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.

Smoking Toad

I generally try to keep my research and posts confined to medical and scientific journals for a couple of reasons. First and foremost is that well documented bias against psychiatrists and whatever version of monolithic psychiatry that authors and editors in the popular media choose to embrace. Secondly, the information content of professional journals is much higher and the theories and concepts are what I have been studying for decades at this point. For the purpose of this post, I am making an exception and will be writing about a story from the New Yorker about hallucinogens (1).

Being child of the 1970s and a psychiatrist starting a short time later, I have had plenty of academic and professional experience with hallucinogens.  Given that experience, I am very skeptical about how the new wave of hallucinogens have been portrayed as a panacea for psychiatric problems.  Even more problematic is the portrayal that these compounds are generally well tolerated and have no significant adverse effects. I will be the first to acknowledge that there is a selection bias. People don’t end up coming to see me because they had a good experience with hallucinogens. They see me because they had a very bad experience and that is generally severe anxiety, panic attacks, and hallucinogen persisting perceptual disorder (HPPD). HPPD is a permanent change in perception after exposure to hallucinogens.  That can range from looking down and seeing the carpet moving continuously to noticing that there are trailers streaming from objects moving across your visual field.

If you research HPPD or hallucinogen side effects – relatively little turns up in the medical literature. There are probably less than 100 papers written on HPPD since the 1960s.  They are typical case reports, anecdotal treatment, and a call for more research on treatment. A major LSD study documenting disability had to wait until recently for an analysis of side effects.  I contacted 2 current hallucinogen researchers and asked them for a copy of the consent form they are using for their research projects in order to see what adverse effects their were advising their patients about. That was two years ago and I have yet to receive a reply. It is against this backdrop that I am going to present some concerns noted in the New Yorker article. 

The bulk of the story involves a trained Mexican physician who first gained some fame in 2013 when he gave a testimonial about overcoming crack cocaine addiction by using a psychedelic produced by the Sonoran Desert Toad – Incilius alvarius.  This toad is in the family of true toads or Bufonidae and that may be why the toad is also referred to as Bufo alvarius using an incorrect genus name.  The Sonoran Desert extends through southern Arizona and California and along either side of the Gulf of California down the Baja Peninsula on the West and contiguous Mexico on the East.  This toad secretes a toxin to protect against predators.  The article points out that dogs have died as a result of this toxin. The toxin has been analyzed and it contains 5-methoxy DMT – the psychedelic claimed to treat the addiction. Since the research literature uses the abbreviation 5-MeO-DMT that is how I will refer to this compound. The usual superlatives are used to describe the psychedelic experience. Endorsements from celebrities are there endorsing the spread of toad medicine around the world.  The actual experience is described in eerie terms like: “completely dissolves reality as we know it” or “terror and a sense of ego dissolution” followed by what is described by uncertainty over what happened along the way.  I have abstracted the side effects listed in this article in the table below.

5-MeO-DMT Adverse Effects
General	Pain Shortness of breath
Cardiovascular	High blood pressure Tachycardia
Neuropsychiatric	Flashbacks Extreme anxiety Hyperventilation Insomnia
Intoxication	Agitation Aggressive behavior Vomiting
Death	The article lists about 6 deaths that occurred while smoking 5-MeO-DMT – one of these deaths was attributed to anaphylaxis

 The main focus of the article is a single practitioner who is described as actively promoting this treatment and at the same time is considered problematic for inadequate monitoring of the patients he treats with 5-MeO-DMT. Doses are approximate, patient monitoring is lax to non-existent, and he has run into some legal problems, problems with practitioners of ethnic medicine, cultural problems with a local tribe, and ecological problems due to toad depletion.  Against that backdrop are the usual testimonials that  5-MeO-DMT has cured intractable substance use problems and psychiatric disorders like depression and PTSD. There are also examples of substance use problems getting worse to the point of a fatality and the whole experience of causing PTSD as well as alleviating it. Expert opinion is included with the usual qualifiers about how clinical trials might provide clearer answers and venture capital funding being available for depression trials.  

