Package Insert For Epidiolex - Does It Suggest A Problem With Medical Cannabis?

Cannabidiol (C₂₁H₃₀O₂)

Epidiolex was approved by the FDA two weeks ago for Lennox-Gastaut syndrome or Dravet syndrome in patients 2 years of age and older.  Epidiolex is cannabidiol (abbreviated CBD) one of several compounds in the plant Cannabis sativa.   I had a previous post on this compound but that was before the package insert came out.  I like to study package inserts of all of the pharmaceuticals I encounter to prevent unexpected side effects, anticipate drug interactions, look at the current prescribing recommendations, and study all of the safety considerations.  Every drug has a section in that package insert about the pharmacokinetics, pharmacodynamics, and considerations in the case of hepatic or renal impairment.  In some cases there are very specific recommendations for dosing with metabolic impairment or potential drug-drug interactions.  The other interesting aspect in this case is that Epidiolex is considered the first botanical extract to be FDA approved and the first cannabis derived compound.  A significant part of the population considers cannabis to be a benign natural product with none of the usual pharmaceutical concern about organ toxicity and drug interactions.

Reading the actual package insert a few things jump out at me today.  The original indications are the same, but the logical question is whether this medication will be used for off labeling prescribing for other indications.  After hearing one of the top epileptologists  in state talk about the use of cannabinoids for epilepsy, there is also the question of whether the diagnosis is correct.  In that lecture he pointed out that a case example in the news media probably did not have the diagnosis and that the expert in the state who could make that diagnosis was not consulted.

The dosing of the drug is fairly robust going from 5 mg/kg/day up to 20 mg/kg/day.  For a 70 kg man that comes out to a max dose of 1400 mg/day putting it in the range of several other anticonvulsants from different classes.

There are warnings about hepatotoxicity.  Early in the document, it states that some patients will experience elevated liver function tests and in some cases with develop overt side effects leading to drug discontinuation.  Baseline screening is recommended with AST, ALT, and total bilirubin.  Patients with elevated baseline transaminases were more likely to experience further elevation of these tests than those subjects with no baseline elevation.  The Child Pugh classification of severity of liver disease is used as a metric with dose adjustments suggested for mild, moderate, and severe disease.

Thirteen percent of patients had ALT elevations that were three times the upper limit of normal (ULN).  Less than 1% had transaminases that were 20 times the ULN and some patients were hospitalized.  In a third of the cases the transaminase elevation resolved without treatment.  In the other two thirds it resolved with discontinuation of the Epidiolex or the associated anticonvulsant (valproate).

Risk factors (associated drugs - clobazam, valproate), dose, and baseline transaminases) were discussed as well as monitoring.  Given the prevalence of the problem screening transaminases at 1 month, 3 months, and 6 months and as indicated after that.  More importantly - screening for the physical illness from drug induced liver disease ("explained nausea, vomiting, right upper quadrant abdominal pain, fatigue, anorexia, or jaundice and/or dark urine") can lead to further evaluation.  Three scenarios for discontinuing the Epidiolex are recommended:

1.  Transaminase levels greater than 3 times the ULN.

2.  Bilirubin levels greater than 2 times the ULN.

3.  Transaminase levels greater than 5 times the ULN. 

My read of the difference between 1 and 3 is that 1 can be a temporary measure but 3 should be permanent.  In my experience with valproate, I would definitely discontinue with these levels.  That is based on the well validated concern that valproate can cause significant hepatotoxicity. It is still possible that additional trials and post marketing surveillance will show that there is not long term concern with CBD.  In the trials transaminase elevation was the most frequent reason that the drug was discontinued (24% versus 3% on placebo).

Drug interactions noted that could be clinically significant. Epidiolex is metabolized by  CYP3A4 and CYP2C19 so that inhibitors of these enzymes can potentially increase the plasma levels.  Strong inhibitors of CYP3A4 include HIV antivirals, antifungals, and buprenorphine.  There are no strong CYP2C19 inhibitors.

Inducers of the same enzymes can lower Epidiolex levels and the standard inducers of those enzymes are carbamazepine, oxcarbazapine, phenytoin, HIV antivirals, prednisone and glucocorticoids, and St. John's Wort. 

Additional warnings about the use of the drug include somnolence and sedation (32%), suicidal ideation and behavior, hypersensitivity reactions, and the risk of withdrawing an anticonvulsant and need to do it gradually.   Regarding the suicidal ideation and behavior the only data presented was from a large (N=199) pooled analysis of clinical trials.  It is a standard warning on all anticonvulsant drugs and there was nothing specific to Epidiolex or CBD.

Clearly Epidiolex or CBD extracted and used at pharmaceutical doses may have some of the power of pharmaceuticals but also has the same significant side effects.  The side effect profile and drug interaction concerns are very similar to other pharmaceuticals that are used to treat epilepsy. This raises some interesting issues in states like Minnesota where high potency extracts of cannabis are being sold as medical cannabis and there is minimal medical supervision - primarily because there is scant evidence that cannabis extracts are medical treatments.  As I previously observed from the most recent report of the Minnesota medical cannabis program, extracts are being sold in this state that result in the ingestion of 12.2 - 1,439.2 mg/day of CBD.  The middle to high end of that range is clearly in the dose range for Epidiolex and the extracts are not prescribed or monitored by physicians - at least there is no requirement for that to happen.  Looking at all of the available data it is clear that the person taking 1,439.2 mg/day is an outlier and the next cluster of patients is at the 100-200 mg/day range. 

In Minnesota, a medical provider certifies a patient as having a condition that qualifies them for medical cannabis. In the case of this report it is chronic pain.  That patient goes to a medical cannabis dispensary and discusses what they want with a pharmacist.  In the case of high CBD products, as far as I know there is no recommended screening, monitoring, or patient education.  Just based on what I read in the current Epidiolex package insert, if the CBD content of the medical cannabis is in a similar dose range that is the equivalent of taking a new pharmaceutical and making it an over the counter drug.  The neurologists prescribing Epidiolex have good guidance on what needs to be monitored and are undoubtedly very familiar with the compound.  Other physicians including psychiatrists need an awareness of the pharmacology of CBD - especially if the dose is in the range suggested by this package insert.

