Kratom - Don't Believe the Hype

The CDC came out with a brief 2 page report on kratom deaths 3 days ago (1). That was all it took for the Twitterati to proclaim that there were many more deaths from alcohol and I suppose there was a post about even more deaths from cigarette smoking but thankfully I missed that one. When I pointed out that it was clearly an addictive drug and lifelong disability (a very significant problem) may be the issue - the defenders of kratom stepped up and talked about how harmless it is and also how it is advantageous for people who cannot afford medication assisted treatment (MAT) (buprenorphine preparations, methadone, or naltrexone extended release injections) for opioid use disorder (OUD). The expected personal attacks and sarcasm followed.

Kratom is an interesting compound because like many psychoactive botanicals there is a history (2). Kratom itself is basically leaf material from the kratom tree (Mitragyna speciosa). The leaves can be smoked or chewed. They can also be dried and powdered. The powdered form is what is typically available for sale. The powder can be packaged in capsules and taken orally, brewed into a tea, or rendered into a syrup and formed into pills. Fresh leaves can be chewed with or without betel nuts. Kratom has been used in Malaysia since the 19th century to “heal opium addiction”. A recent paper referenced a study of kratom users that were using an estimated 4-8 g/day (8). Converting based on typical leaf content means that these users would be exposed to a maximum of 120-180 mg mitragynine and 1.1 - 3.4 mg 7-hydroxymitragynine.   Rӓtsch suggests in his text that “in studies with mice, even extreme dosages of 920 mg/kg did not produce any toxic effects”. He describes “self experiments” in the literature suggesting that kratom can be both stimulating like cocaine and sedating like opium. The only comment on addiction is “The alleged kratom addiction is a Thai cultural phenomenon” (p. 367).  Like most intoxicants in the modern era there is progression to intravenous use.  Although that is currently rare, there are case reports of intravenous use of kratom extracts.

The CDC document describes a series of deaths in 11 states between July 2016 and June 2017 and an additional 27 states from July to December 2017. The data set was from the SUDORS (State Unintentional Drug Overdose Reporting System) and consisted of 27,338 overdose deaths, 152 (0.56%) of which were kratom positive. There is no standard postmortem toxicology protocol and as previously noted that is problematic in determining the drugs present in these analyses. As shown by the table from this report in 91 cases kratom was considered the cause of death, but numerous other substances were present. In seven cases kratom was the only substance noted in postmortem toxicology, but additional substances cannot be ruled out.

A report in the New England Journal of Medicine, looked at 15 cases of death (4) associated with kratom in Colorado. In this series the authors used more rigorous toxicological analysis with high-performance liquid chromatography – mass spectrometry. Whole blood mitragynine concentrations were noted between 16-117 ng/ml and up to 4800 ng/ml. In this series, 14 of 15 deaths had multiple drugs leading the authors to conclude that these deaths were kratom related.  This series of cases illustrates the importance of toxicological analysis and specifically plasma levels of the drug to correlate with various toxidromes and post mortem toxicology.

The leaves of Mitragyna speciosa, contain multiple alkaloids including mitragynine, 7-hydroxymitragynine, paynantheine, speciocilatine, and speciogynine. The crude alkaloid extract consists primarily of 66% mitragynine and 2% 7-hydroxymitragynine. The extraction process may be protective against toxicity for many people that brew the leaves into a tea, chew the leaves, or ingest the powdered leaves as capsules but even then the concentration of these alkaloids may vary from species to species. Counting on an inefficient extraction process for safety is probably not the best idea.  The other property of the raw material is that the alkaloids are mixtures of  opioid receptor agonists and antagonists that may determine the net effect. Searching the way these products are sold there is really not much about concentration of any associated alkaloids other than mitragynine.  The plant itself contains more than 40 unique alkaloids (8).

Until recently, the pharmacology of mitragynine and 7-hydroxymitragynine were unknown. There is research to suggest (5) that opioid receptors mediated the primary effects. Both compounds had binding affinity for the mu opioid receptor (MOR). They were also active in tissue essays and blocked by naloxone.  Some of these effects were inconsistent between laboratory species. Activity was reported at a number of non-opioid receptors as well. The pharmacology of mitragynine and 7-hydroxymitragynine is now well-characterized. Recent studies show that mitragynine is a partial agonist at the human mu opioid receptor (hMOR), and a competitive antagonist at the human kappa opioid receptor (hKOR), and an antagonist at the human delta opioid receptor (hMOR) but with very low potency. The authors studied these compounds against all three human opioid receptors looking at both functional activity (EC50 and IC50) and binding affinities (Ki) and discovered they were consistent across those experiments. They concluded that mitragynine (0.233 μM) And 7-hydroxymitragynine (0.047 μM) had significant binding affinity for hMOR. The remainder of the paper focuses on medicinal chemistry theory, specifically how opioid -like compounds that bias intracellular signaling toward G proteins rather than β-arrestin may be better candidates for opioid analgesics with low addiction potential and better side effect profiles and possibly antidepressant activity. They synthesize a number of analogues and look at their agonist activity at hMOR. The authors conclude that the psychoactive activity of Mitragyna is most likely due to their action at hMOR. They also point out that due to the competitive nature of the alkaloids the gross effects will be due to that balance of agonism and antagonism.