After reading the New Yorker article I went to ClinincalTrials.gov and found 5 5-MeO-DMT current studies listed.  Three appeared to be safety studies in normal volunteers and one of these studies was a dose ranging study. There was another study for treatment of depression. Three studies were completed with no results available.  The fifth study was not yet recruiting subjects. 

By way of contrast, I thought I would look at a paper that surveyed subjects who had taken 5-MeO-DMT (3) at least once especially for the side effect profile.  This study used an anonymous Internet survey to look retrospectively at the epidemiological features of people who have used this compound. The study design is limiting in this case because it likely screens for people who have had positive experiences and in this case may be motivated to promote psychedelics (the incentive for subjects was a very modest donation to an organization that promoted the study and use of psychedelics. The researchers collected demographic data, data on 5-MeO-DMT and other substances used, patterns of use and the effects of use (Mystical Experiences Questionnaire/MEQ) (4) and possible side effects through the Challenging Experiences Questionnaire/CEQ (5) that was apparently designed to study the challenging experiences associated with taking hallucinogens. I encourage reading the entire paper for all of the details. The final version of the CEQ is 26 items that have been factor analyzed to measure fear, grief, physical distress, insanity (fear of losing one’s mind on a sustained basis), isolation, death, and paranoia.

The authors basically conclude that users of 5-MeO-DMT do in fact experience mystical experiences per the MEQ.  The MEQ was originally studied for hallucinogen experiences and the specific questions can be found in reference 4 as well as the body of reference 3. It is probably not surprising that a hallucinogen creates a mystical experience.  The poll here suggests that it may be more intense than the subjects experienced with other hallucinogens. At one point in the paper the authors suggest that the mystical experience is thought to be curative, but that is really unclear at this point. If it is true, the duration of the cure is also unclear. From the New Yorker article there were testimonials that 5-MeO-DMT was useful for substance use and some other psychiatric disorders – but there was also a question of worsening.

Although this was not a clinical trial, medical literature typically describes adverse effects or adverse drug effects (ADEs) from any medical intervention used to elicit a specific therapeutic effect.  Those ADE checklists are used to assess safety as well as producing the warning and side effect literature for the package insert of approved medications.  The literature on psychedelics seems to have taken the direction that the focus should be on what are described as psychological effects (see second column in the following table under neuropsychiatric side effects). This is problematic because it seems to assumes that discrete bodily systems (other than the brain and perhaps the heart) are not involved with potential drug related side effects. The term side effects and adverse effects tend to be avoided other than to say that some people may have an adverse effect from the psychedelic experience. The New Yorker article and even the survey of 5-MeO-DMT users suggests that medical safety is a potential concern and that no matter what the setting a person needs to be carefully monitored after ingestion of this drug.  

5-MeO-DMT Adverse Effects (References 3,4,5)
General	Pain Shortness of breath Nausea
Cardiovascular	High blood pressure Tachycardia
Neuropsychiatric	Flashbacks Extreme anxiety Hyperventilation Insomnia Fear Hallucinations Dissociation	Depersonalization Aggression Violence Confusion Paranoia Grief Insanity Isolation Death Paranoia
Intoxication	No clear distinction
Other

 

A reasonable summary of what is known about currently known this drug at this point is that it is a powerful hallucinogen. The safety and efficacy of this drug is currently unknown. Caution is required in looking at a survey study where the primary interest in taking the drug is wanting a mystical experience and treatment of a psychiatric disorder is a secondary effect and yet the psychiatric disorder tends to improve.  The New Yorker article is a cautionary tale and a counterpoint to a lot of the hype around hallucinogens right now that includes travelling to a foreign spa and having it administered by a self-proclaimed guru. The deaths mentioned in that article and some places in the literature are another red flag in contrast to the universal proclamations about hallucinogen safety. People with complications and severe outcomes don’t generally participate in surveys – therefore surveys are not the best ways to determine how a toad toxin can be used on a therapeutic basis.

