Chemical Imbalance Theory – Again and Again

 

I had this letter published today with my co-author Ron Pies, MD. It is basically a rebuttal to a more elaborate article (linked at the top of the letter) on chemical imbalance theory. I encourage any interested reader to look at that argument and then read our brief essay on why none of it supports a chemical imbalance theory.  Both Dr. Pies and I have written about this in the past – me on this blog and Dr. Pies in other literature (5-8). Several other authors have also discussed related issues (1-4, 9).  I think the refutation is fairly straightforward so this blog will be about the process. Why does this along with many other inaccurate portrayals of psychiatry continue to come up in the literature?  What follows is a few very clear answers but I fully realize that theses and explanations are rarely adequate to counter rhetoric.

1:  Repeating inaccurate claims is a standard strategy these days – it actually has been for decades.  The clearest modern example if the Big Lie of the last Presidential election.  Even a comprehensive presentation of the real evidence by the January 6^th Congressional Panel is not enough to shake the belief of election deniers.  In fact – election denial has become the latest cottage industry delivering hundreds of local lectures across the country.  Chemical imbalance theory has a similar life of its own and a group of proselytizers.  If the political comparison is too harsh – consider the advertising approaches. Any number of products that make health claims are sold every day based on repeating the same messages.  For years alcohol carried the message that it was a heart healthy product that increased HDL cholesterol and reduced the risk of heart attacks. Now we know that those studies were biased because they included alcohol users in recovery in the control group.  Dietary supplements are a $62 billion dollar industry despite questionable value and some concerns about toxicity in healthy populations with no clear nutritional deficiencies. All of these examples illustrate the power of repetitive messaging.

2:  It appeals to anecdotal experience – a common response is “well I heard somebody say it”, “I saw it posted on a web site”, or “my psychiatrist said it to me.”  Anecdotal experiences exist and obviously we cannot examine the intent of every statement. The reality for psychiatrists is that in psychopharmacology and biological psychiatry lectures, in textbooks, and in the published literature there is no reference to “chemical imbalance theory”.   In fact after reviewing the literature I concluded that comprehensive theories really don’t exist in psychiatry. On the other hand, over the past 40 years there have been over a hundred hypotheses about the causes of depression.

3:  There are clear biases against psychiatry as a field – when reading authors whether in professional journals, periodical, or books it is always useful to consider what else they have written. Is the book or paper a one-sided harsh criticism?  Does their previous work seem to make similar statements about the field?  It is already known that psychiatry gets much more than the expected levels of criticism in the press.  Is that criticism warranted? In many areas of this blog, I have pointed out that it is not warranted and, in many cases - it is grossly inaccurate.

4:  There have been no accurate histories of the intellectual development of the field.  To be sure there are specialized biographies of prominent historical figures and some of their influences but no clear timeline of how developments build on previous thought. I recently read that now that one of these historical figures has “scholars” rather than clinicians describing his work – we could expect much more, but I am not seeing it. To me – people who train and teach in the field are still the primary keepers of the working intellectual development of the field and everything that is relevant.

 Given all of these factors what can readers of our published letter do with that information?  If you are a psychiatrist or a physician – think carefully about your use of terms.  If you have used the term “chemical imbalance theory” or just “chemical imbalance” as a metaphor or something else – please reconsider. I think it is more useful to patients to let them know that depression or other clinical entities cannot be reduced to a single chemical event and I would invite you to use a statement from Nicholas Giarman – a noted neuropharmacologist:

“…nosologically it might be fair to compare the depressive syndrome with the anemias. Certainly, no self-respecting hematologist would subscribe to a unitary biochemical explanation for all of the anemias.”

 Nicholas J Giarman (1920-1968)  – The Biochemical Basis of Neuropharmacology – Fourth Edition 1982. p. 212

 

An explanation of heterogeneity and brain function would be ideal, but given time constraints and variable expectations of patients – an illustration of biological complexity is superior to a hopelessly inadequate metaphor. The same is true for literature that is handed out to patients. In that case, quoting the typical disclaimers in FDA approved package inserts as well as a brief summary of the research evidence for specific patients is a more optimal approach.

That is the real take home message.  

 

George Dawson, MD, DFAPA   

 

Supplementary 1:  What about advice to patients?  If you are considering taking an antidepressant or any other medication as a patient that usually means you are having a significant problem that you expect help with. The literature critical of psychiatry often suggests that this decision is casually made but that is not my experience either as a patient or a prescribing physician. Consider what is written about the mechanism of action of antidepressants. Chemical Imbalance Theory often implies that there has been dishonesty in presenting how a medication works and by extrapolation that psychiatrists don’t know much about anything. In fact, there are probably very few medications that you take where the mechanism of action is known with any high degree of certainty.  Aspirin was used for 70 years before its mechanism of action was determined (10).   Acetaminophen was first used clinically in 1887 and a preliminary report suggesting several potential mechanisms of action became available in 2009 (11).   Most decisions to take medications are not made based on knowing a mechanism of action. The overemphasis on mechanism of action of antidepressants is most likely based on pharmaceutical company advertising in the 1980s and 1990s.  At that time, the manufacturers of newer antidepressants emphasized that they were novel agents that probably worked through different mechanisms than the older medications and had a more favorable side effect profile.

As a patient you are entitled to as much detail on mechanism of action as you want and I hope that you will be able to get it directly from your physician or from other sources. I have treated basic scientists for depression and bipolar disorder and was able to give them adequate information – so it is definitely out there. But at a practical level – every person with a significant problem wants relief from that problem and no additional problems. The clinical discussion needs to be focused on whether the medication is working and the side effects are either non-existent or tolerable.  Further – informed consent means that you should have adequate information to make a decision about taking a medication.  That includes the likelihood of severe adverse drug events as well as more common side effects. Another common discussion in the media these days is withdrawal from antidepressant medications. A prescribing physician should be able to discuss that side effects in detail as well as rare events and a plan to address them.

 Credits:

1:  My co-author Ron Pies, MD read this post and made valuable suggestions for modifications.  It is difficult to indicate but he is a co-author of this post.

2:  Eduardo A. Colon, MD took the photograph used at the top of this post.