If it was needed, this seems like further evidence that the miracle of medical cannabis has affected the judgment of many who seem to consider it a benign natural product. It turns out in this case, it can have a therapeutic effect on specific seizures at a significant dose for conditions that did not have many good options.  That treatment comes with clear risks.  The risk is reduced since all of the patients treated for the indicated seizure disorders are being followed by neurologists who specialize in the polypharmacy necessary to treat complex seizure disorders.  That includes monitoring potential drug interactions and toxic effects.  Can we say the same thing for people obtaining it through the medical cannabis program or being prescribed the drug off label?

Medical cannabis needs to be taken as seriously for the side effects as it does for the purported benefits.


George Dawson, MD, DFAPA


Reference:

Full Prescribing Information for Epidiolex. FDA approved package insert.


Supplementary 1:

Any FDA package insert is available online by Googling:  "[Drug name] FDA Package Insert"   The PDF of that drug insert will pop up and you will have access to same the full prescribing information that any physician has.

Supplementary 2:

In Minnesota, there are two companies that are the exclusive providers of non-smokable medical cannabis products Leafline Labs and Minnesota Medical Solutions.  Actual THC and CBD content is available on the web sites of both companies.

Leafline Labs has a vaporization product, a sublingual spray, an oral suspension, and a topical preparation.  The highest concentration of CBD in the oral solution is 20 mg/ml.  Epidiolex is 100 mg/ml.

Minnesota Medical Solutions has similar delivery forms and their oral products are capsules and solutions in both 47.5 mg CBD or 100 mg per milliliter CBD.  The latter is the same as prescription strength Epidiolex.

The Problem of Antidepressant Discontinuation

Antidepressant discontinuation is a useful topic to discuss for a number of reasons.  First, it is a legitimate problem for a number of people who want to stop the medication and find that they can't for one reason or another.  Secondly, some of the people are unable to stop because they have discontinuation or withdrawal symptoms from the antidepressants and for some people these symptoms are extremely distressing.  In other cases the people trying to stop get recurrent symptoms of anxiety, insomnia, and depression and have to resume the medication.  Thirdly, the solutions to the problem are poorly defined.  In the US, antidepressants are prescription medications and that should mean that they are prescribed for a clear indication and carefully monitored.  Those safeguards are not clearly present any more and even if they are having the indication and carefully monitoring the medication does not guarantee that the patient will not get severe side effects or problems with discontinuation.  On a population wide basis, prescribing antidepressants for only clear cut indications will mean that the minimum number of people are affected and that an antidepressant will be stopped at the earliest sign of problems.  All of the current trends in screening for depression, encouraging treatment by nonspecialists, and limiting the availability of non-pharmacological methods for treating psychiatric and emotional problems suggests that a major cultural change would be required to reverse those trends.    Fourth, because of these problems - the antidepressant issue is an informed consent issue to patients.  In addition to warnings about the usual side effects they also need to hear about the more serious side effects including serotonin syndrome, cardiovascular side effects, possible drug interactions and withdrawal and discontinuation symptoms.  Finally, it is not clear that liberal antidepressant creates more problems than it solves.  The best example I can think of to illustrate this fact is a paper I posted here in the past showing that there was a clear trend in decreased suicide in the elderly with increased antidepressant prescribing across the entire population of Denmark.  On  clinical basis I have had conversations with hundreds of people about stopping antidepressants and the results of many of those conversations is surprising.  Although the main FDA psychiatric indications for antidepressant prescribing are mood disorders, anxiety disorders, and obsessive compulsive disorder - it is common to find people who are taking them for other reasons. Extreme irritability and anger control is one.  Needing to have a "level mood" is another.  Taking antidepressants for menstrual and menopausal mood symptoms that do not meet diagnostic criteria for major mood and anxiety disorders is another. 

The two main considerations for antidepressant discontinuation are whether the person experiences recurrent symptoms of the primary problem or specific discontinuation or withdrawal symptoms or a combination of both. 

A few addition points about antidepressant withdrawal.  The first case in the medical literature was reported for tricyclic antidepressants in 1959 (1) and the first review in 1993 (2).  The symptoms were also described in the first edition of a major psychopharmacology text (2):

"There is no withdrawal problems with the TCAs of the type seen with narcotics, alcohol, or sedatives.  Instead, abrupt discontinuation of 150-300 mg/day or more of a tricyclic, especially after 3 or more months of treatment can induce autonomic rebound (ie, gastrointestinal disturbances, autonomic symptoms, anxiety, agitation, and disrupted sleep)."  p 276.

Gradual taper rather than abrupt discontinuation was recommended.  The issue of rebound from REM suppression and nightmares or intensification of dreaming was also discussed.

For the sake of brevity, I am going to discuss a recent trial of antidepressant discontinuation (4), what is wrong with that trial, and how to improve the state of affairs in the future.  For some reason, I could not find this study indexed by the National Library of Medicine.  Full text is accessible by the DOI number.

This is a study of an attempt to withdraw patients from antidepressants with success in doing that designed as the primary end point - further defined as no antidepressant use in 6 months and no depression or anxiety by a standard rating at 1 year follow up.  The patients were selected from 45 primary care practices across the Netherlands between February 2010 and March 2013.  The algorithm for patients selection in each stage with the resulting numbers are available in diagram form in the body of the paper.  Anyone not meeting criteria for maintenance anti-depressant or anxiolytic treatment were identified as possible candidates for the study.  Appropriate use of antidepressants for depression and anxiety was defined as a history of recurrent depression [≥3 episodes] and/or a recurrent psychiatric disorder with at least two relapses after antidepressant discontinuation.

6442 long-term antidepressant users were identified in these primary care settings.  2411 (37%) were eligible with that determination made by their primary care MD. 358/2411 (15%) consented to participate and 146 were included in this study.

The specific intervention is hard to get at in the description given.  For the intervention group a patient specific letter was sent to the general practitioner with the recommendation to taper the antidepressant. Antidepressant tapering instructions, antidepressant discontinuation symptoms, and the recommendation for slow tapering were all included.  The GP discussed this with the patient and then sent a response to the research team on whether or not the patient would comply with the recommendation.  Reasons for not complying were requested.  For the control group, patients continued their usual care and their GPs were unaware of their participation in the study.  In US studies this would be the treatment as usual group.

34/70 rejected the intervention citing fear of relapse or recurrence as the primary reason.  That is interesting giving the inclusion criteria.  Is it possible that disorder severity or anxiety or depressive subtypes were perceived as more severe by the patient than the recorded primary care diagnosis? None of those patients cited antidepressant discontinuation symptoms as a reason.