It always seems to come back to controlled randomized clinical trials that are carefully optimized for patient safety. I have been the medical person responsible for the safety of patients in many of these trials and that typically involves weekly visits with physical examinations and any indicated labs.  It is a tedious and expensive process and there are no good short cuts. Until then I advise extreme caution with hallucinogens or psychedelics. It is always good to keep in mind that human biology varies greatly. What some people tolerate without a problem for years can cause severe side effects or even death for others. I expect that will eventually be documented for hallucinogens.  

 

George Dawson, MD, DFAPA

Supplementary 1:  For past links to posts here on hallucinogens please see the following:

Are Hallucinogens the New Miracle Drugs:  https://real-psychiatry.blogspot.com/2016/06/are-hallucinogens-new-miracle-drugs.html

JWH Compounds Make the NEJM:  https://real-psychiatry.blogspot.com/2017/01/jwh-compounds-make-nejm.html

Supplementary 2:  I am always looking for suggestions on how to improve this blog. I have considered a post that is basically a primer on hallucinogens and psychedelics. Let me know if you are interested or if there is anything that I can write about this general topic that you might be interested in. It is probably obvious that I am a skeptic about all of the hype suggesting that hallucinogens/psychedelics are the new miracle drugs. 

References:

1: De Greef K. Toad Smoke. New Yorker. 2022 Mar 28: 38-45.

2: Larsen JK. Neurotoxicity and LSD treatment: a follow-up study of 151 patients in Denmark. Hist Psychiatry. 2016 Jun;27(2):172-89. doi: 10.1177/0957154X16629902. Epub 2016 Mar 10. PMID: 26966135.

Revisits the Danish LSD Study and concludes that “Most of the patients suffered from severe side effects of the LSD treatment many years afterwards.”

3: Reckweg JT, Uthaug MV, Szabo A, Davis AK, Lancelotta R, Mason NL, Ramaekers JG. The clinical pharmacology and potential therapeutic applications of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT). J Neurochem. 2022 Feb 11. doi: 10.1111/jnc.15587. Epub ahead of print. PMID: 35149998.

4:  Maclean KA, Leoutsakos JM, Johnson MW, Griffiths RR. Factor Analysis of the Mystical Experience Questionnaire: A Study of Experiences Occasioned by the Hallucinogen Psilocybin. J Sci Study Relig. 2012 Dec;51(4):721-737. doi: 10.1111/j.1468-5906.2012.01685.x. PMID: 23316089; PMCID: PMC3539773.

5:  Barrett FS, Bradstreet MP, Leoutsakos JS, Johnson MW, Griffiths RR. The Challenging Experience Questionnaire: Characterization of challenging experiences with psilocybin mushrooms. J Psychopharmacol. 2016 Dec;30(12):1279-1295. doi: 10.1177/0269881116678781. Epub 2016 Nov 17. PMID: 27856683; PMCID: PMC5549781.

“…challenging psychological experiences during the acute effects of psychedelics are not uncommon.”  p. 1279

6:  Murdaugh LB.  Adverse drug reaction reporting. In: Competence Assessment Tools. 2015. American Society of Health-System Pharmacists.  Bethesda, MD.  Accessed Online:  https://doi.org/10.37573/9781585284030.040

 

 

 

Prolonged Grief Disorder - A Few Comments

The New York Times came out with an article on prolonged grief disorder.  I thought I would write about it because in some ways it is a continuation of the criticism that started with the DSM-5 release in 2015.  The response to that piece is one of the most read articles on thisblog. As I pointed out in that article and several since, the release of the DSM-5 has been a predicted non-event. There were no scandalous developments based on releasing a document that hardly anyone reads and is not even owned by most of the people who prescribe medications for psychiatric indications – primary care physicians.