References:

1:  Morehead D. It’s Time for Us To Stop Waffling About Psychiatry. Psychiatric Times.  Dec 2, 2021  https://www.psychiatrictimes.com/view/its-time-for-us-to-stop-waffling-about-psychiatry

2:  Morehead D.  It’s Time for Us to Realize We Are All on the Same Side.  Psychiatric Times. Jan 18, 2022  https://www.psychiatrictimes.com/view/its-time-for-us-to-realize-we-are-all-on-the-same-side

3:  Morehead D.  The History of Psychiatry—A History of Failure? Psychiatric Times. April 19, 2022  https://www.psychiatrictimes.com/view/the-history-of-psychiatry-a-history-of-failure

4:  Morehead D.  Is There a Cure for Ignorance? The Shocking Truth About Psychiatric Treatment.  Psychiatric Times. June 27, 2022  https://www.psychiatrictimes.com/view/is-there-a-cure-for-ignorance-the-shocking-truth-about-psychiatric-treatment

5:  Pies RW.  Debunking the Two Chemical Imbalance Myths, Again.  Psychiatric Times. August 1, 2019  https://www.psychiatrictimes.com/view/debunking-two-chemical-imbalance-myths-again

6:  Pies RW. Nuances, narratives, and the “chemical imbalance” debate. Psychiatric Times. April 1, 2014.  https://www.psychiatrictimes.com/view/nuances-narratives-and-chemical-imbalance-debate

7:  Pies RW.   Psychiatry’s New Brain-Mind and the Legend of the “Chemical Imbalance”.  Psychiatric Times.  July 11, 2011 https://www.psychiatrictimes.com/view/psychiatrys-new-brain-mind-and-legend-chemical-imbalance

8:  Pies RW.  Doctor, Is My Mood Disorder Due to a Chemical Imbalance? Psychiatric Times.  August 12, 2011  https://www.psychiatrictimes.com/view/doctor-my-mood-disorder-due-chemical-imbalance

9:  Ruffalo, M. L., & Pies, R. W. (2018, August 19). The reality of mental illness: Responding to the criticisms of antipsychiatry. Psychology Today. https://psychologytoday.com/us/blog/freud-fluoxetine/201808/the-reality-mental-illness…

10:  Montinari MR, Minelli S, De Caterina R. The first 3500 years of aspirin history from its roots - A concise summary. Vascul Pharmacol. 2019 Feb;113:1-8. doi: 10.1016/j.vph.2018.10.008. Epub 2018 Nov 2. PMID: 30391545.

11:  Smith HS. Potential analgesic mechanisms of acetaminophen. Pain Physician. 2009 Jan-Feb;12(1):269-80. PMID: 19165309.

 

 

 

 

Gun Extremism Not Mental Illness

With the most recent school shooting in Uvalde, Texas the familiar repetition persists. There is public outcry to do something.  Many commentators make the comparison to the Sandy Hook Elementary School shooting a decade ago that produced public outcry but no effective response.  In fact, since Sandy Hook there have been 266 additional incidents of school shootings. Member of the pro-gun party have already spoken out and it is clear that their position of supporting gun ownership at all costs is essentially unchanged. That includes access to military grade weapons and high capacity weapons, with minimum and in many cases no regulations.  We keep hearing about all of the polls of “responsible gun owners” who support more reasonable regulation of firearms and more reasonable firearms – but they are generally drowned out by the aggressive tactics of the gun extremism faction.

Before going any further, I will provide my assessment of gun extremism. It is based on my personal observation about how guns have essentially been radicalized over the past 50 years.  When I was in middle school in the early 1960s living in a small town in northern Wisconsin, gun ownership by adults was common.  That gun ownership was focused on hunting seasons – primarily water fowl and deer hunting.  Middle schoolers took the NRA Hunter safety course in order to be able to handle firearms and hunt. Gun safety was taught primarily with the use of lectures and pamphlets. I can still recall some of the passages in the pamphlet with captions like “alcohol and gunpowder don’t mix” and a page with suggestions about what a safe target was. There was no explanation about why a crow is a safe target. The practical side of the training was with BB guns and then a .22 caliber rifle. Even though the common deer hunting rifles at the time were larger calibers like 30.06 there was no training with those guns. There was a competition series based on accuracy and most people in the class were eventually awarded Distinguished Marksman if they practiced and submitted enough targets. Memberships in the NRA was required and for $18.00/year – you got the National Rifleman magazine sent to your home every month.  The centerfold of that magazine was an array of inexpensive rifles, often “sporterized” surplus rifles from WWII.  They typically held 5 cartridges and could be used for hunting.

But like most kids taking the course. I never went hunting or acquired any additional firearms. My family was not a family of hunters and we did not have a typical cabin in the woods where everybody gathered during hunting season. The course was taught by an instructor who had been doing it for years. His overriding message was that guns had to be taken very seriously. In fact, one of the prerequisites for taking the course was that students had to vow never to “play” at guns again. That involved never pointing a gun at a person, even accidentally on the gun range. He described a number of incidents where people were accidentally shot by relatives to emphasize that point.  We all took it very seriously and there were no close calls in the class. There was no emphasis on “gun rights”, the need for self-protection, or the Second Amendment.  Handguns were not discussed because they were not used for hunting and you had to be 21 years of age to own one.  Gun rights was not an issue in any political campaign.

I don’t want to create the impression that the firearm situation was idyllic during my childhood.  Two classmates died by firearm suicide and one was killed in a hunting accident. I knew all three of them.

That is the backdrop against which gun extremism has evolved and it contains several elements.  First of all, politics. There are obvious contradictions when politicians say it is not a time for politics in the wake of the next mass shooting after they have passed laws that allow people to avoid background checks, carry military grade weapons with high capacity magazines, allow large purchased of ammunition, carry guns without permits, carry guns openly, and not have to “stand down” in confrontations – even when their opponent is not armed. That is all politics and if you are trying to deal with the aftermath pf a shooting – you are dealing with the aftermath of that politics especially if your politics facilitated that.

At a broader political level what has to be considered is how most polls show that Americans favor “common sense” gun laws – but the gun extremists continue to have their way.  In the decade following the Sandy Hook Elementary School Shooting, nothing has been done at the federal level.  Even the most basic fix of eliminating loopholes in the background checks laws has been avoided. Even when a law has been passed in the House (HR8) that makes a few changes – to the background check law there is practically no chance that it will pass in the Senate, even though the Republicans in the Senate represent 44 million fewer people. This situation has been referred to as the tyranny of the minority or a highly motivated smaller group of people dictating in this case the laws of the nation. That tyranny is even more complicated by Republican appointed Supreme Court making decisions on both gun laws and probably abortion consistent with what the minority party wants. Demographically that comes down to white, rural, less college educated voters making the laws that in the case of guns carry out an extremist agenda.

What do I mean about gun extremism?  Basically, all of the interventions over the past two generations that have allowed lax background checks and registration, lowered minimum age to purchase handguns and high-capacity military grade weapons, the increased carrying of weapons (both concealed and open) in many cases without permits, and stand your ground laws that say there is no obligation to retreat in a confrontation – even in the case where one of the parties is unarmed. There is an associated lack of gun safety and that has clearly been a factor in accidental death of adolescents and teenagers, suicides, carrying firearms into schools, and even arming mass shooters. That lack of basic gun safety is a likely contributing factor to firearm deaths being the leading cause of death in children and adolescents (1). And finally, there is a constant stream of pro-gun rhetoric that routinely distorts those facts about gun availability and usefulness.   There is good evidence that this gun extremism began in the 1970 and 1980s and has been unabated since then. 

Since the school shooting in Uvalde, gun extremists jumped to the defense of permissive to non-existent gun laws.  They offered alternate explanations for the school shooting. Governor Abbot of Texas suggested the shooter had a “mental health challenge” since anyone who shoots someone does.  That is clearly not true.  Recent evidence from high profile media cases where a homicide occurred during a fight over a firearm are cases in point. The vast majority of homicides by firearms does not involve mental illness of any kind.  In carefully selected samples – probably biased because they are selected based on forensic criteria – only 10-25% of the sample is described as having a mental illness diagnosis (2,3).