Only 4 (6%) patients in the intervention group and 6 (8%) patients in the control group were able to successfully stop antidepressants.  There was a slightly higher relapse rate in the intervention (18/70)   versus the control group (10/76).  No other variables other than duration of antidepressant (5.7 years versus 9.6 years) were significant in who could discontinue the antidepressant and who could not.

In their discussion the authors comment on a higher relapse rate in the intervention group that was not associated with antidepressant discontinuation.  They attribute it to anxiety about wanting to comply with the recommendation but not being motivated to do it.  I think that any anxiety about the recommendation is more likely due to the fact that the recommendation is coming from a source that is not their primary care physician.  Most people in primary care with longstanding relationships with their physicians are there for a reason.  Taking a recommendation in opposition to their GP would be highly problematic for many.  They cite several other reasons among them a poorly done meta-analysis of antidepressant trials suggesting a large placebo effect.  In fact, all of these meta-analyses are significantly flawed based on the included studies.  But more on how to sort that out below.   

I am going to avoid constructing my own antidepressant discontinuation checklist but plan on that in the next several days.  My extensive clinical experience and the literature lead me to the following conclusions:

1.  Expose only the subpopulation who needs antidepressants to them:

This is easier said than done because of the literature on under diagnosis of depression in primary care settings, the literature (and lack of evidence supported guidelines) on screening everyone for depression, the new collaborative care initiative encouraging the use of a checklist to diagnose and treat depression, and the massive bureaucratic interventions to encourage screening and treatment with medication.  Like opioids - primary care physicians were scapegoated for not recognizing and treating depression.  Now both of the primary care professional organizations have their own depression treatment guidelines and these physicians are criticized for overprescribing antidepressants.  Things might go a lot better if the politics was wrung out of medicine.

2.  Recognize that some patients have severe discontinuation effects: 

There is 60 years of literature on this topic, we have all seen it, and it should be a given.  It should be addressed even if there is not perfect research on how to help these people.  I have said it in the past and will say again - I have treated people with severe discontinuation symptoms and helped them stop the medication.  Some syndromes are much more complicated than others - like SSRI withdrawal that has an anticholinergic component.  As I have said in the past - I just don't prescribe some of these medications (paroxetine) and have not in decades.  I would never have prescribed venlafaxine again if they had not invented an extended release version and found it was very useful for people who can't tolerate any SSRIs - but that does not mean that there aren't people out there who don't get severe discontinuation symptoms because of venlafaxine XR.  All of this is an informed consent issue and you can't have that discussion seeing people very 10 minutes and handing them a prescription.

I will say that the majority of people that all psychiatrists treat routinely go on and off antidepressants without problems.  It is so commonplace that many health care companies have systems that send the physician a letter if the patient has not picked up their antidepressant prescription.  That is very common and typically because patients have reservations about starting the medication or how the appointment went.

3.  Study the problem in a realistic setting: 

The study I discussed above was destined to fail. A more realistic study should reflect the clinical reality that every psychiatrist knows.  Instead of an intervention telling people when to stop, the intervention could look at all episodes of antidepressant discontinuation in a health care system.  Various strategies could be used and data on the reason for stopping and any discontinuation symptoms could be gathered in a systematic way.  There are several statistical models that can be applied to multiple episodes across fewer patients.

I would suggest that the intervention not be conducted by the physician who prescribed the original treatment because of the aforementioned conflict of interest.

As in antidepressant trials, the nocebo effect is significant and needs to be studied in discontinuation.  In other words, if a person is told that the antidepressant is being discontinued and they are given the exact same dose of the same antidepressant will they develop symptoms of discontinuation?  Will people being treated with placebo develop discontinuation symptoms?

There is also a lot to be said for an unblinded study of people who are motivated to just get off the antidepressants with a standard protocol. I would not mind conducting that study myself and also adding a component to see, if the success of people who are highly motivated to stop could be predicted.

4.  Despite the evidence-based crowd, the experts need to be heard: 

Like many other psychiatrists, I have seen severe antidepressant discontinuation symptoms, but have been able to get the patient off of the antidepressant.  The idea that there are people who cannot get off these medications and they need evidence to get off the medications is a circular argument.  The evidence is out there, and the experts should write a consensus statement.  That should be the basis for further trials and those trials should employ psychiatrists who know how to do this.  If there are that many people with the problem - it should be easy for any University department to recruit them and study them in detail in the hope that they can successfully get off the medication.

5.  The issue is important in everyday clinical practice:

The best illustration is changing antidepressants.  There are three methods, abrupt discontinuation and starting the new one, gradual taper and start, or taper with cross titration.  The majority of people I see can tell me if they have ever had discontinuation symptoms when they stopped or ran out of the antidepressant that we are changing. That turns out to be a good predictor of who can just stop the antidepressant and start a new one the next day.

That concludes my brief discussion of the problem and what I think can be done about it.  One thing is for sure - political discussions of this issue fail to advance getting the best care to the maximum number of people - whether that is a bitter discussion of how antidepressants are poison and nobody should take them to how they should be casually prescribed as part of a screening process.



George Dawson, MD, DFAPA



References:

1: Mann AM, MacPherson AS. Clinical experience with imipramine (G22355) in the treatment of depression. Can Psychiatr Assoc J. 1959 Jan;4(1):38-47. PubMed PMID: 13629473.

2:  Garner EM, Kelly MW, Thompson DF. Tricyclic antidepressant withdrawal syndrome. Ann Pharmacother. 1993 Sep;27(9):1068-72. Review. PubMed PMID: 8219442.

3:  Philip G. Janicak, John M. Davis, Sheldon H. Preskorn, Frank J. Ayd.  Principles and Practice of Psychopharmacotherapy.  Williams and Wilkens, Baltimore Maryland, 1993.

4:  Eveleigh R, Muskens E, Lucassen P, Verhaak P, Spijker J,  van Weel C,  Voshaar RO, Speckens A.   Withdrawal of unnecessary antidepressant medication: a randomised controlled trial in primary care.  BJGP Open 2018; 1 (4): bjgpopen17X101265.  DOI: 10.3399/bjgpopen17X10126


Supplementary:

Reviews of antidepressant discontinuation syndrome. Link


Polling Question:

I thought I would add a polling question to this post for any physicians out there treating depression.  One of the commonest encounters that I have had due to this blog have been people who claim:

1.  Severe antidepressant discontinuation/withdrawal.
2.  Associated long term conditions with withdrawal.
3.  A complete inability to stop antidepressants.
4.  Extraordinary measures needed to stop antidepressants - like breaking the capsule or grinding up the tablet and reducing the dose by 1 mg amounts.