The new piece based on the release of DSM5-TR is much more balanced.  A well-known psychiatric researcher Katherine Shear, MD is quoted as well as an epidemiologist Holly Prigerson, PhD who discovered data supportive of the diagnosis and studied the reliability and validity.  Paul Appelbaum, MD is the head of the committee to include new diagnoses in the manual and he also explains the rationale.

What did I not like about the article?  It starts out with the old saw about how the DSM 5 is sometimes known as psychiatry’s bible. I appreciate the qualifier but let’s lose the term bible in any reference to the DSM.  That descriptor is wrong at several levels – the most important one being that it is a classification system.  Please refer to it as psychiatry’s phone book or catalogue from now on, even though it is nowhere near as accurate as a phone book or any commercial catalogue.

The author goes on to describe the inclusion of prolonged grief disorder into the latest revision of DSM as controversial and then collects opinions on either side of what I consider to be an imaginary controversy. Why am I so bold to call this controversy imaginary?  Maybe it is not entirely imaginary, but it certainly is not as big a deal as it is portrayed in the article and here is why.

The first argument is that including it in the DSM means that professionals can now bill for it. In fact, all hospitals, clinics, public payers, and insurance companies require ICD-11 codes and not DSM codes.  Granted, the DSM codes are typically coordinated to match ICD-11 codes but there is not a perfect match.  ICD-11 codes are available for free and do not require a copy of the DSM 5 TR. The diagnosis of prolonged grief disorder was included in the ICD-11 in 2020 (2) and it is easier to make the diagnosis.  Quoting from reference 2:

“To meet PGD_ICD-11 criteria one needs to experience persistent and pervasive longing for the deceased and/or persistent and pervasive cognitive preoccupation with the deceased, combined with any of 10 additional grief reactions assumed indicative of intense emotional pain for at least six months after bereavement. Contrary to the 5th revision of the Diagnostical and Statistical Manual of Mental Disorders [DSM-5; (11)] and the 10th revision of the International Classification of Diseases [ICD-10; (12)], the ICD-11 only uses a typological approach, implying that diagnosis descriptions are simple and there is no strict requirement for the number of symptoms one needs to experience to meet the diagnostic threshold.”

The insurance company billing is further complicated by the fact that there are many other current diagnoses that can be used to treat a person severely incapacitated over a prolonged or severe course of grief.  Per my original blog Paula Clayton, MD explained this 45 years ago based on her research that also showed a small percentage of people become depressed during grief and require treatment. A prolonged grief disorder (PGD) diagnoses is not necessary and, in some cases, may lead to problems with insurance companies. It is well known that some insurance companies will not reimburse for some diagnoses that they think do not require treatment by a mental health provider. What they think of a PGD diagnosis is unknown at this time.

The second argument is that it may lead to biological treatments for the disorder. They cite a naltrexone trial for this disorder. Let me be the first to predict that the naltrexone will probably not work but I will also point out it is a medication that could be prescribed right now without putting PGD in the DSM 5 TR. The author states this may set off a competition among pharmaceutical companies for effective medications. That may be true – but what will the likely outcome be?  We already know that many people with PGD actually have treatable depression and respond to conventional treatments. We also know that those medications are all generics, very inexpensive, and the pharmaceutical benefit managers control most prescriptions for expensive drugs. These factors combined with the low prevalence of this disorder and well as the responsiveness to psychotherapy and supportive measure will not produce a windfall for Big Pharma.

There is an inherent bias by some against medical interventions for any disorder that seems to start out as a phenomenon seemingly explained by social or psychological factors. Grief was listed as one of the four major causal factors for depression in Interpersonal Psychotherapy (IPT) and there were no complaints.  IPT has been around for 40 years. Is that because the treatment emphasized was psychotherapy?  Throughout my career I have always had resources available for people who were grieving. Clergy are a professional resource but with the continued secularization of the country it is common to find that most people do not have an identifiable clergy person. Grief support groups are very common – both as self-help groups and groups run by professionals. The question is what if those resources are not enough to assist the grieving person? 