If mental illness is not an explanation for a mass shooter or mass school shooter behavior what is more likely? Given the fact that this behavior has been going on for at least 2-3 generations at this point it likely represents a subcultural phenomenon.  Subcultures are cultural groups within a larger culture that hold beliefs at variance with the larger culture.  American culture in general is steeped in violence and crime largely through entertainment and news media outlets. There are well known violent subcultures in the United States including organized crime, gangs, domestic terrorists, and various hate groups that perpetrate violence against specific people.  These other crimes are frequently seen in the news. It is easy to ascribe some of the behaviors of these groups to individual psychopathology. You can see these efforts in many true crime television shows. Crime dramas are likely to emphasize profiling as a way that the crimes are solved. Practically all of these cases lack features that are typically seen with individual psychopathology. Instead, we hear about a profile of social factors and circumstances that are cited as motivations for the violence and aggression. Those factors are also not uniform explanations for all of the violence and aggression seen across all categories and typically are collected long after the commission of the crime and by people who seemingly have unlimited time to do that task.  A good example was a forensic psychiatrist giving a profile of the Uvalde, Texas shooter describing him as a marginalized loner who had been bullied in the past and pointing out that many shooters have this profile but only a small number of people with the profile ever engage in firearm violence.

I think it is highly likely that the mass shooter and mass school shooter have become a meme that is passed in this subculture of primarily men or boys who feel that they have been victimized and they begin to see this as acceptable payback for their perceived victimization.  It is subculturally acceptable even though it produces outrage and is completely unacceptable in the larger culture and that is why the questions about “motivation” always go unanswered. Firearms and secrecy are obviously a big part of this meme and the way it is typically enacted. Gun extremism makes it much easier to enact.  In analyzing these situations, the usual starting point is where the individual perpetrator has gone wrong.  From the perspective of an alienated subculture these people and those who identify with them consider what they are doing to be correct for various reasons and more importantly widely accepted in that subculture (7). There are many reports that these subcultures are reinforced and more accessible through social media sites where manifestos, threats, time lines, and in some cases photos and recordings of the violence are posted.

In addition to the subcultural effects, important developmental effects are seldom considered.  In the past 20 years development and brain maturation has been the object of increasing neuroscience scrutiny and in addition to structural brain changes – correlations with culture, socioeconomic class, and social network/peer environment have also been investigated. In an excellent review of this topic Foulkes and Blakemore (3) point out that averaging of large samples has been used so far to get to statistical significance – but they discuss the benefits of looking beyond the averages at the total variation of normal brain development. They illustrate significant variation in the brain volume of subcortical grey matter structures over the course of ages 7 to 23.3.  I think it is generally accepted that brain maturation by these indices is not complete until mid-20s for most people, but the graphs also suggest that there may be quite a lot of variation even at that point. Beyond that they discuss several aspects of cognition and social cognition that develop in the transition from adolescence to adulthood including reasoning, risk perception, risk taking, the varied effects of social exclusion, and the use of others’ perceptions in decision making. They demonstrate what appear to be specific cultural, socioeconomic and peer effects and discuss the neuroscience correlates where they are known.  An analysis of mass shooters at this level of detail may provide better answers in terms of prevention.

What can be done to interrupt this cycle of school and mass shooter violence? Plenty can be done.  A basic time-tested public health intervention is to remove the means for perpetrating the violence and injury. This has worked in the case of suicide prevention by specific methods as well as preventing gun violence.  In a previous post, I pointed out that Tombstone had an ordinance in 1881 forbidding the carrying of deadly weapons within the city. This was a time commonly referred to as the Wild West (1865-1895).  This period is typically idealized by movies like Gunfight at the OK Corral. That was a 30 second gunfight between three Earp brothers and Doc Holiday and 5 cowboys that occurred in 1881.  One of the precipitants of that gunfight was violation of the city ordinance about carrying deadly weapons. Contrary to most accounts – both Wyatt Earp and Doc Holliday were arrested and charged with murder.  They were released after a three-day probable cause hearing. Even during America’s Wild West days, people knew that removing deadly weapons would lead to less violence.

In many ways American streets are less protected from gun violence than they were in Tombstone in 1881.  All 50 states allow people to carry handguns.  Twenty-four states require no permit to carry a firearm.  Federal law requires a handgun holder to be 18 years of age and 21 years of age to purchase a handgun. There are currently 21 million concealed carry permit holders in the US.   There is no minimum age for possessing a rifle or a shotgun.  There was a ten-year ban on assault rifles at the federal level from 1994-2004.  The ban grandfathered in all assault weapons before 1994 and there were also many other qualifications that decreased the overall impact of the bill.  Despite these limitations the ban may have decreased the frequency of mass shootings when it was in effect. (6).  Considering that there are 258.3 million Americans over the age of 18, the manufacture and importation of firearms is brisk to say the least as well as the concentration of handguns. (Click to expand the graphic)

Concluding this post, the most clearcut path to reducing gun violence of all kinds is to improve gun regulation.  The evidence is clearly there in terms of reductions in suicides, homicides and accidental deaths. The idea that gun regulation has no effect on gun deaths or that the Second Amendment is a sacred clause that mandates gun extremism is pure misinformation.  Even as I typed this post today, the Prime Minister of Canada announced stricter handgun regulations in the interest of safety.  There is absolutely no reason that high-capacity military grade weapons are necessary in society and there are many groups of responsible gun owners who openly acknowledge that fact.

Gun extremists’ additional rhetoric about how mental illness is the real problem rather than gun access is also incorrect.  Mental illness is not defined by homicide, but by constellations of findings and associated disability. There are general developmental, socioeconomic, cultural and subcultural trends associated with violence and aggression – but none are precise enough to allow for predictions of who will likely perpetrate mass homicide.  It will take continued large longitudinal studies to examine all of these factors close enough to produce an effective population wide intervention. One of my suggestions since I started writing this blog is explicit homicide prevention.  You won’t be able to find that is a book or research paper – it is based on my experience in acute care psychiatry. In that context, I encountered many people with acute homicidal thinking who ended up on my inpatient unit.  Irrespective of any psychiatric diagnosis, we were able to help them resolve that crisis.  Before the rationed mental health system takes on another significant task, it has to be adequately funded.  And beyond the mental health system – social services are required to address many of the factors associated with violence and aggression.

George Dawson, MD, DFAPA

 

 

References:

 

1:  Goldstick JE, Cunningham RM, Carter PM. Current Causes of Death in Children and Adolescents in the United States. N Engl J Med. 2022 May 19;386(20):1955-1956. doi: 10.1056/NEJMc2201761. Epub 2022 Apr 20. PMID: 35443104.

2:  Stone MH. Mass murder, mental illness, and men. Violence and Gender. 2015 Mar 1;2(1): 51-86.