I don't doubt #1 at all because I have seen it and treated it.  In the case of #2, the only medication I have seen this occur with was beta blockers - metoprolol  specifically.  In that case the patient was taking the medication for blood pressure control and developed severe panic attacks and associated tachycardia and insomnia trying to taper and discontinue the medication.  There was no previous history of anxiety.

I am interested in what physicians have directly observed in these areas.

They Don't Even Know What They Are Seeing.......

I was walking back from a meeting with a psychiatric colleague the other day.  There was the usual grousing about the practice environment and miscommunication and she made the following observation about why physicians and psychiatrists don't get the information they need.  She pointed out that in many cases the nonphysician  observers: "Don't even know what they are seeing."  If you are counting on people for observational data and that is true - that is a setup up for suboptimal care at the minimum and a catastrophe at the worst.

Take the case of a very basic measurement - blood pressure and pulse.  Anyone taking those measurements should be aware of the guidelines and whether or not the patient has a baseline abnormality, condition that can affect either, or medication effect that leads to changes in the vital signs.  They should also be aware of the limitations of measurement.  All of the automatic blood pressure machines in the world will not be able to assess and treat the patient unless the operators know what the numbers mean.  They also need to know that one of the problems with single operator and strictly machine operated approaches is that arrhythmias are problematic even if the blood pressure is fine.  There have been situations where I had to put together a continuing education course on blood pressure and pulse and the correct assessment of both.  That was a long time before the recent article on common mistakes made by medical students in these measurements.

If measurements that are considered routine and done hundreds of times a day are problematic what about observations that occur on the other end of the spectrum.  A common health care myth today is: "If I have a checklist and check off all of the boxes on that list that will lead me to some kind of diagnosis."   That is probably a minimization of the myth.  In the case of psychiatry, the myth is more: "If I convert a standard psychiatric assessment into a form (or a checklist) - the ultimate product of going through that list will basically be a psychiatric evaluation and diagnosis."  Systems of care who use this approach can deny these myths as much as they want but I see this happening every day. Organized psychiatry and the DSM approach to diagnostic criteria is partially responsible, although the manual does say that it can't be used by anybody.  It doesn't say who specifically should use it and it does not suggest (like Kendler) that it is an indexing approach.

Looking at the graphic at the top of the page illustrates why a form or a checklist does not suffice.  The observer/psychiatrist in the drawing is doing more than asking the subject a series of yes or no questions.  The psychiatrist is looking for patterns in symptoms (medical and psychiatric), what is happening in relationships with the person (including the relationship to the psychiatrist), and the person's conscious state - specifically whether there has been a departure from baseline.  There is often a balance between historical detail, phenomenology, the person's ability to describe what has happened and a plausible scenario based on probability estimates from the psychiatrist's previous experience.  Any psychiatrist who has been trained in many presentations of complex psychiatric illness is more likely to see those patterns than somebody who has not been.

To illustrate some of these concepts I will describe several cases that are all what non-psychiatrists (nonphysicians and other physicians) called hysteria. Hysteria is an old word that dies hard.  The DSM equivalent is histrionic personality disorder.  The generic use of the term suggests a person who is overly emotional, dramatic and attention seeking but there are 8 diagnostic criteria that are unchanged between DSM-IV and DSM-5.  Many clinicians opt for the term Cluster B - a DSM-IV originated term that grouped personality disorders in groups according to some common diagnostic features.  The Cluster B group included individuals that often appear dramatic, emotional, or erratic.  Those personality disorder diagnoses include antisocial, histrionic, narcissistic, and borderline.

The rule-in criteria (significant impact on life circumstances and onset when you expect a personality disorder to occur) and the rule-out criteria (not due to another mental or physical disorder) are predictable for any causal reader of a DSM and could be included on any checklist or form.  How does all of that play out?  Well here are a few examples:

Hysterical patient #1:   A 30 year old woman presents for a therapy intake.  She is mumbling and laughing.  The therapist describes her as "odd and having an odd affect."  She alludes to some suicidal behavior in the past but is smiling and joking about it.  The therapist has the impression that she is manipulative and overly dramatic.  He contacts the clinic psychiatrist and says that she is histrionic but he is concerned about her suicide potential.  The psychiatrist sees her that day and makes a diagnosis of bipolar disorder-mixed type with psychotic features.  The patient is eventually stabilized on lithium and an atypical antipsychotic.

Hysterical patient #2:  A 25 year old woman is being treated on a general medicine ward for dehydration from a respiratory infection.  She suddenly gets tearful and agitated.  Family members visiting have to physically restrain her when when she tries to get out of bed.  She starts to make very loud high pitched vocalizations.  A psychiatrist is called to go in to assess hysteria and possibly sedate the patient.  The psychiatrist sees an agitated young woman who is not able to respond coherently to any examination questions.  Brief neurological examination suggests increased intracranial pressure is the problem and the patient requires immediate transfer to a neurological intensive care unit. 

Hysterical patient #3:  A 58 year old man is referred acutely from a therapist for acute panic attacks and "probable Cluster B" personality traits.  He has recently retired due to osteoarthritis of the knees.  He had no earlier history of panic attacks but the therapist thought that he was overly dramatic at the initial session 2 days earlier when he was unable to relax and breathe normally with behavioral techniques that are usually effective.  The psychiatrist gets a history of the patient needing to abort an exercise stress test two weeks earlier due to the arthritis and having  a prolonged period of immobility at home due to sore knees. During that time he developed acute shortness of breath.  The episodes of anxiety that he described were secondary to shortness of breath and not panic attacks.  The psychiatrist sends the patient to the emergency department where an acute pulmonary embolism is diagnosed and he is admitted to the ICU.     

These are just a few examples restricted to one collection of psychiatric symptoms that illustrates what my colleague was referring to.  The value of psychiatric training goes far beyond what is in the DSM and what checklists and templates can be extracted from it.  I have never really met a psychiatrist who was focused on the DSM probably because it is implicitly evident to us that it is an index more than a diagnostic manual. We are focused on what is not in the DSM and as far as I know that is not well documented in many places.  Those are the patterns associated with clinical practice and that should have been gleaned along the way with medical training.  The DSM doesn't tell you how a pulmonary embolism presents. It is possible that you night have never seen one. But in medical training I can guarantee that it was discussed somewhere along the line in the differential diagnosis of dyspnea.  I can guarantee that one of those attendings discussed the phenomenon of the healthy young adult immobilized by air travel who gets off at their destination and suddenly has an acute pulmonary embolism. All of those features and urgencies should be in a physicians conscious state when they are seeing the whole patient and not some DSM/checklist version of a patient.