The alkaloid and methanol crude extracts of kratom are both inhibitors of CYP3A4 and CYP2D6 in vitro. No specific components have been identified with this activity and there has been in vivo confirmation (8).

Another paper (6) looks at the “unanticipated toxicity” of kratom. This group looked at the LD50 of mitragynine, 7-hydroxymitragynine, and heroin. The LD50 is a measure of acute toxicity and what single dose will kill half of the research animals. In this case mice were used and the researchers were surprised to find that an intravenous dose of either mitragynine or 7-hydroxymitragynine were as lethal as heroin. No lethal doses were observed for oral dosing in a range of 6.25-50 mg/kg. the lethal intravenous dose was midpoint in that range. Researchers observed that the mice appeared to die from respiratory depression within 10 minutes of direct exposure. In the surviving mice many were noted to have seizures in the first 20 minutes.  In a separate review, the authors point out that with a typical 8 g dose of kratom powder, the levels of 7-hydroxymitragynine, may be too low to cause a pharmacologically relevant effect at the opioid receptor. 

The research on kratom has elucidated receptor activity in opioid receptors. The activity is complex but the mu opioid receptor is clearly involved and is the likely site of the psychoactive effects and the application of opioid substitution in people with addictions. The receptor effect is complicated and likely involves more than the mu opioid receptor. The research also suggests that activity at murine and human opioid receptors are not equivalent. Persons acquiring kratom in the powder form need to consider that the ratio of mitragynine to 7-hydroxymitragynine likely varies with species and source. The 7-hydroxymitragynine is 52 times as potent as mitragynine at the MOR and 13 times as potent as morphine. Products made from extractions will be more potent.

All of this information should create skepticism in prospective kratom users. As addiction psychiatrist I can attest to the fact that it is addicting and with any addiction there is a tendency to escalate the dose. Many people with addictions as noted in the above table are using multiple substances some of which are also agonists at the opioid receptor. If you are considering kratom as a treatment for opioid addiction or chronic pain there are much, much safer and effective ways to proceed.


George Dawson, MD, DFAPA



References:


1. Olsen EO, O’Donnell J, Mattson CL, Schier JG, Wilson N. Notes from the Field: Unintentional Drug Overdose Deaths with Kratom Detected — 27 States, July 2016–December 2017. MMWR Morb Mortal Wkly Rep 2019;68:326–327. DOI: http://dx.doi.org/10.15585/mmwr.mm6814a2External

2: Rӓtsch C. The Encyclopedia of Psychoactive Plants: Ethnopharmacology and Its Applications. Park Street Press. Rochester, Vermont, 2005. pages 366-367.

3: Olsen EO, O’Donnell J, Mattson CL, Schier JG, Wilson N. Notes from the Field: Unintentional Drug Overdose Deaths with Kratom Detected — 27 States, July 2016–December 2017. MMWR Morb Mortal Wkly Rep 2019;68:326–327. DOI: http://dx.doi.org/10.15585/mmwr.mm6814a2

4: Gershman K, Timm K, Frank M, Lampi L, Melamed J, Gerona R, Monte AA. Deaths in Colorado Attributed to Kratom. N Engl J Med. 2019 Jan 3;380(1):97-98. doi: 10.1056/NEJMc1811055. PubMed PMID: 30601742.

5: Kruegel AC, Gassaway MM, Kapoor A, Váradi A, Majumdar S, Filizola M, Javitch JA, Sames D. Synthetic and Receptor Signaling Explorations of the Mitragyna Alkaloids: Mitragynine as an Atypical Molecular Framework for Opioid Receptor Modulators. J Am Chem Soc. 2016 Jun 1;138(21):6754-64. doi: 10.1021/jacs.6b00360. Epub 2016 May 18. PubMed PMID: 27192616; PubMed Central PMCID: PMC5189718.

6: Smith LC, Lin L, Hwang CS, Zhou B, Kubitz DM, Wang H, Janda KD. Lateral Flow Assessment and Unanticipated Toxicity of Kratom. Chem Res Toxicol. 2018 Nov 16. doi: 10.1021/acs.chemrestox.8b00218. [Epub ahead of print] PubMed PMID: 30380840.

8: Kruegel AC, Grundmann O. The medicinal chemistry and neuropharmacology of kratom: A preliminary discussion of a promising medicinal plant and analysis of its potential for abuse. Neuropharmacology. 2018 May 15;134(Pt A):108-120. doi: 10.1016/j.neuropharm.2017.08.026. Epub 2017 Aug 19. Review. PubMed PMID: 28830758.

9: Post S, Spiller HA, Chounthirath T, Smith GA. Kratom exposures reported toUnited States poison control centers: 2011-2017. Clin Toxicol (Phila). 2019 Feb 20:1-8. doi: 10.1080/15563650.2019.1569236. [Epub ahead of print] PubMed PMID:30786220.

Supplementary:

FDA Guidance On Lead and Nickel Exposure from kratom products:  Link

"Based on these test results, the typical long-term kratom user could potentially develop heavy metal poisoning, which could include nervous system or kidney damage, anemia, high blood pressure, and/or increased risk of certain cancers."