3:  Hall RCW, Friedman SH, Sorrentino R, Lapchenko M, Marcus A, Ellis R. The myth of school shooters and psychotropic medications. Behav Sci Law. 2019 Sep;37(5):540-558. doi: 10.1002/bsl.2429. Epub 2019 Sep 12. PMID: 31513302.

4:  Firearms Commerce Report in the United States: Accessed 05.29.2022:  https://www.atf.gov/firearms/docs/report/2021-firearms-commerce-report/download

5:  Foulkes L, Blakemore SJ. Studying individual differences in human adolescent brain development. Nature Neuroscience. 2018 Mar;21(3):315-23.

6:   DiMaggio C, Avraham J, Berry C, Bukur M, Feldman J, Klein M, Shah N, Tandon M, Frangos S. Changes in US mass shooting deaths associated with the 1994-2004 federal assault weapons ban: Analysis of open-source data. J Trauma Acute Care Surg. 2019 Jan;86(1):11-19. doi: 10.1097/TA.0000000000002060. PMID: 30188421.

7: Simon Cottee (2021) Incel (E)motives: Resentment, Shame and Revenge, Studies in Conflict & Terrorism, 44:2, 93-114, DOI: 10.1080/1057610X.2020.1822589

8: Rostron A. The Dickey Amendment on Federal Funding for Research on Gun Violence: A Legal Dissection. Am J Public Health. 2018 Jul;108(7):865-867. doi: 10.2105/AJPH.2018.304450. PMID: 29874513; PMCID: PMC5993413

9:  Loftin C, McDowall D, Wiersema B, Cottey TJ. Effects of restrictive licensing of handguns on homicide and suicide in the District of Columbia. N Engl J Med. 1991 Dec 5;325(23):1615-20. doi: 10.1056/NEJM199112053252305. PMID: 1669841.

Graphics Credit:

Photo by Ed Colon, MD

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Racism and gun violence both exist in an overtly gun extremist society: They cannot be explained away by mental illness.

I suppose I should have not been very shocked that a Wall Street Journal editorial this morning (1) chose to double down on both gun rights and the myth that racism is not a problem and had nothing to do with the recent mass shooting – while scapegoating both mental illness and the rationed system of mental health care that we have in this country.  For good measure he added another conservative agenda item - that there was also blame for the public health officials like Dr. Fauci for mismanaging the pandemic.  This post is to straighten all of that out.

Let me preface these remarks by saying that I have no information about the most recent mass shooting other than what is reported in the media.  The author of the editorial does not seem to either. What I do have is 22 years of experience in acute care psychiatry and involuntary care. That’s right – for 22 years I was one of the guys you would have to see if you were admitted to my hospital on a legal hold for behavior that involved threatening or harming other people or yourself.  That included all kinds of violence - homicide, suicide attempts and severe self injury, and violent confrontations/shoot outs with the police.  I had to evaluate the situation with the considerable assistance from my colleagues and decide if that person could be released or needed to be held for further assessment and treatment. People (including psychiatrists) like to summarize that situation by saying: “Nobody can predict future dangerousness” and that is certainly true. But we do pretty well in the short term (hours to days).  We also do well coming up with a plan to prevent future violence.

The details about the most recent mass shooting are still being reported at this time, but so far include interviews with the families of the victims, police reports, videos, and excerpts from a manifesto written by the perpetrator.  According to reports that manifesto discussed Replacement Theory as a potential motive for the mass shooting.  Replacement Theory is a white nationalist, far right ideology that claims non-whites are a threat to the white majority in several countries including the US. A corollary is that the Democrats are trying to get aligned with more non-white voters to develop more political power. This is the rationale currently given in the media for the actions of the mass shooter who scouted neighborhoods and said very explicitly in documents that his intent was to murder as many black people as possible. He had no difficulty obtaining firearms legally – even though he was detained and sent for an emergency evaluation a little less than a year earlier for stating “murder-suicide” in response to an online question about what he planned to do upon retirement.  Those details and his response talking about how he got out of it and continued to plan to kill people are at this link.  

As a psychiatrist and member of the American Psychiatric Association, I can’t speculate on the diagnosis of anyone who I have not personally assessed and if I did do an assessment – I would need a release from the person to discuss any details.  The editorialist is under no constraints speculating that “signals were missed” and that “psychotic young males whose outlet is killing” is not the object of his column.  Instead, he makes the claim that he is really concerned about the post pandemic mental illness and addiction trends in this country. He is apparently not consulting the correct sources about what has happened in this country in terms of mental health care before the pandemic.

I will start with his anchor point in the 1970s.  At about that time Len Stein, MD and coworkers invented Assertive Community Treatment and a number of additional innovative approaches that were focused on keeping people with severe mental illnesses in their own homes.  Dr. Stein was one of my mentors and in seminars he would show what Wisconsin state hospital wards used to look like. About a hundred patients in one large room with their cots edge-to-edge and all wearing hospital pajamas. By the time I was working with him in the 1980s, those folks were living independently supported by case management teams and psychiatrists. Dr. Stein and his colleagues also ran a community mental health center that included crisis intervention services and outreach. That model of community mental health and crisis intervention is still practiced and has been covered in the New England Journal of Medicine.  Psychiatric residents are still trained in community mental health settings and many prefer to practice there.  Counties are not as enthusiastic and have shut down many if not most community mental health centers.

Community psychiatry is an obvious 50-year-old solution but it has to be funded. The same is true of affordable housing.  In some cases that housing needs to be supervised and also a sober environment. Both community psychiatry and affordable housing are casualties of business rationing that can only occur with the full cooperation of both state and federal governments. The current system costs about a trillion dollars in overhead that is directed to Wall Street profits and unnecessary meddling by middle managers. The only people who “sweep mental health under the rug” are large healthcare organizations and state bureaucrats who disproportionately ration it.  The "science of mental health" is not difficult at all.  Being forced to do it for free is difficult.

The 1980s were a critical time in establishing the managed care industry and taking all healthcare out of the purview of physicians.  While rationing psychiatric resources was being ramped up, services to treat alcoholism and addiction were essentially demolished. Suddenly you could not longer get detoxification services at most hospitals.  People were sent to social detox units run by counties where there was no medical coverage.  The thinking was that if a person developed medical complications like seizures or delirium tremens they could always be sent back to the hospital. The biggest risk was continued substance use and immediate relapse. Residential and outpatient treatment facilities never materialized.  Inadequate funding was a significant problem.  The managed care industry played a role in that case as well with absurd expectations and limits on treatment.  It is no accident that treatment for substance use disorders basically became non-existent.  None of the disproportionate rationing of mental health or substance abuse treatment is new.  It has been like this for 30 years because it is the government endorsed model of care.  

