih.gov/pubmed/18978492
{a small 2008 study showing that 50-100 mg of trazodone may reduce SSRI-induced sexual dysfunction}

http://www.ncbi.nlm.nih.gov/pubmed/16968574
{a small 2006 study showing equivalence between trazodone and sertraline in treating depression over 6 weeks}

http://www.ncbi.nlm.nih.gov/pubmed/10507215
{a small 1999 study from a podiatry journal, showing that trazodone can help with painful diabetic neuropathy symptoms}

http://www.ncbi.nlm.nih.gov/pubmed/8010365
{a 1994 American Journal of Psychiatry article showing that trazodone can help with antidepressant-induced insomnia, particularly helping with overall subjective sleep quality, reducing waking in the middle of the night, and reducing early morning waking}

http://www.ncbi.nlm.nih.gov/pubmed/8988452
{this awkardly-designed 1996 study suggests that combination treatment including 100 mg of trazodone may help in treatment-resistant depression}

http://www.ncbi.nlm.nih.gov/pubmed/11518472
{this quite weak 2001 study nevertheless suggests that trazodone helps to reduce nightmares in PTSD patients}

http://www.ncbi.nlm.nih.gov/pubmed/6337131
{an early, 1983 study, of trazodone vs. imipramine for treating moderately to severely depressed outpatients. Despite the weaknesses of the study design, it did have some follow-up over 3 years, showing that trazodone works well for some people, and worked as well as imipramine overall}

http://www.ncbi.nlm.nih.gov/pubmed/18311107
{an example of a small study suggesting that adjunctive trazodone could help improve OCD symptoms. Some studies have shown no anti-OCD effect with trazodone alone, but others have shown trazodone alone to be beneficial in refractory OCD. In any case, I think the evidence base suggests that trazodone could at least be worth a try, either together with an SSRI, or even on its own.}

Beta-Blockers

Here's a link to a very interesting study which shows that the beta-blocker propranolol can interrupt the consolidation of fear in humans:

http://www.nature.com/neuro/journal/vaop/ncurrent/pdf/nn.2271.pdf

This study suggests a novel use for beta-blockers, which could facilitate behavioural therapy for PTSD. The study demonstrates a variety of things:
1) as was well-known before, when people experience something fearful or traumatic, it sensitizes them to react more strongly to the same fearful stimulus in the future
2) when people re-experience a fearful or traumatic memory, this re-experience consolidates, or strengthens, the strong fearful reaction. This is consistent with the evolution of PTSD and other anxiety disorders, in which an expanding variety of daily events can trigger and consolidate the fear (e.g. a survivor of a bad traffic accident may constantly re-experience traumatic symptoms when hearing traffic noise, loud sounds, etc.--and may start to avoid these situations. Every time this happens, the anxiety disorder becomes more entrenched).
3) Fears can be "extinguished" by re-experiencing the feared stimulus repetitively, in a safe setting. But the fear can be "re-kindled" after extinction more easily than in non-traumatized people (this suggests a permanence to "emotional memory" that can be only temporarily over-ridden by psychological techniques)
4) If the consolidation phase of fear or traumatic memory could be interrupted, then a person might not develop ongoing post-traumatic symptoms at all. In this experiment, there is evidence that propranolol can interrupt this consolidation.
5) Propranolol may disrupt the "emotional memory" consolidation but not the "declarative memory"--the former process may occur primarily through the amygdala, whereas declarative memory is consolidated mainly in the hippocampus. So, the use of propranolol would not "erase the memory" of a traumatic event--the facts of the event would still be remembered normally--but it might reduce the painful, reflexive feeling of emotional trauma associated with the event.

The study does NOT show that "propranolol erases memories", as some of the news headlines seem to be proclaiming. It DOES suggest that adjunctive propranolol may greatly enhance the effectiveness of behavioural therapy. It requires that the person use propranolol while engaging in exposure therapy. So, for example, a possible technique for treating PTSD or panic (especially new-onset) might be to use a 40 mg dose of propranolol 1-2 hours before a therapy session. In the therapy session, the memories of the upsetting events could be discussed. The propranolol might interrupt the process of these upsetting memories getting further consolidated, might facilitate a behavioural therapy process which would help the person feel emotionally comfortable with their thoughts and memories. This process may occur because of direct beta-blockade in the amygdala, which may interrupt consolidation of emotional memory directly.

Despite this encouraging study, there are a number of negative studies looking at using propranolol similarly, for example:
http://www.ncbi.nlm.nih.gov/pubmed/18761097

http://www.ncbi.nlm.nih.gov/pubmed/19060728

I think the main thing to take from the first study is that propranolol may help, but probably only as an augmentation to enhance the effectiveness of behavioural therapy (or CBT) for treating post-traumatic stress or other anxiety disorders.