Graphics Credit:

1.  Mitragynine and 7-hydroxymitragynine were done with ChemDoodle.

2.  Table is from the CDC per reference 3 and public domain.

Drug Outbreak Testing Service (DOTS)

I wanted to get this information out as soon as I saw it. It is a service that offers free testing for drug outbreaks that are occurring more frequently as the pendulum swings to more acceptance of using various intoxicants.  This is a valuable service because many of these outbreaks occur so rapidly and with an unknown compound that leads to a sudden burst of morbidity and mortality and the medical systems in some towns are ill equipped to identify the offending agent.  I have posted about an epidemic of synthetic cannabinoids that required an intensive effort to look identify the compound being used.

This service offers rapid testing for up to 240 prescription and primarily nonprescription street drugs.  In their first paper on methodology at the references below they describe the rationale and procedure.  To qualify as a DOTS site, there has to be an identifiable outbreak of intoxicant use that cannot be identified locally.  That site needs to be able to submit 20 identified urine samples for testing.  In the following references the patterns of detected drugs vary considerably by site and level of sophistication necessary to identify the compounds.  For example, the King County DOTS samples yielded bufotenine, cathinine, alpha-PVP, mitragynine/7-hydroxy mitragynine, and U-47700 - compounds that are unlikely to be picked up in standard testing even at most substance use treatment centers.  Their assays also have sensitivity enough to pick up compounds like fentanyl that may be missed with lower sensitivity assays.

A brief discussion of the sample sites is required.  Comparing the toxicology data shows considerable variation across the sites.  The first sample was from an emergency department (ED) at the University of Maryland looking at the question of agitated patients and suspecting the use of cathinones or Bath Salts.  There were only 8 samples submitted.  There was more evidence that fentanyl may have been involved but there were a wide variety of compounds noted including diphenhydramine.  The King County Medical Examiner samples were from 20 people who had died of drug overdoses. Fifteen of the 20 samples contained methamphetamine and 14/20 contained fentanyl or analogues.  None of the 20 sample contained 10 or more compounds showing a high degree of polysubstance use in this sample.  The Montgomery County Maryland site is 20 samples from an outpatient clinic treating uninsured or publicly insured patients. The majority (75%) contained THC with 6/20 containing cocaine and 3/20 containing methamphetamine.  The Recovery Research Network submitted 23 samples from patients who were all in voluntary outpatient treatment.  The samples show a high degree of polypharmacy with 35% containing 10 or more drugs and 91% containing 5 or more drugs.   Aspenti Health submitted 20 samples on outpatients and their interest was in detecting possible fentanyl use.  12/20 samples were positive for fentanyl even though the lab results from the originating facility were b=negative due to a higher detection limit on their assay.  90% were positive for buprenorphine and 53% contained naloxone.

All together there are 91 samples from the 5 sites.  There is a lot of information contained in that data.  There is more detailed toxicology here that is available on most reports that I have reviewed, although data is generally not presented well in electronic health records.  I have included the data form the King County Medical Examiner's Office because it is the most complex and because this appears to be a publicly funded document with no copyright constraints.  Click to enlarge the graphic.

 
This is the way the data is presented from all 5 sites.  Major drug categories are color coded across all of the sites and there are row and column sums.  Interesting observations can be made in the data, but incident and sampling heterogeneity precludes any scientific conclusions.  One of the first things I noticed was the low frequency of psychiatric medications 26/91 were on antidepressants. One sample contained haloperidol and there were no samples containing quetiapine - a medication commonly used in residential treatment centers for insomnia. This could mean that much of the psychiatric comorbidity in the sample was not addressed.  The autopsy samples contained the fewest antidepressants.  Despite the recent concerns about gabapentin it was found in 13 of 91 samples and 4/20 autopsy specimens.

The greatest totals were for THC (50/91) and fentanyl and fentanyl metabolites (46/91).  The fentanyl was overrepresented in the autopsy specimens where 11/20 were positive and the Recovery Research Network sample where 19/20 were positive for fentanyl.  More  concerning 5 or those samples were also positive for buprenorphine indicating that patient may have been on MAT for opioid use disorder (OUD).  A similar pattern exists in the Aspenti Health sample where  11/20 were positive for both fentanyl and buprenorphine.  That is not to say that MAT for OUD is not indicated, but it probably reflects that fact that a significant number of drug users are not risk averse and do not consider MAT as a way to help them avoid the risks of OUD.  It is consistent with a recent story I heard about a number of OUD patients leaving a residential treatment facility because they heard that fentanyl was available in that community.  Many of those patients were on buprenorphine at an appropriate maintenance dose.

In may last look at the DEA schedule of controlled substances it contained about 330 compounds and I am sure that number has grown by now.  DOTS tests for 240.  If you have an outbreak in your community and the sources are not clearly known and little toxicology is available - it might be worthwhile to give them a call.  This is a valuable service to provide insight into what intoxicants may be responsible.