This brief post also illustrates the biasing effects of language.  What  does "Cluster B" really mean?  Aren't people who are acutely medically (or psychiatrically) ill dramatic, emotional, or erratic?  Hysteria is an extremely biasing term that over the centuries has been applied selectively to women rather than men.   The examples above illustrate that point.  If you are seeing the world through DSM language and that is your only lens - you are by definition not seeing the whole patient.  The list of possible errors in that landscape is very large.

There are a number of constraints that will get  in the way of a trained psychiatrist trying to see the whole patient.  Inadequate time is one, but time frames vary significantly.  Diagnosing a life threatening medical problem upon seeing a patient may take a matter of minutes and is clearly the most important diagnosis.  Seeing a long series of new patients briefly to prescribe treatment will necessarily mean that certain features in the above diagram will be missed.  So-called measurement based care depending on a large number of checklists to "quantitate" affects or other psychiatric states makes the same mistake.  Collaborative care where a psychiatrist looks at these rating scales and recommends treatments makes the same mistake.

The best assurance that the critical aspects of care will not be missed is to be sitting across the room from someone who has been taught all of the critical aspects of care.  That process is complex and as far as I know has never been adequately described.  A first approximation is whether that person knows what they are seeing and how to respond.

George Dawson, MD, DFAPA     

Conscious States and Suicide.....

When I first starting writing this blog - I decided that I was not going to make the common mistake of using celebrity tragedies as a springboard for posts.  I have been very pleased with that decision.  Given recent events - it is evident that people who use that approach are speculating and either don't know enough of the details or make sweeping statements that they could have made without any specific reference to the person or their family.  It is also evident that in some cases, the potential for damage to the survivors is great and should be avoided at all costs.  The only rationale that I hear is they were celebrities and the people want to know.

I will comment on the mystery of suicide.  How is it that a highly accomplished person with ample resources and even supportive people and family in their life can make a decision to take their life?  The press has settled on a couple of unsatisfactory answers that flow from the risk analysis approach to suicide.  In other words, let's look at number of modifiable and unmodifiable correlates of suicide attempts and use those in an analysis of a specific death by suicide.  After the fact it is basically a fishing expedition trying to fit the pieces together in a way that there is a logical and linear story about how the incident unfolded.  If the person is famous enough there may not be a final judgment until the autopsy toxicology comes in many weeks later.  Even if a coherent story is constructed, the story may be debated for years on cable TV shows that have medical experts second guessing real time experts.

Serious and intractable disorders and impulsivity is a big part of the current media story.  I had somebody ask me today: "Is it true that people just make the decision and in 5 minutes they are dead?"  People tell me stories about Golden Gate Bridge jumpers who survived to tell about it and that is what they reported.  All of the stories are very linear - there is a precipitant and then depression with depressed moods and then an impulsive suicide attempt. 

Psychiatrists are trained to recognize and treat all of the major disorders that are thought to increase risk for suicide including substance use disorders.  We are also trained to be optimistic about the treatment and consider these diagnoses to be modifiable - if they are treated correctly they will respond to treatment and improve thereby reducing risk for suicide.  Overall psychiatrists are successful in that approach as evidenced by reduced suicidal thinking and in some cases behavior that is directly observable in hospital units.  Self report by patients is another valuable metric that is rarely talked about.  Patients can at some point say: "I seriously contemplating suicide and had a plan to kill myself until I came here for treatment." or "During my last pregnancy - at one point I was going to kill myself.  I don't want that to happen again.  I want to have a plan this time to prevent that from happening."

From an epidemiological standpoint, psychiatrists in general treat people who are at much higher risk than the general population for suicide.  The CDC, just came out with data to show that the suicide rate in the USA from 2014 was 13 per 100,000.  Many of the disorders treated by psychiatrists have lifetime suicide rates of 10-15%.  In a cohort of 100 people with the disorder, 10-15 are expected to die by suicide over the course of their lifetime.  Suicides by people in active treatment by psychiatrists is rare relative to those numbers but they do happen.  They are more likely to happen during transitions between care settings like hospital discharges or when care is fragmented. They are more likely to happen when there are destabilizing factors in the person environment and easy access to highly lethal methods of suicide - like firearms.

Even in the case where a person has survived a potentially lethal suicide attempt it may be difficult to piece together what has happened.  Consider the following case.  John M. is interviewed in his hospital bed by a consult psychiatrist.  Three days earlier he shot himself through the left shoulder with a handgun and barely survived.  He has extensive damage to the structure of his left shoulder and it will be a while before his surgeons can advise him on whether to not it can be reconstructed.  It is clear that he has been depressed and somewhat paranoid for years.  The psychiatrist asks him about the injury.

JM:  "I guess I shot myself?"
PSY: "Can you tell me about the sequence of events?"
JM:  "Well - I was feeling very depressed.  I thought about calling my parents but they have done too much for me already.  I started to think that I was not worthy of their help anymore.  I feel worthless and like a burden to my family.  I knew they would miss me - but at some point you realize sure they will feel bad for awhile, but they will get over it in a while and the burden will be lifted.  At that point I thought I would get out my .44 and shoot myself in the chest..."
PSY: "Tell me exactly what you were thinking.."
JM:  "Like I said I felt hopeless and like I was a burden. At some point I realized that I was pointing the gun at myself.  I knew I did not want to shoot myself. I have a nephew and I wanted to see him again. And then the gun just went off.."
PSY: "The gun went off?  Don't you remember pulling the trigger? Were you holding the gun in your right hand or your left hand?"
JM:  "I am right handed.  I was holding it in my right hand and pointing it at the center of my chest."
PSY: "Do you remember what you thought when you pulled the trigger?"
JM:  "I don't remember pulling the trigger.... One minute I see my hand and wrist and the gun barrel and then it goes off and I am on the floor bleeding."