Overall, this editorial is a smokescreen over the proximate issues of guns and racism.  The author trivializes this as political rhetoric when in fact the rhetoric has all been pro-guns and pro-white supremacy.  It is the only rational explanation for turning the United States into an armed camp that has progressively increased the likelihood of gun violence. We are not talking about a pandemic precipitated phenomenon.  The gun violence has been multi-year and the pro-gun party has “doubled down” on it to make it more likely.  As far as politics go – now that we know how a partisan Supreme Court works – the Heller decision and the resulting liberalization of gun ownership should not come as a surprise.  On the issue of hate crimes, I can’t really think of anything more relevant in a case based on the public disclosures.  This was a specific crime directed at black Americans intentionally perpetrated in a neighborhood that was scouted ahead of time for that ethnicity. Brushing that aside to claim that this is a response to an embarrassing record on mental illness, when there is no evidence that is a factor is disingenuous.

American history including other recent mass shootings tells us that racism can be a causative factor.  What is never addressed is the omnipresent gun culture in the USA.  People with an apparent need for military weapons and handguns and politicians willing to give them unlimited access to carrying them in public, carrying them without permits, and stand your ground laws - encouraging violent confrontations with firearms.  All fueled by one party and their affiliated special interests.

Disingenuous discourse and misinformation is what we typically see these days. If you want the facts about what needs to be there in terms of a functional mental health system (and I know there are absolutely no business people and very few politicians that do) – ask a psychiatrist. If you want to know about what gun control needs to be in effect rather than claiming that psychiatrists are not preventing gun violence from people with no mental illness – you can also ask me.

I could put all of those details on a 4” x 6” card and it would work. 

But there is certainly nobody on the right or at the WSJ who wants to know that either.

 

George Dawson, MD, DFAPA

 

References:

1:  Daniel Henninger. The Next Pandemic: Mental Illness.  Wall Street Journal. May 18, 2022.

Graphics Credit:  Eduardo Colon, MD

Knowledge Workers

 

I wrote this editorial in 2010 for the Minnesota Psychiatric Society newsletter Ideas of Reference as part of my role as the President at the time. Since then, things continue to go in the wrong direction.  Some knowledge workers get more recognition from the business managers than others but it is based on income generation rather than the cognitive aspects of the job. And of course, psychiatrists are managed as if there is no cognitive aspect as all.  In an interesting development at the time, I was contacted by Canadian physicians after this editorial was published in the newsletter, but no American physicians.

 

Imagine working in an environment that is optimized for physicians. There are no obstacles to providing care for your patients. You receive adequate decision support. Your work is valued and you are part of the team that gets you immediate support if you encounter problems outside of your expertise. In the optimized environment you feel that you are working at a level consistent with your training and current capacity. That environment allows you to focus on your diagnosis and treatment of the patient with minimal time needed for documentation and coding and no time wasted responding to insurance companies and pharmacy benefit managers.

As I think about the problems, we all encounter in our work environment on a daily basis I had the recent thought that this is really a management problem. Most of the management that physicians encounter is strictly focused on their so-called productivity. That in turn is based on an RVU system that really has no research evidence and is clearly a political instrument used to adjust the global budget for physicians. Current state-of-the-art management for physicians generally involves a manager telling them that they need to generate more RVUs every year. Managers will also generally design benefits and salary packages that are competitive in order to reduce physician loss, but this

is always in the larger context of increasing RVU productivity. Internet searches on the subject of physician management gener­ally bring back diverse topics like "problem doctors", "managing physician performance", "disruptive behavior", "anger manage­ment", and "alcoholism", but nothing about a management plan that would be mutually beneficial for physicians, their patients and the businesses they work for.

In my research about employee management, I encountered the work of the late Peter Drucker in the Harvard Business Review. Drucker was widely recognized as a management guru with insights into how to manage personnel and information going into the 21st century. One of his key concepts was that of the "knowledge worker".  He discussed the evolution of managing workers from a time where the manager had typically worked all the jobs he was supervising and work output was more typically measured in quantity rather than quality. By contrast knowledge workers will generally know much more about their work than the manager. Work quality is more characteristic than quantity. Knowledge workers typically are the major asset of the corpora­tion and attracting and retaining them is a corporate goal. Physicians are clearly knowledge workers but they are currently being managed like production workers.

The mistakes made in managing physicians in general and psychiatrists in particular are too numerous to outline in this essay. The current payers and companies managing physicians have erected barriers to their physician knowledge workers rather than optimizing their work environments. The end result has been an environment that actually restricts access to the most highly trained knowledge workers. It does not take an expert in management to realize that this is not an efficient way to run a knowledge-based business. Would you restrict access to engineers and architects who are working on projects that could be best accomplished by those disciplines? Would you replace the engineers and architects by general contractors or laborers? I see this dynamic occurring constantly across clinical settings in Minnesota and it applies to any model that reduces psychiatric care to prescribing a limited formulary of drugs.

I think that there are basically three solutions. The first is a partial but necessary step and that is telling everyone we know that we have been mismanaged and this is a real source of the so-called shortage of psychiatrists. The second approach is addressing the issue of RVU-based pay directly. I will address the commonly used 90862 or medication management code. As far as I can tell, people completing this code generally fill out a limited template of information, ask about medication side effects, and record the patient's description of where they are in the longitudinal course of their symptoms and side effects. I would suggest that adding an AIMS evaluation or screen for metabolic syndrome, an in-depth probe into their current nonpsychiatric medications and how they interact with their current therapy, adding a brief psychotherapeutic inter­vention, case management discussions with other providers or family, and certainly any new acute medical or psychiatric problems addressed are all a la carte items that need to be assigned RVU status and added to the basic code. Although there are more, these are just a few areas where psychiatrists add quality care to the prescription of medicines. The final solution looks ahead to the future and the psychiatrist's role in the medical home approach to integrated care. We cur­rently have to decide where we fit in that model and make sure that we don't end up getting paid on an RVU basis while we are providing hours of consultation to primary care physicians every day.

Overall, these are political problems at the legislative, bureau­cratic and business levels. It should be apparent to anyone in practice that when political pressure succeeds in dumbing down the profession, it necessarily impacts adversely on work environ­ment, compensation, and most importantly the ability to deliver quality care. The continued mismanagement of psychiatrists by businesses and bureaucrats who have nothing more to offer than a one-size-fits-all productivity-based model, is the biggest threat to psychiatry today and a much more enlightened man­agement strategy is urgently needed. The Minnesota Psychiat­ric Society and the APA need a strong voice in that change.

 

George Dawson, MD, DFAPA

Committees and Stakeholders

 

I wrote this editorial in 2010 for the Minnesota Psychiatric Society newsletter Ideas of Reference as part of my role as the President at the time. It was subtitled: "A new approach is needed and I think that approach needs to be psychiatrists redesigning the system."  Since then, things continue to go in the wrong direction. I still find the term "stakeholders" to be cringeworthy. The only stakeholders as far as I am concerned are physicians, patients, and their families. 