Being an undergrad chemistry major, this project also lead me to think about why every metropolitan area with a university or college having a chemistry major and access to GC/Mass Spectrometry should not have similar testing services.  These departments could be subsidized or reimbursed for the testing, incentivized for quality, and train the next generation of analytical organic chemists all in the same process.



George Dawson, MD, DFAPA


References:

1:  DOTS Bulletin A Pilot Study of the National Drug Early Warning System (NDEWS) University of Maryland, College Park Drug Outbreak Testing Service July 2018. Issue 6 DOTS Web Site

Epidemiology and Toxicology of Aircraft Assisted Pilot Suicides

I thought I would add a few facts to the speculation about what is really known about the epidemiology and toxicology involved in aircraft assisted suicides. It turns out that there are substantial studies that have been written.  If you are a bottom-line kind of person and want to avoid further reading, I can tell you that the events are rare especially events involving commercial aircraft where the incident is ruled a suicide by aviation authorities.  The events are so rare that prediction is doubtful.  In many cases the descriptions of suicidal statements and behavior occur on the day of the events and there are further extenuating circumstances like the use of alcohol and other intoxicants.  If you are really interested in these events, there are numerous places where you can see the analysis of what happened and what the ruling was by the National Transportation Safety Board (NTSB). 

The media reaction is similar to what is seen following mass shootings in the United States.  After the initial shock, there is typically a period of speculation about the causes of the disaster of the form: “What motivates a person to do something like this?”  There is the invariable dissection of their life in the media.  Were they bullied?  What was their personality like? What was on their computer?  Were there any clues that were missed that suggested that one day they would start shooting people?  Were psychiatrists involved?  How did they get the firearms?  When all of those familiar touchstones are exhausted (and it does not take long), the analysis starts to take on the characteristics of groups with agendas.  Gun advocates will suggest that this person was not a typical gun owner and therefore tighter gun laws are not needed.  Gun control advocates will provide the counter arguments that usually involve how easy it was for this person to get a gun.  There is a political impasse largely due to the power of the gun lobby and some politicians start to talk about “being in the wrong place at the wrong time.”  Mental health advocates, especially anyone who wants to talk about the real problems of mental illness and violence are as disenfranchised as the gun control advocates.  Nothing ever happens.  The screening advocates step up and suggest that many of these incidents could be prevented if we just “screened” enough people.  Anyone familiar with Bayesian statistics knows why that won’t work and may cause more harm than good. 

After that impasse, a second wave of speculation starts driven largely by people who ascribe to the theory that psychiatric medications and psychiatric treatment can cause homicidal behavior.  There are a couple of schools of thought on that one.  The first has to do with medications and the idea that specific medications like SSRIs can lead to homicidal behavior.  The other has to do with the fact that seeing a psychiatrist is associated with homicidal behavior and therefore psychiatric treatment must at some level cause homicidal behavior or at the very least the psychiatrist is responsible for not stopping it.  As I explored in a previous posts – there is not a shred of evidence that any of that is true.  There is however more evidence about pilot safety, pilot use of antidepressants, and incidents ruled pilot suicide than I have seen discussed in the media.  Here are a few bits of solid data to ponder during the expected swell of speculation about causes, who is to blame, and possible solutions.

1.  The denominator is huge:  

When the FAA or NTSB looks at all certified pilots in the US that includes a total of roughly 620,000 people per year including classifications for student, recreational, sport, private and commercial.  Roughly 1/3 of the FAA certified pilots are classified as commercial.  The US government also collects detailed statistics on the total number of passengers flown per year (815.3 million), the total number of flights per year (9.821 million) and a host of associated statistics on the Bureau of Transportation Statistics web site. 

2.  The numerator is very small:  

A quick glance at the table below on either antidepressant use by pilots or the total incidents rules as suicide shows that a small proportion of the total deaths are associated with either suicide or antidepressant use.  The proportions of the total pilots in the data base is much smaller and the rates of both suicide and antidepressant use are much lower than expected on a population wide basis.  Data from the Aviation Safety Network suggests that there were 8 to 10 incidents involving commercial aircraft and pilots since 1976 or about 9 in the last 40 years.

3.  The data on pilot use of antidepressants in fatal crashes: 

 Until about 2006, the FAA prohibited the use of antidepressants by commercial pilots.  They have since modified their stance to allow for specific antidepressants.  The European Aviation Safety Administration has publicly posted information of the safety of pilots and necessary screening for psychiatric disorders as well as prohibitions on certain diagnoses.  There have been studies that look at positive toxicology for antidepressants in the cases of fatally injured pilots.  These studies have looked for the presence of tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) in in fatal crashes.  Tricyclic antidepressants were the predominant antidepressants prescribed before the approval and release of fluoxetine in 1987.  One study by Dulkadir, et al looked at fatal crashes between 1990 and 2012.  In this study the researchers received biological samples from 7,037 fatally injured pilots out of a total of 8,429 fatal accidents.  2,664 were positive for drugs on toxicological analysis.  Of those positive samples TCAs were found in 31 samples, TCAs alone in 9 and TCAs with other drugs in 22.  None of the pilots involved reported TCA use during their aviation medical exam.  The authors point out that at the time covered in this study that TCAs were not approved for pilot use and that selective serotonin reuptake inhibitor antidepressants or SSRIs were approved on a case by case basis.  That is a prevalence of TCA use in this database is less than 0.5% ( 31/7,037 aviators).  That number is much lower than estimates of population wide use of antidepressants.