Further discussion of the incident does not provide any further degree of clarity.  The psychiatrist has to come up with a diagnosis and a formulation as well as a risk assessment of future suicide potential.  There are several diagnostic possibilities including mood disorders with or without psychotic features including substance induced mood disorders.  Alcohol, stimulants, and opioids can all  cause acute suicidal thinking during intoxication and withdrawal states.  The suicide assessment is basically a collection of risk factors that at the time of this interview may not be entirely relevant.  For example, the patient in this case did not have any suicidal thinking at all and was pleased that he had survived at the time of this interview.  Irrespective of all of those considerations there may be some psychiatrists who would be comfortable discharging the patient at that point.  I am not one of them. In this case I would opt for a more detailed assessment and period of observation and an attempt to restore the person to his baseline level of functioning.

In acute care psychiatry, we talk a lot about baseline and cannot always achieve it.  People my not be aware of the fact that they are not at baseline, insist they are fine, and want to go home even if they are at high risk.  People may not want to access help in the first place for the same reason.  We can only assess baseline very indirectly.  The best current way is an extended conversation with a person who knows them very well.  Is their social behavior and personality the way it should be? How do they differ from that.

This baseline that we refer to and assess only peripherally is critically important when it comes to suicide risk.  We are actually referring to the person's conscious state.  There are no ways to assess baseline conscious states.  All of our energy has been focused on extreme psychopathological states and the handful of criteria that are used to define them.  By way of contrasts the human brain is designed to generate billions of unique conscious states - no two are ever alike because these billions of states have all had unique life experience to think about.  There is no universal agreement -even among researchers about how to define conscious states - but discussing the contents of consciousness is a fairly universal approach. I typically ask students to imagine their own stream of consciousness and why it night be unique. But that is only part of what defines a unique conscious state.  Subjective experience is another.  Unique subjective experience is diametrically opposed to the usual methods in psychiatry of trying to index disorders based on a handful of common features.  A person's unique experience is much less likely to be recorded anywhere in today's era of rationed psychiatric care and poor documentation.  Conscious states are also subject to perturbations that are transient  based on internal and external conditions.  In the case of suicidal thoughts, in my thousands of interviews of people the most common reply I get is: "Yeah - I have had a few suicidal thoughts -hasn't everybody?"

In this era of inability to assess and essentially predict a person's conscious state it should not be surprising that we have only the most basic knowledge about the assessment and treatment of suicide potential.  We are generally using a very crude risk assessment and many of the variables may be unchanged for years.  It is not like an actuarial assessment for insurance purposes where the outcomes and statistics are not that dynamic.  In the case of suicide assessment, we don't know all of the variables, the number of variables is large, and we may not even know the person's baseline conscious state unless we have known them for years.  To further complicate matters - they may not be able to tell us about their baseline state until they have recovered it and recognize that they have changed.  The change we are interested in is going from a state that would never consider suicide to one that would.

 The media storm around recent events, will seem to provide a number of pat answers based on society, culture, pop psychology, and special interests.  They seem to ignore the fact that in any given society, these rates rise and fall.  The current rate was the same in 1950 and 1970.  Moreover American society is intermediate relative to the rest of the world when it comes to suicide rates. Some countries with more psychiatrists per capita have higher suicide rates.

On an individual level, suicidal thinking especially if it is combined with of other psychiatric  symptoms is a red flag.  It suggests that a person should try to obtain professional help.  There is no easy way to discuss the consciousness issue on more than a fragmentary basis at this point.  I do try to discuss it with people as a risk factor, but if they are in an altered state they may not be able to hear what I have to say.  The current practical approach is to listen carefully to people who know that person well and have their best interest in mind. 

A reasonable pathway to assessment and treatment is paying attention to any changes that a concerned third party may have noticed and if that person with the problem can't see it - get a neutral third party professional involved and give them all of the information.



George Dawson, MD, DFAPA 

The New York Times - Steers Mental Health Conversation In the Wrong Direction

An editorial came out today in the New York Times entitled The Crazy Talk About Bringing Back Asylums.  They took a line from President Trump that the Parkland shootings could have prevented if there were more psychiatric beds.  I am  sure was intended to temper any anti-gun sentiment rather than suggest the need for reform of mental health services, but the editorial suggests that this triggered a new debate about the need for asylum beds and looks at (on the negative side) a caricatured extreme view of increased bed capacity.  This political approach to mental health care is exactly what is wrong with policy for the past three decades.

The first mistake in the article is the following sentence:

"Psychiatric facilities are unlikely to prevent crimes similar to the Parkland shooting because people are typically not committed until after a serious incident."

Any acute care psychiatrist can attest to the fact that this is incorrect.  A considerable amount of mayhem, violence and aggression is prevented by the availability of both acute care inpatient beds and psychiatrists treating potentially aggressive people in both inpatient and outpatient settings.  There are no controlled studies of the problem because they would be unethical.  You can't randomly assign homicidal or suicidal people to placebo treatments.  They all have to be actively treated.  At times courts release people who have threatened suicide, violence or homicide without treatment for the associated mental illness and they go on to complete exactly what they said they were going to do.  At other times patients will say that they are very satisfied that they were treated because they recognized they were irrational and about to commit an irreversible act.  The clearest example is the person who is aggressive form the time of admission and the aggression does not abate until they have been actively treated for several days.  People are committed on the basis of all of these scenarios and before serious incidents occur.

Instead of Bring back the asylums they thought they would attempt other slogans to "steer the conversation" presumably about improving the care of mental illnesses in the United States.

1. Demand sensible commitment standards:  

There are essentially just three commitment standards:  dangerousness to self (or suicide potential), dangerousness to others (or aggression and in some cases homicide potential), and grave disability (or an inability to care for oneself).  What could be more sensible?  The problem is that the law is subjective and there is always a way around sensibility.  That workaround could involve a highly aggressive defense attorney with a goal to get the patient "off" rather than worry about any consequences. It could involve a number of administrative issues like the cost of civil commitment (obviously cheaper to not try) or an arbitrary decision by a hospital or court administrator that there are just "too many commitments" and it is time to roll them back- at least until the next adverse outcome.  Another common way around commitment is just to ignore the grave disability standard and in effect say commitment will occur only for dangerousness. If someone really wants to split hairs - the dangerousness has to be "imminent" and it can always be not imminent enough.  For commitment standards to have any meaning at all - they have to be implemented by sensible people.  We need to demand sensible people. More importantly there needs to be accountability and available data from commitment courts on outcomes.