Beta-blockers are drugs used primarily in cardiology. Some beta-blockers, such as atenolol, act only peripherally, that is they do not enter the brain very much. Others, especially propranolol, can more easily enter the brain, and therefore can act in the central nervous system as well as peripherally.

In psychiatry, propranolol has been useful to treat performance anxiety, especially if there is a component of tremor (e.g. shaking hands) accompanying the anxiety. Many musicians use doses of propranolol to reduce tremor during performances. The anti-tremor mechanism is most likely peripheral beta-blockade (i.e. outside the brain), but the accompanying reduction of subjective anxiety may also be due to central beta-blockade (i.e. inside the brain). This is consistent with some studies which show that peripherally-acting beta-blockers reduce tremor as well as propranolol, but people subjectively prefer the propranolol.
(Reference: http://www.mdconsult.com/das/citation/body/121508141-4/jorg=journal&source=&sp=6333536&sid=0/N/6333536/1.html?issn= )

Beta-blockers have been studied in the treatment of panic disorder, decades ago. They don't work. Here's a link to one of the many studies showing this:
http://www.ncbi.nlm.nih.gov/pubmed/2651490

Yet, these old studies don't look at the possibility that the beta-blocker could work as an "augmentation" to psychological therapy. Many effective treatments do not work on their own, they work only in conjunction with something else.

Beta-blockers have also been used to treat irritability or rage problems. Here are a few references:

http://www.ncbi.nlm.nih.gov/pubmed/15764868
{one of the studies in the geriatric psychiatry literature, showing possible benefit for using propranolol to help agitated dementia patients}

http://www.ncbi.nlm.nih.gov/pubmed/2136070
{an example of a study showing some benefit of propranolol treatment for reducing rage outbursts -- however the study is of low quality}

http://www.ncbi.nlm.nih.gov/pubmed/3546964
{another study from the Mayo Clinic in 1985, showing some success using propranolol to treat patients with rage outbursts}

http://www.ncbi.nlm.nih.gov/pubmed/9196923
{a review paper from 1997, looking at various pharmacologic treatments for aggression; some of the research about beta-blockers is reviewed here}

In summary of the above studies, beta-blockers may help a bit for irritability, aggression, rage outbursts, and agitation, due to a variety of causes, but the evidence base is mainly from before 1990, and the studies are not very rigorous.

Beta-blockers also help diminish a very uncomfortable symptom called "akathisia". Akathisia is a state of external, and internal, restlessness, that can be caused by older antipsychotic drugs.

Beta-blockers are also useful in migraine prophylaxis. Migraine is associated with depression, so a beta-blocker could be a good therapeutic choice in someone with migraines as well as anxious, irritable, or agitated depression.

There were a few studies suggesting beta-blockers could cause or worsen depression, but many of these studies are weak. Here is a review:
http://www.ncbi.nlm.nih.gov/pubmed/16466322

In a more recent major JAMA review, beta-blockers were not found to be causative of depression or fatigue:
http://www.ncbi.nlm.nih.gov/pubmed/12117400

In my opinion, beta-blockers should be used cautiously in people who have or develop depressive symptoms, but I don't think they are contraindicated, since they may be beneficial overall if they help other symptoms. Also, if there are depressive effects, these may be dose-dependent, and may disappear just by reducing the dose.

---

Beta-blockers literally "block" beta-adrenergic receptors in the body. These beta receptors are normally stimulated by the catecholamines adrenaline and noradrenaline (also called epinephrine and norepinephrine), which are hormones secreted by the adrenal glands and by a small area of cells deep in the brain called the locus ceruleus. There is always a little bit of these hormones in circulation (in quantities in the order of parts per trillion, concentrations which would be achieved by adding a single drop of hormone to the volume of 1-10 olympic-sized swimming pools).**

Here is a reference showing resting adrenaline and noradrenaline levels in healthy subjects:
http://hyper.ahajournals.org/cgi/content/abstract/30/1/71

These tiny quantities of hormone are nevertheless enough to stimulate beta receptors; such stimulation is required to maintain or increase the output of the heart, also many other actions in the body, including in kidneys and muscle tissue.