Where the blood levels were determined they clearly indicate that some overdoses had occurred (see Table II and III).  Blood concentrations greater that 1,000 ng/ml are usually very consistent with overdoses and that is the case with nortriptyline and imipramine/desipramine in these tables.  The authors were able to determine that the TCAs were prescribed for depression in three cases, pain in two cases, and chronic insomnia in one case.  Other antidepressants were listed along with opioids, anticonvulsants, cold medications, antihypertensives, benzodiazepines, muscle relaxants, diabetes medications and ethanol were detected but the epidemiology was not reported.  In both the studies by Akin and Dulkadir “drugs and alcohol and/or a medical condition” was given as “a probable cause or contributing factor in about 1/3 of the accidents where antidepressants were detected.

There was an earlier study of the epidemiology of SSRIs in pilot fatalities from 1990-2001 (Akin, et al) that showed they were involved in 61/4,128 pilot fatalities or a total of 1.48%.

The available data suggests that pilot suicide by aircraft is very rare and much lower than the pilot suicide rate by all methods.  There is also a suggestion that the suicide rate in pilots has actually decreased.  Searching the NTSB database yielded 74 fatal accidents using the search term "suicide" dating back to 1966. 

Explanations given in the article for the fewer pilots taking TCAs was that they are more toxic and less preferred agents.  Certainly in the 1990s SSRIs were heavily promoted along with the medical treatment of depression.

4.  Intoxicants are found in toxicology specimens –

The study by Canfield, et al identified a greater percentage of specimens that were positive for cannabinoids (relative to antidepressants) and additional performance impairing drugs in 38% of the individuals who tested positive to cannabinoids.  They also looked at the mean THC concentration in the blood and concluded that during 1997-2001 it was 2.7 ng/ml and for 2002-2006 it was 7.2 ng/ml.  The rate of increase in THC levels over those years exceeded the increase in cannabis potency as reported by the National Institute of Drug Use (NIDA) over the same years (2.7 fold as opposed to 1.5 fold).  Some authors have concluded that THC levels between 2 and 5 ng/ml represent the lower and upper ranges of significant impairment from cannabis use on performance tests measuring driving skill (see Ramaekers, et al) in recreational cannabis users.

The study by Bills, et al looked at the toxicology in a cohort of 36 pilots who committed suicide by aircraft during a 21 year period from 1983 and 2003.  Each suicide case was matched against 2 randomly selected control accidents.  In this study, the pilot characteristics included positive toxicology for alcohol, prescription drugs, and illegal drugs in 24.3%, 21.6%, and 13.5% of cases respectively.  An exhaustive list of drugs found was not available in the paper.  The authors were also not able to compare the toxicology of the cases to controls because 84% of the controls survived and their toxicology was unknown.  

5.  The baseline rate of pilot suicide is low or is it? -

Bialik looked at the issue of workplace suicide, the data quality estimates for pilots in the US.  One of the key references was a paper by Tiesman, et al that looked at the issue of workers who suicide in the workplace.  It used databases from the CDC (National Occupational Mortality Surveillance (NOMS)) and  Bureau of Labor Statistics (Census of Fatal Occupational Injury (CFOI)).  The NOMS database has no granularity and does given intentional self harm as a search parameter.  Unfortunately only "transportation occupations"  can be searched grouped by age, race, and sex.  I did not find the number of deaths or the PMR (Proportionate Mortality Ratio) to be useful.  The NOMS did have granularity with specific occupations and there was a homicide definition but none for suicide or intentional self harm.  Bialik concludes that pilots in general may have a slightly higher rate of suicide than the population in general but there are problems with that estimate and he was able to consult with an epidemiologist from the CDC.

Another approach to looking at this issue to to find a study with a very well characterized database that looks at the occupational issue.   Roberts, et al meets that criterion in a 2013 study of high-risk occupations for suicide.  The researchers looked at the numbers of suicides and numbers in all occupations in England and Wales for specific time intervals.  They determined the 30 occupations with the highest suicide rates (generally greater than 20/100,000).  In comparing the time intervals (1979–80, 1982–83) to  (2001–2005) they determined shift in the ranking and discussed possible causes of those changes.  Pilots were not listed in the top 30 occupations by suicide rate.  The only transportation workers listed were "rail transport operating staff".  They noted that suicide rates for professional occupations decreased over the time interval studied while there were sharp increases in the suicide rates for manual occupations.  As a comparison the 2013 suicide rate in the US was 12.6 per 100,000.

6.   The accident rate due to suicide attempts in commercial aviation is lower than that found in general aviation - 

These incidents are tracked  by the Aviation Safety Network and their web site currently lists intentional incidents and accidents caused by pilots dating back to 1976 in commercial flights.   There is a separate list of aircraft accidents caused by pilot suicide and that lists 9 suicides in the same time period but proportionally more associated fatalities. 