 

Who are the real stakeholders when you are face to face with your patient and you are being coerced into doing something that is not in the patient's best interest? Where does the profession stand on this? For almost two decades now we have been complacent while insurance companies, government bureaucrats and politicians, and pharmaceutical companies have directly intruded on the physician-patient relationship in a way that has seriously impacted the resources available for patient care and the quality of that care.  The operative word is complacency. I still have a habit that I learned from my freshman English composition professor. I compulsively look up word definitions to make sure I am using them correctly. I think you develop a lot of insight into your changing knowledge base when you look up words that you think you know very well and find that they seem to have taken on more important meaning. For me complacency has become such a word. Looking it up in several dictionaries, the definition I like the best is: "self-satisfied and unaware of possible dangers". With few exceptions, that seems to be the position we have been in for the past 20 years.

I can't think of a better word to describe how physicians were duped into believing that an RVU based pay system would somehow result in better reimbursement for cognitive specialists. Or that coders could determine who was submitting correct billing based on documentation, much less committing fraud. Or that utilization review for inpatient stays and prior authorization for medications is a legitimate practice. Or that managed care com­panies and behavioral carveouts reduce health-care inflation. Or that the focus of psychiatric assessment and treatment involves the prescription of a pill in roughly the same time frame that an antibiotic could be prescribed for otitis media. The list of things that we've been complacent about is long and it is growing every day.

For those psychiatrists working in institutions, committees are often a starting point. Much of the time, committees and meet­ings focus on issues that are peripheral to patient care and quality care. They rarely focus on the actual practice environment for the psychiatrist and the patient. In many cases, the fatal flaw is that the people making the major decisions are not in the meetings. The meetings are frequently held to make it seem like physicians actually have input into what is going on. At times the physicians are prepared by someone telling them that the old days in medicine are dead. The implication is that physicians used to be all powerful, now they are not, and in fact they should expect to have the equivalent input of any other employee.

The strategies we have observed for dealing with a broad array of stakeholders at the table have all been inadequate. We have allowed stakeholders with clear conflicts of interest to suggest that we are more conflicted than they are. The only solution is to be clearly differentiated from everyone else. We are squarely focused on assessing and treating patients in an ethical manner and any political initiative that we endorse or participate in should be consistent with that focus.

What does this mean in a practical sense? First off, it means coming into a meeting with a clear position rather than showing up to broker a deal. It means prioritizing patient care over profits from rationing or political gain from rationing. It means pointing out that the physician-patient dyad is in no way equivalent to any other political agenda in the room. It means not signing off on the status quo when we are the only people in the room speaking to the interests of physicians and their patients.

The recent changes to the way that psychiatric care is delivered to the state's low-income population illustrate all of the problems. Patients with GAMC have significant psychiatric comorbidity, and, even prior to the cuts by Governor Pawlenty, were also subjected to more rationing by private and government payers than other patients. The ultimate change, in the form of Coordinated Care Delivery System (CCDS) clinics, takes this rationing to a whole new level. At the same time the state has attempted to reinvent the state hospital system. Both of these changes disproportionately affect patients with severe mental illness. Any rational analysis would show that these patients did not have enough treatment resources before the new rationing initiatives. A new approach is needed and I think that approach needs to be psychiatrists redesigning the system. That needs to happen through the MPS because we have psychiatrists with the knowledge and focus to accomplish this task. Rather than endorse a rationed and blended version designed by people who are not providing the care, psychiatrists need to articulate a clear statement of what public mental health should be like in the state of Minnesota.

 

George Dawson, MD, DFAPA

The Best Neurosurgery Clinic in the World

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I wrote this editorial in 2010 for the Minnesota Psychiatric Society newsletter Ideas of Reference as part of my role as the President at the time. Since then things continue to go in the wrong direction.  We no longer have insurance that covers the Mayo Clinic. My wife continues to do very well.

 

"We have the best neurosurgery clinic in the world." My wife Linda was in a conversation with a staff person at the Mayo Clinic, and somewhere along the line that statement was made. Just a few weeks earlier she had been diagnosed as having a growth hormone secreting pituitary adenoma and we were in the process of looking for neurosurgeons. I was concerned about that statement and wondered what the motivation was. I have called a lot of clinics and never heard a statement like that. I had talked with a lot of doctors and had never really heard many physicians talk like that.

The pituitary fossa is a dark and dangerous place for even a small tumor. Psychiatrists are generally familiar with the area because of patients with microadenomas that have been discov­ered during evaluations for what is usually hyperprolactinemia secondary to D2 receptor antagonists. In Linda's situation it was a 1.3 cm diameter cystic lesion that involved the cavernous portion of the right carotid artery. The surgery involves a transnasal and transsphenoidal approach to remove the tumor through an endoscope. Cutting into the carotid artery is a potential catastrophe. Damaging the pituitary and needing lifelong hormone supplementation was also a possible outcome. We wanted the best neurosurgeon for the job.

I had just finished reading a NEJM article on robotic surgery that suggested that surgeons need to do 150-200 procedures with this device to be proficient. There was no data available for endoscopic transsphenoidal tumor resections, much less what might be reasonable stratifications like size and type. I figured that the surgeon doing the most was probably the best bet.

At Mayo we were given a timely appointment and met the surgeon. He was confident, detail oriented and personable.

He assured us that his goal was to cure Linda, but that he was not going to trade off safety at any point for a cure. He openly acknowledged the potential problem of the carotid artery being involved with the tumor.

He performed the surgery and the next day came by to explain the results. They were uniformly good but would need confirmatory IGF levels at 3 months. He carefully explained the possible post op complications, how long we had to look for them, and exactly what to do about them. He told me that if any­thing happened during recovery and I was not at the hospital, I would be called immediately. At the time of discharge, he said that he was available through the hospital operator, and that if we called from a cell phone we might have to pull over and wait for him to call back.

While all of this was going on, I learned from other health care providers in the state that the "Mayo Clinic option" was being eliminated from some employee health plans. I had just spoken with a local expert in health economics who said that this suggestion had been made in the past and plan subscribers had rejected it. I thought about the implications for all of the free market and "quality" hyperbole that we hear from politi­cians and business leaders. If we have the best neurosurgical service in the country, why are health plans limiting access to it? If it is the best on a competitive quality basis, why aren't they rewarded rather than being penalized by the market? Most of all, what are the implications for the most heavily rationed health care, namely mental health care?

From a quality perspective, I was hard pressed to think of the best psychiatric service in the state, and not because we lack great psychiatrists. Most of the ·inpatient units I know of are pretty intolerable places. The emphasis is largely to put the patient on medications and discharge them as soon as pos­sible, even when many are highly symptomatic. By comparison with medicine and surgery services, it is difficult to consider this as even a minimal standard of care. Imagine the patient with congestive heart failure being placed on medications and discharged, and making it the family's responsibility to monitor the response and adjust cardiac medications. Imagine me doing post operative neuro checks and monitoring urine volumes, labs, and pain medications on my wife in a Rochester hotel room. In either example, medicine and surgery patients are more likely to follow recommended discharge instructions compared with over half of discharged psychiatric patients not recognizing that they are ill.