The third argument is that there will be “false positives” or people given the diagnosis when they are emerging from the symptoms. That supposes that the doctor has no discussion with the patient about what might be helpful including non-medical supportive measures and watchful waiting. It also supposes that the patient’s interest in what is happening with them specifically how it is affecting their life and whether they want to do anything about it is never discussed.  I don’t think most doctors – even if they are in a hurry operate that way.

The fourth argument is the danger of making a diagnosis and how that impacts the person. Grief is a universal phenomenon that everyone experiences many times in their life. Everyone knows that through experience. Empathically discussing with a person that this episode of grief is affecting them differently than others does not seem to be discounting or minimizing their emotions or experience to me. The very definition of empathy is that the patient agrees with the empathic statements as adequately explaining their experience.

A fifth argument buried in there is that clinician want to rapidly classify people so that they can get reimbursement. I have already addressed each half of that argument about but let me add – does naming a disorder mean that it did not exist before? There are thousands of examples in medicine and psychiatry of new diagnoses that basically classify earlier conditions where the diagnosis was never made before. A striking example from psychiatry is autoimmune encephalitis.  It was previously misdiagnosed as either a psychosis or bipolar disorder until the actual diagnosis was discovered. Rapid classification leads to many paths other than reimbursement. In the case of autoimmune encephalitis – life saving treatment.

The fundamental problem in writing articles about human biology from a political perspective is that it fails to address the biology. The biology I am referring to here are unique human conscious states and all of the associated back up mechanisms that make them more or less resilient, intelligent, and creative. Is the general classification “grief” likely to capture a large enough number of possibilities to qualify as a rigorous definition? We have known for some time that is not supported by the empirical evidence and that evidence has become more robust over the past 20 years. A small number of people experiencing grief will have a much more difficult time recovering and, in some case, will not recover without assistance. In spite of that, there remain biases against studies that focus on elucidating biological mechanisms or treatments.  It is easier to invoke emotional rhetoric like medicalization or psychiatrization and try to avoid the issue.  To the author’s credit none of those terms were used.

There is also the issue of what this new diagnosis suggests in terms of the science of psychopathology. Does this mean we are closer to classifying all of the possible problems of the human psyche and developing treatments? It reminds me of what one of my psychoanalyst supervisors used to say about the state of the art.  In those days there were basically biological psychiatrists and psychotherapists. He referred to anyone without a comprehensive formulation of the patient’s problem as a dial twister. Are we closer to becoming dial twisters?  I have some concerns about the checklist approach associated with the diagnosis and its understudied phenomenology. That is compounded by the limited time clinicians have to see patients these days and the predictable electronic health record templates with minimal typing of formulations.

Practical considerations aside only time will tell if the new research leads to better identification and treatment of people with clear complications of grief. That does not mean that science has all of the answers. It should be clear that the science of prolonged grief disorder like most of psychiatry only deals with the severe aspects of human experience.  There are clearly other ways to conceptualize grief and learn about it without science. The science is useful for mental health practitioners charged with providing treatments to the severely distressed and with grief the vast majority of people (90+%) will never see a practitioner and even fewer than that will ever see a psychiatrist.

 

George Dawson, MD, DFAPA

 

1:  Ellen Berry.  How Long Should It Take to Grieve? Psychiatry Has Come Up With an Answer. NY Times March 18,2022.

2:  Eisma MC, Rosner R, Comtesse H. ICD-11 Prolonged Grief Disorder Criteria: Turning Challenges Into Opportunities With Multiverse Analyses. Front Psychiatry. 2020;11:752. Published 2020 Aug 7. doi:10.3389/fpsyt.2020.00752

Excerpted per open-access article distributed under the terms of the Creative Commons Attribution License (CC BY).