7.  Pilots can already self report substance use problems - 

There have been some suggestions that screening would be enhanced if pilots could self report problems without the fear of recrimination - the same way that licensed health care professionals are allowed to do in many states.  The focus would be on treatment rather than punishment.  The health care professional experience demonstrates that this leads to significantly more self reports and that is consistent with the goal of public safety.  Since pilot certification occurs at the federal level and health care professional licensing occurs at the state level - there is an opportunity to develop a more standardized approach to the potentially compromised pilot that depends more on self-report than screening.  There is currently an "occupational substance abuse treatment program" called HIMS that states at least part of their goal is to preserve careers.  A broader focus to include voluntary self- report of psychiatric conditions and suicidal thinking would result in more referrals for treatment and potentially impact the suicide rate.

8.  Aviation regulators and the aviation industry collect data that the healthcare industry can only marvel at - 

Reading through the sheer amount of data and how it is acquired it is evident that anyone involved in aviation has a single-minded focus on safety.  The methods of data acquisition through flight recorders and the checks and balances on the ground are far superior to any safety standards in the health care industry in the United States.  As a basic thought experiment, can you imagine recording similar outcome data from patients rapidly discharged from hospitals in the US?  I am talking about real data and not the survey that the nurse hands a patient after they have coached them on what to check off. 

I don't have to imagine what that data would look like.  I know what that data looks like and it is quite ugly.  It is more than a little ironic that health care experts, especially in this case psychiatrists and other behavioral experts are going to rush in and correct what is wrong with the aviation industry.  By comparison, health care measurement and incident analysis is all smoke and mirrors.  They don't know how to collect relevant data and many of the outcome measures are strictly political and meaningless.  If anything we should be bringing in aviation safety experts to run hospitals instead of MBAs.

With what I have read, I doubt that there is any possible improvement beyond voluntary reporting and making sure that there is always a second crew member in the cabin on commercial airliners.  In some of the commercial aircraft crashes the planes were stolen by staff who were not pilots and crashed.  But in the case of air disasters that resulted in multiple passenger deaths a second person in the cabin is a clear safeguard.  I am not an expert on how many people are in air crews, but I know that there is also a flight engineer in the cabin in some cases.  Given that these incidents are rare by any combination of numerators and denominators that are chosen and the fact that screening for rare events is generally not successful, screening for these rare events is not likely to work.  Flight crews currently undergo random urine toxicology to prevent the use of intoxicants that can impair the ability of a pilot.  Anecdotal evidence would suggest that is useful, but in the case of addictions there are often attempts to circumvent this intervention or use a drug that is not detectable.  The experience of health care professional screening programs would suggest that voluntary reporting can both improve public safety and preserve careers.  That seems like a useful approach for pilots.

Most importantly, the aviation industry is a model for safety assurance and the investigation of incidents where there were lapses.  It holds many lessons for the health care industry.        




George Dawson, MD, DFAPA



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Ramaekers JG, Moeller MR, van Ruitenbeek P, Theunissen EL, Schneider E, Kauert G. Cognition and motor control as a function of Delta9-THC concentration in serum and oral fluid: limits of impairment. Drug Alcohol Depend. 2006 Nov 8;85(2):114-22. Epub 2006 May 24. PubMed PMID: 16723194.

Roberts SE, Jaremin B, Lloyd K. High-risk occupations for suicide. Psychol Med. 2013 Jun;43(6):1231-40. doi: 10.1017/S0033291712002024. Epub 2012 Oct 26. PubMed PMID: 23098158; PubMed Central PMCID: PMC3642721.

Total FAA Certified Pilots:  http://www.aopa.org/About-AOPA/General-Aviation-Statistics/FAA-Certificated-Pilots

Aviation x Antidepressant Medline Search April 2015:  http://www.ncbi.nlm.nih.gov/sites/myncbi/1-MAvBcofi/collections/47791909/public/

Carl Bialik. We Don't Know How Often Pilots Commit Suicide.  FiveThirtyEight (a very sophisticated blog)

Clozapine As A Fictional Murder Weapon On The Walking Dead

clozapine (Clozaril)

clonazepam (Klonopin)

When something doesn't fit my typical hypothesis testing interview style, I start to think that there are other things going on.  Things that might not be obvious and things that I will need to piece together with further evidence gathering and collateral information.  That is what happened when I was watching television last weekend.  It happens all of the time in real life.  I remember the day when I was a second year resident and my attending asked my: "Suppose that you are at a party and this person comes up to you and starts to act in a certain way.  Do you tell yourself: "I am off the clock" and try to react in a way other than a psychiatrist might act or do your think about that interaction like a psychiatrist would?"  There was some uncertainty there as a rookie, but not after 3 decades of practice.   You see the world as a psychiatrist.  That is why I suddenly became much more attentive when I heard the words clozapine and clonazepam mentioned in a very popular television drama last weekend.