The other part of the problem is that psychiatric beds are so rationed that in order to get into one - managed care organizations say that you need to be dangerous in order to get admitted.  That creates a false burden on court systems who may not be sensible about commitment in the first place.  In the context of this demand they are even less sensible.     

2.  Create a continuum of care:

The NYTimes takes a historical approach going back to the Kennedy era and the deinstitutionalization argument.  First of all there are places that have a continuum of care. The community psychiatry movement was highly successful in following people outside of state hospitals and supporting them in independent living.  Some cities like Madison, WI have a large community mental health center as well as several assertive community treatment (ACT) teams that follow people with serious mental illnesses.

The reason why there is no followup similar to medical and surgical patients with significant disabilities is several fold.  Rationing by the insurance industry and federal and state governments is the primary cause.  It is easy to save money by denying equivalent care to the mentally ill and people with severe addictions.  Over time this has led to separate acute care services in some community hospitals and long term care facilities that are typically run by the state. The large majority of hospitals in most states do not provide acute psychiatric care.  Both acute care and state systems are rationed to provide as little care as possible. It is currently in the financial interest of every managed care and insurance company in the country to maintain this fragmented system of care because it saves them all money.  In the meantime disproportionate amounts of money and resources are funneled to very other type of specialty care.

At the state level, the bed situation is so dire or nonexistent in state hospitals that it should be very clear that they have adopted the managed care rationing plan to eliminate care for the mentally ill.  That is the reason that jails are the defacto psychiatric hospitals at this time.  There is of course no standard for psychiatric care in jails and most people tell me they do not get their prescribed medications.  This is also the reason why asylum care does not work.  Asylums were basically buildings that were poorly managed by the state.

3. Stand up for insurance parity:  

Parity is a joke.  Insurance industry rationing and micromanagement of mental health treatment has continued unabated since the passage of the  Mental Health Parity and Addiction Equity Act.  After watching professional organizations and  mental health advocacy organizations patting themselves on the back after this legislation was passed - it has been more than a little depressing for psychiatrists on the front lines to watch as the denials of care are unchanged from before the bill.  Those organizations have been standing up for parity and against stigma for about 20 years with no results.

It is difficult to get parity when most states have an insurance industry friendly complaint system and the physicians who want to complain are either employees of a managed care company or limited by confidentiality laws.  Standing up for parity is meaningless symbolism at this point. It doesn't require a complicated HHS investigation.  What is needed is a review panel in every state - staffed by psychiatrists who have no financial conflicts with the insurance companies being complained about.  The precedent for those review panels was the Peer Review Organization (PRO) panels that were set up to review all Medicare financed care in the 1980s and 1990s. There is no reason why those reviews should occur today.  The only really effective alternative has been an activist attorney general ordering some of these companies to correct egregious denials of care.  Activist attorney generals do not occur frequently enough to make a sustained difference.

The larger problem is the way that healthcare is funded in the USA. I will add an illustrative post later in the week, but the percentage of the health care dollar dedicated to the treatment of mental illness is at an all time low.  The Hay Report of the 1990s documented the disproportionate drop in health care funding and it seems that governments and insurance companies expect it to stay at that level.

The NYTimes says that all it will take is a "collective will and a decency to act".  Are they serious?  Isn't that all it will take to end mass shootings in public schools?  This is just another naive approach to public policy written by people with no expertise who are ignoring the political landscape.  It is fashionable to call those people stakeholders these days.

As usual the real stakeholders - people with mental illness, their families, and psychiatrists are left out.  The suggested slogans are as problematic as the one about bringing back asylums that the NYTimes was concerned about.


George Dawson, MD, DFAPA



Supplementary:

For detailed information about this problem go to the pinned Tweet at the top of this feed and all of the links.


References:

1.  The New York Times Editorial Board.  The Crazy Talk About Bringing Back Asylums.  New York Times June 2, 2018.


Graphics:

Kodachrome slide shot by me in 1982 of Milwaukee County Hospital.  Not an asylum but it looked like one.

           

       

The Victim Meme In Addiction and Recovery

The popular press has created a victim meme in discussing addiction and the recovery process.  An example would be the popular quote from the NYTimes: "Only in death do drug users become victims. Until then, they are criminals".  I have problems with these quotes that have become memes in social media because the idea that people with substance use disorders are victims does not seem to originate in either the medical field and the physicians who treat them or the recovery literature written by the affected people themselves.  The other operative word in this quote is "users".  To me that means that nobody here is forced to initiate drug use or assaulted and forcibly given addictive drugs.

My first year as a psychiatry resident, I can recall a fellow resident presenting a patient to the senior attending.  He used the term unfortunate to describe the patient, a homeless middle aged man with a chronic psychosis and alcoholism.  The attending cut him off and said "What do you mean by unfortunate?"  In the next ten minutes or so, we learned that the patient was no more unfortunate than any of the other 20 men with severe psychiatric disorders on that unit. By extension the term was essentially meaningless, because it did not discriminate that person from any one else and it was irrelevant to the diagnosis and treatment planning. Years later, I learned it could also be an impediment to the treatment relationship.  A ban on smoking rapidly went into effect and the staff were split on what that meant. Many believed that it would result in more violence and aggression. Part of the ensuing rhetoric was "That is all that these unfortunate people have.  If we take smoking away from them - what's left?"  A very dim view of a person's life is required to see it as existence for the sake of smoking.  I would go so far to say it is blatantly dehumanizing.

The idea of patient as victims occurred again in psychiatry during the satanic ritualistic abuse phase and more recently during the patients are all victims of childhood abuse phase.  In the former case it lead to a proliferation of multiple personality disorder diagnoses and encouraging the proliferation of this myth with the associated unnecessary treatment.  In the case of treating everyone like a victim,  that program was correlated with an increase in aggression and staff assaults in state hospital settings and an eventual abandonment of the program.  Somewhere along the way, the application of a broad implementation of treatment based on whether or not a person is a victim is problematic from a programmatic standpoint, as well as the individual treatment relationship.