What about actual time spent with a psychiatrist? The time that my wife and I spent with her neurosurgeon probably exceeded the time that many hospitalized patients see their psychiatrist. Inpatient settings are usually very poor work environments for psychiatrists because the central fact is that it is no longer an environment where high quality work can be done. Unlike our neurosurgeon, psychiatrists have been mar­ginalized to the role of medication prescribers in both inpatient and outpatient settings. In many inpatient settings psychiatrists no longer control crucial discharge decisions.

When I walked out of the hospital with Linda, we were hope­ful that she had been cured. We knew what we needed to look out for and that there were future options. I noticed that the hospital looked like most of the teaching hospitals I had worked at in the past. There was no valet parking, massage or aroma therapy, harpsichord player, or high-end coffee shop. There were 19 plaques on the wall showing that Mayo Clinic Neurology and Neurosurgery was ranked #1 in the country for each of the past 19 years by US News and World Report. But most of all, we knew that we had just encountered medical and hospital staff with a high degree of expertise and professionalism and that there was an administration supportive of their efforts.

We need to get that back in psychiatry.

 

George Dawson, MD, DFAPA

 

Supplementary 1:

Since writing this I read Neurosurgeon Henry Marsh’s book Do No Harm. In it he describes how modern technology has reduced the risk of neurosurgery but not eliminated it and how even operations that seem to have gone well can have catastrophic results.

 

Xylazine – Another Dangerous Street Drug

Xylazine is the latest veterinary tranquilizer to be sold as a street drug. It has no approved human uses.  It is used as both a light and general anesthetic for horses depending on the extent of the surgery. Xylazine is a presynaptic alpha-2 adrenoceptor agonist inhibiting the release of norepinephrine from synaptic vesicles. This leads to decreased postsynaptic activation of adrenoceptors, inhibited sympathetic activity, leading to analgesia, sedation and anxiolysis.  This mechanism of action is also seen with clonidine and dexmedetomidine.  Xylazine has low potency and affinity for Alpha-2 receptor adrenergic receptors. It has been demonstrated by the use of a knock out genetic mouse model that the clinical effects are mediated through the alpha-2A receptor subtype (5).

Alpha-2 receptor adrenergic receptor (AR) profiles are complicated by the fact that there are 4 subtypes with central, peripheral and behavioral effects but very little seems to be written about the D subtype so I have not included it here.  The general associated mechanisms include a decrease in adenyl cyclase activity, suppressed voltage gated calcium currents, increased potassium currents and increased mitogen-activated protein kinase (MAP kinase) activity. At steady state the α-2A and α-2B receptor types are at the cell surface and the α-2C type is at the cell surface and intracellular.  Some drugs like clonidine and guanfacine promote α-2A internalization. The author (3) of the review suggests that this may account for the unique duration of signaling. α-2AR trafficking and signaling also undergoes complex regulation by a number of factors including protein kinases, G protein coupled receptors (GPCRs), and scaffolding proteins.  A table of receptor affinities for various drugs are listed below. These affinities are primarily from reference 2 and generally represent results for human cloned receptors of the averages of several experiments. Please note the very low affinities for xylazine. I have tried to corroborate these numbers from outside sources and have not been successful. If you have better affinities for xylazine please email me or post them here in the comments section.  

From a pharmacodynamic standpoint there are several relevant Alpha-2 AR polymorphisms that have been tentatively linked disease states like ADHD and hypertension. They have also been studied in heart rate, heart rate variability, blood pressure control, obesity and insulin resistance (4). As expected, these polymorphisms also effect drug response.  

Although Xylazine is approved only for veterinary uses, reports of human use and accidental or inadvertent overdoses began to appear in the 1980s.  A review of initial reports looking at the compound as an adulterant that was done in 2014 (7) and concluded that half of the human overdoses resulted in death.  

Central effects of alpha 2 agonists, results in decreased sympathetic output and resulting imbalances in the peripheral autonomic nervous system.  Decreased sympathetic output leads to the expected effects of bradycardia, hypotension, sedation and decreased level of consciousness. Unopposed vagal parasympathetic effects can lead to increasing heart block and arrhythmias.  

In addition to the central effects of α-2 agonists there are also peripheral effects.  A common α-1 and α-2 agonist used peripherally is oxymetazoline that is used as a topical nasal decongestant. It exhibits very high affinity for both receptors and the following K_is  α-2A (7.24 nM), α-2B (483.5 nM), α-2C (144.07 nM), α-1 (402.75 nM).  Peripheral α-2 adrenergic effects can lead to increased systemic vascular resistance due to effects at the level of arterioles. This is important from a toxicological perspective because it can cause hypertension and is probably the mechanism leading to soft tissue necrosis at injection sites.

The epidemiology of xylazine use is discussed in a few studies at this point (7,12,13). The original paper suggested it may have started in Puerto Rico and spread Philadelphia with the highest prevalence of overdoses in eastern states.  It is well described at this point both in terms of overdoses and as an adulterant when it is added to heroin, fentanyl, cocaine, methamphetamine, alcohol or combinations like heroin + cocaine. There are expected synergies with opioids including a depressed level of consciousness, and decreased respiratory drive. Synergies with stimulants would include increased likelihood of cardiac arrhythmias, hypertension, and tissue necrosis.

The CDC recently published a study of xylazine in Cook County, IL (Chicago area) in MMWR (12).  The study ran from January 2017 to October 2021.  Xylazine associated deaths were defined as positive post-mortem toxicology in any substance related death where the intent was unintentional, undetermined or pending. The authors identified 236 xylazine associated deaths that increased over the study period and are graphed below. The graph on the right is the percentage of fentanyl associated deaths involving xylazine by month. That graph peaks at 11.4% in October. Overall, fentanyl or its metabolites was present in 99.2% of xylazine associated deaths. The authors point out that naloxone does not reverse the effects of xylazine but it should be administered for any suspected opioid use in a polypharmacy toxidrome. They also state that better surveillance for this compound is probably indicated.  

 

The toxidromes from these drug combinations can be complex so that on a clinical basis it will be hard to tell if the patient you are seeing has used xylazine. I was fortunate enough to attend a Hennepin County Medical Center Addiction Medicine Journal Club on 4/5/2022. In that presentation the pharmacology, clinical effects and toxicology of xylazine were discussed. The cases presented all had xylazine combined with other substances and severe necrosis of the lower extremities in two cases and hand and wrist in the other. In one case the patient no longer had venous access and was injecting into the area of necrosis.  All of these patients required skin grafting wanted to leave the hospital after the acute phase of intoxication had passed. In these cases, the transition to detoxification and maintenance medications is complicated because of the possible synergy between opioids and α-2 adrenergic agonists and the question of rebound or withdrawal from preadmission use of xylazine. The question of Takotsubo cardiomyopathy was discussed because some patients the literature were described as using xylazine. Rebound or withdrawal from xylazine and the associated rapid increase in catecholamines was discussed as a potential mechanism. A toxicologist attending the meeting also pointed out that with overdoses the α-2 adrenergic agonists can cause hypertension by peripheral effects and this has caused some acute cardiac problems. That toxicologist was also familiar with local testing for xylazine and it was not currently being done. He pointed out that a half life of 5 hours was determined in humans as contrasted with a few minutes in several animal species.   He suggested that in the case of a patient unresponsive to high dose naloxone, without hypercapnia via arterial blood gases, and normal brain imaging it would be reasonable to request xylazine toxicology.