Before any further consideration, this is about the implications of a purely fictional scenario.  This post is more about the motivations of the author or authors than psychiatric treatment.  At that level it is probably more about individual or cultural perceptions than reality.  I was watching the highly popular television series the The Walking Dead  last weekend.  This series is all about surviving a zombie apocalypse.  In this scene, a group of survivors is providing some kind of emergency medical care.  They are in a large hospital building.  I was surprised when the ragged physician gave the order to give a patient "75 mg of IM clozapine".  Any psychiatrist or psychiatric nurse knows that there is no IM form of clozapine and that according to the standard titration that dose is probably too high in any clozapine naive patient on day 1.  Apparently the writers of the show knew at least some of that because the actress who was working on the doctors orders had to take clozapine tablets out of a standard large pharmacy bottle and grind them up with a mortar and pestle so that they could be dissolved and injected.  She proceeded to inject the fictional patient with clozapine.  In a few minutes, the treated patient developed tonic-clonic seizures and dies.  She goes back to confront the original physician who gave her the order and is told: "No I said clonazepam and not clozapine."  Interestingly this combination is not on the list of look-alike, sound-alike or confused drug names by ISMP , but it is in this document about using TALL MAN font conventions to prevent mistakes among drugs that look alike.  On page three we learn that clonazePAM- cloZAPine-KlonoPIN are confused medications.  I think that anyone without experience in these medications might make that mistake.  Of course for the purpose of drama, we learn later that the physician giving the order actually knew that the deceased man was a physician.  They previously worked together in a hospital setting.  In the dog-eat-dog world of the zombie apocalypse, the ordering physician did not want any competition for his medical position.  He did not want to risk elimination by his more ruthless leader.  He intentionally ordered his assistant to give a clozapine injection and then lied and told her that he said clonazepam and not clozapine.

I posted the structures here to illustrate that before there were administrators focused on the confusion between names there were chemists to show that each of these compounds is unique.   Studying pharmacology and those technical details adds another layer of appreciation.  Psychiatry adds another layer of meaning on top of that.  I have seen the benzodiazepine trends and concluded like many psychiatrists after years of practice that clonazepam and other benzodiazepines might be useful for the first months of treating anxiety or panic.  As an add-on for anxiety in people with severe problems they don't add much.  In the end there are still the same problems and an additional addictive medication.  When I think about clonazepam, I am also reminded that even the professionals can be confused.  I used to work at a place where it was not considered a benzodiazepine and not subject to the same security precautions - even after I pointed that out.  Clozapine on the other hand can be a life changing medication.  People with refractory psychosis and mood symptoms become clear and function at a much better level.   If clozapine did not have significant limitations from toxicity, I doubt than there would be a need for any other antipsychotic.  It is the only one with clear advantages in terms of symptoms relief, improved function, protection against suicide, and it even treats tardive dyskinesia and other movement disorders.  But the way it stands there are significant side effect limitations and  it is the antipsychotic that psychiatrists worry about the most.  

We have a case of homicide by injection of 75 mg clozapine.  Does that hang together as being plausible?  It also triggers an entire series of question about: "Why clozapine?"  Clozapine is a fairly esoteric second generation antipsychotic.  It is indicated for treatment refractory schizophrenia and a lot of experts believe it is underutilized because of its superior efficacy in this population.  It also is the only medication that has been shown to have anti-suicide properties in a double-blind clinical trial.  Those superior effects occur in the context of a wide range of toxicities that require close monitoring including weekly to monthly complete blood counts with differentials (depending on the time course of treatment)  for the length of treatment with the drug.  In addition to hematological side effects the drug can cause seizures and a number of other organ specific toxicities like myocarditis.  It should only be prescribed by experts familiar with its use and registered to prescribe it and follow the white blood cell counts.  If the white blood cell counts fall below a certain parameter, the clozapine must be discontinued and not restarted.  Clozapine can cause fatal agranulocytosis.  I view clozapine as one of the most beneficial drugs in psychiatry and one of the most toxic.  Clonazepam on the other hand is a benzodiazepine.  It can be used to treat anxiety and panic attacks.  It can also be used to treat seizures, but I have rarely seen it used for that purpose.  The main toxicity is excessive sedation and the main clinical problem is that it can be addicting.  But in terms of toxicity, it is generally well tolerated.

My first question is why clozapine would be available in the post apocalyptic pharmacy?   In any shorter term situation the medications that run out first are maintenance medications for chronic conditions.  In this case, the survivors are supposed to be in Grady Memorial Hospital, one of the largest hospitals in Atlanta.  I suppose it is possible that they would have a larger supply of clozapine since they are a metro hospital and if psychiatric services were as bad before the apocalypse as they currently are they would typically have a significant number of people in the emergency department that may be taking clozapine.  The second question is - can it be given intramuscularly?  It turns out it can be.  A 1999 reference from Lokshin, et al describes their use of parenteral clozapine in 59 patients.  They are using the drug for acute stabilization of inpatients and they do not describe whether or not their patients are taking other medications or are medication naive.  They do not specify dosing but in one case described the problems with giving large intramuscular injections of up to 300 mg in injectable clozapine when  patient refused the same oral dose.  They had surprisingly few side effects, no fatalities, and no seizures.   Unless I missed a reference somewhere this may suggest that the author of The Walking Dead episode believed that clozapine is a lot more toxic (and lethal) than it really is.   Or do they have access to other information?  That also brings up the question, if you were a physician with access to the post-apocalyptic pharmacy would there be more toxic and more lethal medication that could be used for that purpose.  Most probably, but I will not be speculating about that here.