http://www.psychosomaticmedicine.org/cgi/content/abstract/52/2/129
{An excellent study looking at peripheral catecholamine levels (norepinephrine and epinephrine) in groups of patients with anxiety, patients with pheochromocytoma (a disease causing huge increases in catecholamine levels), and normal controls; they found that peripheral norepinephrine levels correlate with anxiety, but NOT in the pheochromocytoma patients; this supports a theory that anxiety states cause central, and secondary peripheral, stimulation of catecholamine release--but the catecholamines themselves do not necessarily CAUSE the anxiety, but are a RESULT of it. Incidentally, Psychosomatic Medicine is another excellent journal worth following}

http://www.psychosomaticmedicine.org/cgi/reprint/66/5/757
{a study showing that norepinephrine levels in the brain correlate highly with blood pressure in normal controls; but do not correlate at all with blood pressure in people with PTSD, suggesting that in PTSD there is an abnormality in catecholamine regulation}

http://ajp.psychiatryonline.org/cgi/reprint/158/8/1227.pdf
{a study from The American Journal of Psychiatry showing that people with PTSD have levels of CSF norepinephrine almost twice as high as normal, and that the norepinephrine levels correlate with the severity of PTSD symptoms}

http://www-personal.umich.edu/~nesse/Articles/AdrenFunctPanic-ArchGenPsychiatry-1984.PDF
{a study from Archives of General Psychiatry in 1984, showing higher levels of plasma catecholamines in panic disorder subjects; but less responsiveness to further adrenergic stimulation in the panic subjects--this suggests that anxious subjects have chronically high catecholamines, and consequently are actually LESS sensitive to catecholamine changes}

http://www.csbmb.princeton.edu/ncc/PDFs/Locus%20Coeruleus/Aston-Jones%20&%20Cohen%20(ARN%2005).pdf
(an article about the role of norepinephrine released in the brain's locus ceruleus, and its importance for optimizing performance of tasks)

**For the math, let us assume that the resting concentration of epinephrine is 100 pMol, or 10^-10 moles/litre; a litre of water has about 55.5 moles of water, so the concentration can be expressed as one part in (55.5 / 10^-10) or one part in 555 billion. A drop of water has a volume of about 1/20 mL. So this concentration of epinephrine corresponds to an analagous concentration of one drop in (555 billion/20) mL, which is about 1 drop in 28 million litres. An olympic swimming pool has a volume of about 2.5 million litres (http://en.wikipedia.org/wiki/Olympic_size_swimming_pool). So this concentration corresponds to 1 drop in a volume of over 10 swimming pools.

Brainstem Stimulation - cranial nerves

There are some novel therapies such as vagal nerve stimulation or deep brain stimulation, which can improve symptoms of depression. These treatments may be increasingly important sources of relief for chronically suffering depressed patients-- particularly as the technology advances, becomes safer and more refined.

Here are a few links to references about these treatments:

http://www.ncbi.nlm.nih.gov/pubmed/16641939

http://www.ncbi.nlm.nih.gov/pubmed/19137233

Of greater interest to me in an outpatient office psychiatry practice, is an idea based on looking at trivially available techniques to accomplish "deep brain stimulation" or "vagal nerve stimulation", etc. All parts of the brain -- even the "deep brain", and even the vagal nerve -- are connected to all other parts of the body! Specific life events can obviously affect deep brain or vagal nerve stimulation, without requiring an implanted electrical device or neurosurgery! Some of these life events could be deliberately sought out as therapeutic strategies.

Something I've noted about some of these new, radical techniques, is that they involve stimulation of brainstem structures, often involving the cranial nerves. It seems to me that the cranial nerves are an extremely visceral set of portals through which stimuli are exchanged between the environment and the deep structures of the brain which regulate mood and consciousness. Here's a summary of all the cranial nerves, with speculations about techniques to "stimulate" them in a way that might be therapeutic:

Cranial Nerve I (olfactory): Stimulation of this nerve requires exposure to different scents. Aromatherapy is a familiar component of alternative health strategies. Here is some evidence from the mainstream medical literature, showing that aromatherapy can be helpful:
http://www.ncbi.nlm.nih.gov/pubmed/19125379
(a review article)
http://www.ncbi.nlm.nih.gov/pubmed/18178322
(a randomized study showing that the scent from lemon oil improves mood, compared to water or lavender, and regardless of expectancies or past experience with aromatherapy)
http://www.ncbi.nlm.nih.gov/pubmed/18713168
(a study showing improvement with lavender oil aromatherapy vs. controls in neuropsychiatric symptoms of elderly dementia patients)
http://www.ncbi.nlm.nih.gov/pubmed/17342790
(another study showing improvements in dementia patients with lavender)

Given the fact that there is virtually no risk to aromatherapy treatments, why not give it a try? It could help with sleep, relaxation, studying, or as a conditioning device (e.g. associating a particular odor with sleep, or with studying a particular subject, etc.)

Cranial Nerve II (Optic): Bright light therapy has a considerable evidence base. Probably looking at beautiful things in nature is good for your mood (I'll need to find a reference to prove this!). These images would have to pass through Cranial Nerve II, on their way to your brain.