3:  Prigerson HG, Horowitz MJ, Jacobs SC, Parkes CM, Aslan M, et al. (2013) Correction: Prolonged Grief Disorder: Psychometric Validation of Criteria Proposed for DSM-V and ICD-11. PLOS Medicine 10(12): 10.1371/annotation/a1d91e0d-981f-4674-926c-0fbd2463b5ea.

4:  Lenferink LIM, Eisma MC, Smid GE, de Keijser J, Boelen PA. Valid measurement of DSM-5 persistent complex bereavement disorder and DSM-5-TR and ICD-11 prolonged grief disorder: The Traumatic Grief Inventory-Self Report Plus (TGI-SR+). Compr Psychiatry. 2022 Jan;112:152281. doi: 10.1016/j.comppsych.2021.152281. Epub 2021 Oct 21. PMID: 34700189.

5:  Shear MK, Reynolds CF, Simon NM, Zisook S. Prolonged grief disorder in adults: Epidemiology, clinical features, assessment, and diagnosis. In Peter P Roy-Byrne and D Solomon (eds) UpToDate https://www.uptodate.com/contents/prolonged-grief-disorder-in-adults-epidemiology-clinical-features-assessment-and-diagnosis#H210445955 accessed on 03/21/2022

6:  Klerman GL, Weissman MM, Rounsaville BJ, Chevron ES.  Interpersonal Therapy of Depression.  Basic Books, New York, 1984.

7:  Ratcliffe M. Towards a phenomenology of grief: Insights from Merleau-Ponty.  European Journal of Philosophy 2019; 28: 657-669  DOI: 10.1111/ejop.12513

8:  Clayton PJ. Bereavement in Handbook of Affective of Disorders.  Eugene S. Paykel (ed). The Guilford Press. New York. 1982  pages 413-414

Supplementary 1:

Quote from an initial post on this subject 9 years ago as written by Paula Clayton, MD:

"There are many publications that deal with treating psychiatric patients who report recent and remote bereavement. It is possible to find a real or imagined loss in every patient's past. However, for the most part, because there is little evidence from reviewing normal bereavement that there is a strong correlation between bereavement and first entry into psychiatric care, those bereaved who are seen by psychiatrists should be treated for their primary symptoms. This is not to say that the death should not be discussed, but because these people represent a very small subset of all recently bereaved, they should be treated like other patients with similar symptoms but no precipitating cause. A physician seeing a recently bereaved with newly discovered hypertension might delay treatment one or two visits to confirm its continued existence, but treat it if it persists. So the psychiatrist should treat the patient with affective symptoms with somatic therapy but only if the symptoms are major and persist unduly. A careful history of past and present drug and alcohol intake is indicated. Then, the safest and most appropriate drugs to use are the antidepressants. Electroconvulsive therapy is indicated in the suicidal depressed." (Paykel p413-414)

Class Warfare....

Americans operate on the illusion of a classless society. It is generally an implicit understanding that I did not have much of a handle on until I worked with teachers from the United Kingdom in my early to mid-20s.  Those teachers were always talking about the “working class” and those struggles and how it translated to national politics. They had well developed positions on international politics on the same basis. 

For the record, my family of origin was solid working class or the American equivalent “blue collar”.  During my father’s short lifetime, he was a railroad fireman and then engineer.  I can recall watching him shovel coal into a steam engine when I was about 5 years old.  One grandfather was an ore puncher or a guy who attends to an emptying iron ore rail cars - until he died from an apparent head injury.  My other grandfather ran a dray business hauling goods for other people and moving families from house to house. In late high school I assisted my grandfather moving and hauling things around ranging from flower boxes to grave sites to carrying very large pianos up several flights of stairs.