There are a large number of questions that come up if you think about the possible intentions or biases here that involve the use of clozapine in a fictional plot.  In situations like this, I prefer to contact the author directly and ask them what they were thinking.  After a significant amount of time searching, I learned that there may have been some controversy with the writers of this series, but I could not find a single e-mail or snail mail address where I could send them that question.  I would certainly prefer to get an answer from the author or authors.  How did they first hear about clozapine?  Why did they decide to use it in this case?  Do they have a medical advisor who suggested it?  Do they have a personal relationship with anyone who takes clozapine?  Do they have an opinion about the medical treatment of psychiatric disorders in general?  There is really a long list of questions.

And finally there are also the practical treatment implications.  Up to 17.3 million people watch The Walking Dead, a large percentage of them 18-49 year olds.  I am sure that  has implications for informed consent conversations between psychiatrists and patients and their families.  We live in a country where 21% of 18-29 year olds get their news about Presidential campaigns from The Daily Show.  After hearing the name from a psychiatrist somebody is bound to say:  "Wasn't that the medication that we heard about on The Walking Dead?"  The standard reply is that medical conventions and treatments are not immune to artistic interpretation and all areas of medicine are similarly affected.

I may be missing something but it just seems like an unusual choice for this medication in this plot to me.


George Dawson, MD, DFAPA



Ref:

1: Lokshin P, Lerner V, Miodownik C, Dobrusin M, Belmaker RH. Parenteral clozapine: five years of experience. J Clin Psychopharmacol. 1999 Oct;19(5):479-80. PubMed PMID: 10505595.

Homicide Debate Goes Further Off the Rails

Apparently broadcast news is about as reliable as the Internet these days.  I was watching an "expert" on the weekend discuss the connection between homicide and antidepressant medications.  He apparently believed that there was one.  I understand that Sanjay Gupta made a similar comment today on CNN.  The misinformation is flying out there.  There are several political interests that would like that statement to be true and they appear to be out in full force. What is the short answer to the association between antidepressants and homicide?  Who can you believe?

Well there is always the scientific approach and a review of the medical literature.  Admittedly the literature is a lot drier and less entertaining than Dr. Gupta.

There is also simple arithmetic   The American media like to give the impression that violent crime and homicide are at epidemic levels.  It is always a shock when people discover that in fact we are at a 30 year low:

The homicide rate has actually declined from 10.2 per 100,000 in 1980 to 5.0 per 100,000 in 2009.  What are the odds of that happening if a major new cause of homicide is being added at the same time (namely antidepressants).  How does that compare with antidepressant use?  A recent study estimated that from 1996 to 2005, the number of Americans older than 6 years of age in surveyed households who received at least one antidepressant in the year studies increased from 5.84% in 1996 to 10.12% in 2005.  From the table there was a 24% reduction in the homicide rate during a time that antidepressant use nearly doubled.  One in ten Americans received an antidepressant prescription   The authors of this study noted this trend was broad based and correlated with a lower percentage of people receiving psychotherapy.

But what does that tell us about the observation that antidepressants cause homicide?  Technically there is no current way to demonstrate causality from a negative correlation between homicide rates and the rate of people taking antidepressants.  A large scale significant negative correlation between antidepressant use and lethal violence over a 15 year period has already been reported in the Netherlands.

What about the commentator suggesting that the toxicology of homicide perpetrators shows that they can have psychiatric drugs present that explain their homicidal behavior.  In fact, a study looking at that issue showed that 2.4% of 127 murder-suicide perpetrators had toxicology that was positive for antidepressants.  That is a lower than expected rate of antidepressant use than in the general population.   In a study of elderly spousal homicide-suicide perpetrators, depression was seen as an antecedent to this act but none of the perpetrators tested positive for antidepressants.

Given these observations any claim that antidepressant or any psychiatric drug causes homicidal behavior needs to be backed up with some hard data.  I don't mean a series of cases reported by somebody to make a point and I don't mean a legal decision where lawyers and judges can pretend that scientific data do not exist and make a decision about what they hear in a court room.  I also do not mean listening to somebody claim that we will never know the real relationship until we conduct "prospective double blind placebo controlled studies" of homicidality as a medication side effect.  If it isn't obvious, that study would by definition be unethical and would not pass the scrutiny of any human subjects committee.

Anyone with potential homicidal thinking needs close supervision and treatment.  They may need inpatient treatment in a unit that specialized in treating homicidal thinking and behavior.  Any clinician working in these settings will tell you that the people being treated generally come in with aggressive and violent thoughts and behavior before they take any medication.  If they have positive toxicology associated with homicidal thinking it is generally alcohol or an illicit drug like cocaine or methamphetamine.  Anyone with this problem also needs close monitoring and management of medication side effects.  Antidepressants can cause agitation and restlessness.  There are some people who do not benefit from antidepressants.  In the case of persons with the potential for aggression and suicide the medication response may need to be determined in a controlled environment before they can be safely treated.  Like all medications antidepressants are not perfect medications and they need to be administered by an expert who can provide effective treatment while managing and eliminating any potential drug side effects.

George Dawson, MD, DFAPA