In an interesting development, the FDA recently approved a dexmedetomidine sublingual film for the treatment of acute agitation in schizophrenia and bipolar disorder (14).  Dexmedetomidine has been available for intravenous use for 20 years with the indication “sedation of non-intubated patients prior to and/or during surgical and other procedures” (15).  It also has a place in critical care medicine – addressing all three aspects of the ICU triad of pain, agitation, and delirium (16). The film comes in 120 mcg and 180 mcg doses with a schedule in the package insert with dosing for adults and geriatric patients with and without varying degrees of hepatic impairment.  The clinical trials in the package insert describe the medication as effective for this indication. As a psychiatrist who spent most of his career in acute care there are fairly frequent situations where medications that are typically used to treat agitation (antipsychotics and benzodiazepines) do not work – even at high doses. It will be interesting to see if acute care psychiatrists find dexmedetomidine preparation useful. When I ran into that situation it was typically cases of severe mania with agitation or delirious mania with catatonia and the only available option was conscious sedation by anesthesiology. The other unknown at this point is how effective this medication will be over time.  The package insert specifies a maximum of two or three doses.  Clinicians will be on their own after that. It reminds me of how another α-2 adrenergic agonist – clonidine is currently used for anxiety, agitation, and insomnia. Many patients experience it as transiently effective until a more sustained preparation (typically a transdermal patch) is used.  

The appearance and gradual increase in xylazine as a street drug is not good news.  It is clearly used as an adulterant in both opioids and stimulants.  Its use can result in severe complications and death. The surveillance for this compound is not good at this time and clinicians have to have a high index of suspicion to request toxicology for it. People with substance use disorders need to be educated about this compound and its use as an adulterant and that deciding to use it with an opioid or other CNS depressants (including alcohol) is very dangerous and needs to be avoided. Using it with stimulants can also have significant negative effects.  At this point it is also an unknown danger because like fentanyl - it can be sold as anything.

 

George Dawson, MD, DFAPA

 

References:

 

1:  Törneke K, Bergström U, Neil A. Interactions of xylazine and detomidine with alpha2-adrenoceptors in brain tissue from cattle, swine and rats. J Vet Pharmacol Ther. 2003 Jun;26(3):205-11. doi: 10.1046/j.1365-2885.2003.00466.x. PMID: 12755905.

2:  PDSP Ki Database referenced as The Multiplicity of Serotonin Receptors: Uselessly diverse molecules or an embarrassment of riches? BL Roth, WK Kroeze, S Patel and E Lopez: The Neuroscientist, 6:252-262, 2000

3:  Wang Q.  α2-Adrenergic Receptors. In: Primer on the Autonomic Nervous System, Third Edition.  Robertson D, Biaggioni I, Burnstock G, Low PA, Paton JFR. 2012. Elsevier, Amsterdam. 55-58.

4:  Matušková L, Javorka M. Adrenergic receptors gene polymorphisms and autonomic nervous control of heart and vascular tone. Physiol Res. 2021 Dec 30;70(Suppl4):S495-S510. doi: 10.33549/physiolres.934799. PMID: 35199539.

5:  Kitano T, Kobayashi T, Yamaguchi S, Otsuguro K. The α_2A -adrenoceptor subtype plays a key role in the analgesic and sedative effects of xylazine. J Vet Pharmacol Ther. 2019 Mar;42(2):243-247. doi: 10.1111/jvp.12724. Epub 2018 Nov 11. PMID: 30417462.

6:  Weerink MAS, Struys MMRF, Hannivoort LN, Barends CRM, Absalom AR, Colin P. Clinical Pharmacokinetics and Pharmacodynamics of Dexmedetomidine. Clin Pharmacokinet. 2017 Aug;56(8):893-913. doi: 10.1007/s40262-017-0507-7. PMID: 28105598; PMCID: PMC5511603.

7:  Ruiz-Colón K, Chavez-Arias C, Díaz-Alcalá JE, Martínez MA. Xylazine intoxication in humans and its importance as an emerging adulterant in abused drugs: A comprehensive review of the literature. Forensic Sci Int. 2014 Jul;240:1-8. doi: 10.1016/j.forsciint.2014.03.015. Epub 2014 Mar 26. PMID: 24769343.

8:  Sinclair MD. A review of the physiological effects of alpha 2-agonists related to the clinical use of medetomidine in small animal practice. Can Vet J. 2003 Nov;44(11):885-97. PMID: 14664351; PMCID: PMC385445.

9:  Giovannitti JA Jr, Thoms SM, Crawford JJ. Alpha-2 adrenergic receptor agonists: a review of current clinical applications. Anesth Prog. 2015 Spring;62(1):31-9. doi: 10.2344/0003-3006-62.1.31. PMID: 25849473; PMCID: PMC4389556.

10:  Kanagy NL. Alpha(2)-adrenergic receptor signalling in hypertension. Clin Sci (Lond). 2005 Nov;109(5):431-7. doi: 10.1042/CS20050101. PMID: 16232127.

Activation of alpha(2A)-ARs in cardiovascular control centres of the brain lowers blood pressure and decreases plasma noradrenaline (norepinephrine), activation of peripheral alpha(2B)-ARs causes sodium retention and vasoconstriction, whereas activation of peripheral alpha(2C)-ARs causes cold-induced vasoconstriction

11:  Talke P, Lobo E, Brown R. Systemically administered alpha2-agonist-induced peripheral vasoconstriction in humans. Anesthesiology. 2003 Jul;99(1):65-70. doi: 10.1097/00000542-200307000-00014. PMID: 12826844.

12:  Chhabra N, Mir M, Hua MJ, et al. Notes From the Field: Xylazine-Related Deaths — Cook County, Illinois, 2017–2021. MMWR Morb Mortal Wkly Rep 2022;71:503–504. DOI: http://dx.doi.org/10.15585/mmwr.mm7113a3

13:  Friedman J, Montero F, Bourgois P, Wahbi R, Dye D, Goodman-Meza D, Shover C. Xylazine spreads across the US: A growing component of the increasingly synthetic and polysubstance overdose crisis. Drug Alcohol Depend. 2022 Apr 1;233:109380. doi: 10.1016/j.drugalcdep.2022.109380. Epub 2022 Feb 26. PMID: 35247724.

14:  FDA Package Insert. IGALMITM (dexmedetomidine) sublingual film, for sublingual or buccal use.  April 5, 2022.  https://www.igalmihcp.com/igalmi-pi.pdf

15:  FDA Package Insert.  Dexmedetomidine hydrochloride injection. 1999. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206628s000lbl.pdf

16:  Reade MC, Finfer S. Sedation and delirium in the intensive care unit. N Engl J Med. 2014 Jan 30;370(5):444-54. doi: 10.1056/NEJMra1208705. PMID: 24476433.