When you are raised in that environment it is easy to develop a distrust of authority – because let’s face it – in a capitalistic society altruism is at a minimum. People at all levels are trying to exploit you for their own gain. In the case of my father, he was in a system that could potentially pay you well when you were in your mid-50s or 60s.  If you were younger than that a seniority system kept you from working full time or enjoying the more premium jobs that did not require extensive travel or hardship. You could get “bumped” from a job at any time by an engineer with more seniority.  You could also be called up out of the blue to take a job that nobody else wanted.  On the days that my father did not want to work the call up jobs we were all given the code words: “Your father is not here today.”  That meant if I picked up our wall phone and my father was sitting at the kitchen table a few feet away and I heard a dispatcher say: “Is George there?” I knew it was my family duty to say: “No he’s not here.”

And who could blame him? I knew one of those jobs was an all-day run for about 220 miles (switching cars along the way). During the one-night layover – he slept on a wooden bench in the locker room at a train station and then came back the next day. I was a visitor to many of those locker rooms as a kid and knew what they all looked like - stark, dingy, sweaty furniture, and smelling like diesel fuel and Lucky Strikes. I also knew he did this to save money because we were usually strapped for cash.

But my father’s role was to educate me about the basics of growing up in a blue-collar family as well as live the practical aspects. I remember him showing me his union paper.   There on the cover was a picture of the home of the President of the Union. I guess they were unconcerned about optics in those days. It was a large home sitting on the high bank of a river.  I probably inherited my dead pan affect from my father but on this day, he was particularly animated.  I usually only noticed that if he was watching opera or comedy on TV.

“Do you see this house, George?! Do you think the guy who lives in this house cares about what happens to us?!”  It didn’t matter if that guy was once an engineer. He had migrated to the managerial class and that defined the relationship.

Even back then I knew it was a rhetorical question. I had been schooled in the fact that there was a mandatory withdrawal from his paycheck for union dues and that he could not work unless he was a member of the union. There was even an occasion where his union went on strike against the railroad he worked for and after getting appropriate clearances – he went to work for a competing railroad until the strike was over.  It wasn’t like he had a choice anyway. We lived on a paycheck-to-paycheck basis.

The blue-collar ethos was about more than suspicion of the managing class. There was an identification with coworkers and at times joint projects rather than socialization for socialization’s sake. My father decided to replace a rotted footer in the porch just off our kitchen one day.  By noon there were a dozen railroad coworkers there figuring out how to do it for the least amount of money. They finally located a significantly distorted 4” x 12” x 16' plank and used a car jack to bend it into place until it was nailed securely.  That was the first and last time I saw many of those men.  A fellow engineer who was a good friend of my father came over one day and they built an entire set of kitchen cabinets from scratch.  I never saw my father do any carpentry after that. The focus was on doing what needed to be done for the least amount of money.  

During that team effort on our porch on of the common topics of conversation was the work values of some of their colleagues. There was unanimous agreement about a car knocker who everyone seemed to know.  Car knockers on the railroad maintained all of the cars. That job breaks down to many skills and a fairly broad knowledge base. Everyone there commented about how this particular car knocker would always complete everything he knew how to do before passing the job along to someone else. That work practice was very highly regarded.

The social life of my parents consisted of brief daytime visits with two coworker friends from the railroad and a friend who my father used to play baseball with in his early 20s. My parents went out on New Year’s Eve to a local dinner club and that was it. No weekly weekend celebrations that are common today. But even more significantly – no rubbing elbows with the managerial class in hope of advancement. One of the significant blue-collar features is that people only socialize with whom they want to.  Socialization is not seen as a way to advance your career or develop relationships in the workplace apart from your overall competence. Another illusion of the blue-collar existence is the idea that you will be judged on your work quality and nothing else.  At least until you notice people with fewer work skills being advanced due to nepotism and fraternizing with the boss after work.  