Cranial Nerves III, IV, and VI: these innervate the muscles which move the eyes. There is a type of therapy called "EMDR" which calls upon patients to move their eyes back and forth as an essential part of the therapeutic technique. I suspect this acts as a conditioning phenomenon, which at once distracts the person, while perhaps permitting exposure therapy regarding uncomfortable thoughts or PTSD symptoms to take place in a more relaxed state, or in a state associated with therapeutic benefit. But maybe the "brainstem stimulation" from eye movements is an integral part of EMDR's therapeutic effect.

Here are some links to review papers or meta-analyses looking at EMDR:
http://www.ncbi.nlm.nih.gov/pubmed/16740177
(here, EMDR and CBT are both shown to be substantially and similarly effective in the treatment of post-traumatic stress disorder)

http://www.ncbi.nlm.nih.gov/pubmed/17636720
(a Cochrane review also showing EMDR and CBT to be the psychological treatments of choice in post-traumatic stress disorder)


Cranial Nerve V (trigeminal): this nerve transmits tactile sensations from the face into the brainstem. I do not know of any deliberate psychiatric therapy involving this nerve. But there is acupuncture. Also, there is massage, and in particular "facial treatments" (involving massage, aromatherapy, moisturizing creams, etc.) available in health spas--these seem to have a positive effect on overall well-being. I'd be curious to see a controlled study on this: in the meantime, though, it seems another risk-free thing to try.
http://www.ncbi.nlm.nih.gov/pubmed/19129675
(well, this is a pretty weak study -- but it's a start, and it involves a totally harmless treatment -- it shows reduction of anxiety in women receiving facial massage)

Cranial Nerve VII (facial): this nerve innervates the muscles of the face. As noted in a previous post, actions which affect facial musculature can affect emotion, just as emotion changes facial muscle tone (it's always interesting how these phenomena can work both ways). A branch of Nerve VII also conducts information about taste (gustatory sensation) from the tongue to the brain. I have no doubt that enriching one's culinary sensations in life has a positive impact on mood. But I'll have to look for a study to prove it.

Cranial Nerve VIII: the cochlear branch of this nerve transmits information about sounds from the ears to the brain. Hearing music, soothing sounds, and speech clearly affect mood and cognition. Noise, as I claimed in an earlier post, has a negative impact on mental health. Silence itself "rests" the cochlear nerve, which could itself be therapeutic (in moderation).
The vestibular branch of nerve VIII seems interesting to me as a prospective therapeutic target. This nerve transmits signals about balance, head position, and head movement to the brain. Sometimes individuals in an autistic or highly agitated psychotic state will stimulate their vestibular nerve by rocking repetitively. The action of a parent rocking a baby to sleep, or calming an agitated, crying baby, involves stimulating the baby's nerve VIII. It would be interesting to see if various stimulations of the vestibular nerve could be useful in adults, to treat anxiety, agitation, insomnia, or mood disorder. Balance exercises could be a start (perhaps some of yoga's therapeutic effects come from this). Maybe something like sleeping in a hammock, which would rock slowly, could be more soothing on this level, compared to a regular bed. Some people might find a boat to be very soothing (for others it would just cause nausea). If there are any engineers out there, reading this, it would be an interesting project to design a device which could be programmed to gently rock an adult back and forth (with different waveforms and frequencies).

Cranial Nerve IX: Glossopharyngeal. This nerve innervates your throat. The action of swallowing involves this nerve. People with anxiety states often have uncomfortable throat sensations, or problems with swallowing. It's hard to come up with therapeutic ideas directly relating to this one. Except perhaps the idea of eating really spicy food -- which stimulates not only taste buds but also sensory nerves (partly from Cranial Nerve V) in the mouth and throat. Strong culinary sensations can be a source of pleasure, and perhaps can also teach one to be more open about new things (I remember taking a long time getting used to wasabi on sushi after being introduced to Japanese food upon moving to Vancouver in 1995).

Cranial Nerve X: This is the vagus nerve that is stimulated electronically in an advanced surgical treatment for depression. The vagus nerve innervates the parasympathetic system of the body's viscera (e.g. it slows the heart, speeds up the bowel, etc.). One can train the vagus nerve through activities such as yoga, meditation, biofeedback, and through physical exercise.

Cranial Nerve XI: this nerve allows you to turn your head back and forth. Perhaps this could be an element not to forget in your exercise regime -- do some stretching and gentle exercises involving rotation of your head.

Cranial Nerve XII: this nerve allows you to move your tongue. Speech, singing, eating, and a variety of other pleasurable activities -- all involve your tongue. In anxiety states, people can have an exaggerated awareness of their tongue movements. Taking voice lessons or attending a voice coach can help build confidence, reduce social anxiety, literally help you "strengthen your voice"--a strong and clear voice, both metaphorically and literally, can be part of a healthy emotional life.

In conclusion, perhaps there are a variety of readily available techniques that can accomplish "deep brain stimulation" in ways that benefit your mental health, without actually requiring a neurosurgical procedure!