 Another feature of the blue-collar existence was adherence to certain rules about money and specific social relationships.  Illegal activity was to be avoided at all cost. If you don’t have the money, you don’t do the activity. I can recall being lectured by my father for watching a baseball game from outside a ballpark after the fences had been torn down. His emphasis – if you can’t buy the ticket don’t go. Teachers were highly respected but the role of education was uncertain. Good grades were expected but there was minimal help at home and no clear career advice.  Some of the educated were after all members of the white collar and managerial classes. There was an explicit message that if you had a problem with a teacher you would run into an even bigger problem at home.  Teachers were unequivocally understood to be right and you were wrong.

A contrasting feature compared with the current pandemic is that I was born during a polio pandemic. Some kids in the neighborhood were acutely ill and one of them who lived a few blocks away was permanently paralyzed.  We all got the required vaccinations to attend public school and both the Salk and Sabin vaccines for polio. We also got smallpox vaccinations. There were no antivaccination protestors in those days.  Even though medicine was clearly more primitive 50 years ago - blue collar families were all for it. 

The politics was more clearcut even though most politicians on both sides of the aisle were moderates. Both of my parents were Democrats.  My maternal grandmother was a Democrat because “they are for the little guy.”  My maternal grandfather was a Republican because they always talked about cutting taxes but he also would get a faraway look in his eye and say: “George – someday there is going to be a revolution. All politicians are crooked!”  My grandmother encouraged a sensible and moderate life style. She lectured me on “roadhouses” when she learned I had gone to a local college bar.  The Eisenhower administration was ending to be followed in fairly quick succession by JFK and LBJ. America’s streets were not flooded with guns like they are now. Gun violence was not like it is now.  The NRA taught hunter safety courses and most blue-collar kids took the course in order to go hunting or target shooting. There were no school shootings but kids died in hunting accidents and by suicide. There was some building concern about the domino theory of communism in southeast Asia and the threat of nuclear war with the USSR.  The idea that nuclear was survivable was alive and well and there were several bomb shelters designated across the town.  I was charged with dismantling one of them as part of my work-study job in college about a decade later.

The transition to white collar work from a blue-collar family is interesting and complicated by the generations of white-collar people who you encounter. That transition was noticeable at the level of medical school. There it became apparent that there were a number of second and third generation physicians and many did not relate to people the same way that the blue-collar class did.  But the most striking transition occurred in the workplace when you are face-to-face with the same kinds of administrators that my father encountered in his railroad job.  People who have the power to fire you or severely reduce your income or professional prestige and don’t hesitate to do it on a whim. People who can actually do whatever they need to do to discredit you. In the last 40 or 50 years there has been a proliferation of this managerial class and the benefits have been uncertain at best. I have advanced the argument many times that the new managerial class has added no value at all. But then again based on what I have written so far – you knew that I would.

Today we are faced with a severely fractured society. Vast areas of rural American support policies that seem like a return to the 1960s blue collar world in terms of turning back women’s rights, pretending that there has been significant progress on racial equity, maintaining law and order by not questioning the police, and making sure that tax dollars are not given away to people seen as working less hard than they do. In what is the ultimate irony these same people have come to believe that a probusiness party lax on regulation is the best way to preserve their way of life.  They are turning to the same people who they have been skeptical of for decades to make these changes. This pivot has not been without cost.  Many blue-collar families have fragmented over these obvious contradictions as well as problems with the frontman of the party.  If you have blue collar values – the only way you can ignore thousands of lies is to ignore that they are lies in the first place. The only way you can ignore the gun violence in schools and on the streets is to blindly restate that this has something to do with the Second Amendment and all of the political biases that goes along with that, while ignoring the fact that it is a desperate political attempt to stay relevant.

But there is a deep inconsistency in that decision making – not just because of the sudden blind trust of the epitome of the white-collar world. It is a white-collar world that is clearly affiliated with interests inimical to most of the American people both culturally and in terms of foreign security. 

 

George Dawson, MD, DFAPA

Graphics Credit:

Benjamin Morawek, CC BY-SA 2.0 <https://creativecommons.org/licenses/by-sa/2.0>, via Wikimedia Commons