In terms of the individual evaluation, being victimized is a part of the clinical history.  Like grief, practically everyone has a history of some type of physical, emotional, verbal, or sexual abuse in the past.  The psychiatrists job is determining if it is relevant to the current problem and how it has impacted the patient's long term conscious state on an ongoing basis.  At a practical level it has resulted in an  ICD-11 diagnostic criteria set that identifies fewer patients as having PTSD compared with DSM-5.  From the linked reference it appears that there will be concern over identification of PTSD as well as under identification.  It is a more difficult task than just matching clinical criteria.  In many cases, PTSD symptoms recur in the context of depressive episodes and significant episodes of anxiety and resolve again when those episodes are treated.  In acute situations like intimate partner violence, advocates can provide a valuable function until a patient's living situation has been stabilized.  If victimization is a relevant clinical theme, it is addressed by addressing the associated syndromes and psychotherapy that is focused on maintaining safety, alleviating symptoms, and facilitating relevant lifestyle changes.           

Apart from victims the concept of the criminalization of the drug user is also a popular meme.  Simplified it is that drug users and alcoholics should be treated and not incarcerated.  It is based on the assumption that most of these folks are incarcerated on trivial drug or alcohol charges or probation violations from those trivial charges.  That can certainly happen.  Unfortunately real crimes involving loss of life, serious injury, and property crimes also happen.  I recently heard a District Attorney talk about the scope of the problem at the Minnesota Society of Addiction Medicine May 30 meeting.  He was keenly aware of the problem because law enforcement resources are currently flooded with opioid and methamphetamine users as well as people with severe mental illnesses.  He presented the problem to his prosecuting attorney and asked them to come up with a solution for people being prosecuted for drug crimes.   They ended up with a three step plan for sentencing offenders to maximize the likelihood of treatment and the ability to change felony crimes to misdemeanors after adjudication. The main message was that there is no interest on the part of prosecutors to incarcerate drug offenders, but there is clearly a limit with the associated crimes.

In the recovery literature, victim is rarely seen.  The Narcotics Anonymous book uses it in one place in the Eighth Step:  "Many of us have difficulty admitting that we caused harm for others, because we thought that we were victims of our addiction.  Avoiding this rationalization is crucial to the Eighth Step"  (p 38).  The AA 12 and 12 (2) contains the words victim in Steps 1, 3, 4, 10 and 12.  The term is used to make the general argument for powerlessness (Step 1), to discuss the effects of remorse and guilt (Step 3), to discuss the effects of erratic emotions (Step 4),  to illustrate the problem with resentments (Step 10), and how the program can free members from irrational fears (Step 12).  The bedrock of 12-step recovery is powerlessness and that is not the same thing as being a victim even though that word is used in Step 1. 

I don't think that I am going too far out on a limb in suggesting that the victim meme is not relevant in addiction, addiction psychiatry, or recovery. The importance of powerlessness as opposed to being a victim is captured from reference 2:

"Our admissions of personal powerlessness finally turn out to be the firm bedrock upon which happy and purposeful lives can be built."  (p. 21).


George Dawson, MD, DFAPA


Supplementary:

For other variations on the victim meme see these previous posts:


The Whitening of the Opioid Epidemic:

https://real-psychiatry.blogspot.com/2018/05/the-whitening-of-opioid-epidemic.html

Addiction Narratives Versus Reality:
https://real-psychiatry.blogspot.com/2018/05/addiction-narratives-versus-reality.html



References:

1.  Narcotics Anonymous (6th Edition).  World Service Office.  California, USA 2008, p 38.

2.  12 Steps and 12 Traditions.  AA World Services, Inc.  New York City 2007.

Synthetic Cannabinoids and Life Threatening Coagulopathy

Just when I thought that renal failure was the only unexpected complication of synthetic cannabinoids - it turns out they can also cause bleeding or more specifically Vitamin K dependent antagonist coagulopathy.   The basic mechanism of action is noted in the above diagram on the action of warfarin on Vitamin K dependent mechanisms that can lead to an anticoagulated state.  Warfarin and similar Vitamin K antagonists block the function of the vitamin K epoxide reductase complex.  That blocks the recycling of Vitamin K epoxide and eventual depletion of Vitamin K.  That is turn leads to no gamma carboxylation of Vitamin K dependent coagulation factors (depicted here as descarboxy prothrombin being converted to prothrombin (Factor II), but factors VII, IX, and X are also involved).  

The anticoagulated state can be used therapeutically to prevent embolic strokes or recurrent pulmonary emboli, but warfarin has a very narrow therapeutic index and it needs to be monitored closely in patients who are also watching their diet and drug interactions to prevent excessive anticoagulation and bleeding that can be fatal. The warfarin effect can be reversed by Vitamin K administration.

The CDC issued an outbreak alert last month about an outbreak that occurred in the midwest - largely Illinois about unexplained bleeding.  The time frame where this was noted was the previous year.  People were presenting to emergency departments with unexplained bleeding ( no exposure to anticoagulants or anticoagulant containing rat poison and no medical explanation for the bleeding).  In their Clinical Action Alert they explain the symptoms of coagulopathy including bleeding from the gums, nose, gastrointestinal tract, genitourinary tract, excessive bruising, unexplained abdominal of flank pain, mental status change, feeling faint, and collapse.  There were a total of two fatalities at the time of the alert and medical evaluation and treatment with Vitamin K and fresh frozen plasma suggested that the toxicity was due to brodifacoum a long acting Vitamin K antagonist found in rat poison.

Ninety four people were involved through April 5, 2018.  Since that time the Illinois web site following this outbreak reports 164 cases including 4 deaths since March 2018.  They name a few of the brands commonly sold including K2, Spice, Black Mamba, Bombay Blue, Genie, and Zohai but emphasize that there are a large number of these compounds as listed in a previous post on this blog.  As previously noted, synthetic cannabinoids are basically highly concentrated organic chemical that are sprayed in plant material to facilitate smoking.  When I checked the medical literature to see if these cases were written up and specific biochemical analyses done - I found the only reference brodifacoum was a study done (1) that looked at the results of applications to areas around marijuana growing operations.  Anticoagulant based rodenticides are apparently used to prevent damage to the crop and are described as being used extensively.  This study looked at marijuana growers on California and the relationship to wildlife species.  In this case a threatened species the northern spotted owl was necropsied and it was demonstrated that the liver and blood contained high concentrations of brodifacoum.  The authors point out a basic ecological principle that if the target of the rodenticide is rodent - it will be concentrated to higher levels in the predators higher in the food chain.  The alarming situation here is the fact that dead wildlife from rodenticide poisoning have been found around 22% of 41 marijuana growers in 3 California counties.

The message from the CDC and the Illinois Department of Public Health (IDPH) was clear.  Be aware of the problem, recognize coaglopathies, and be prepared to intervene.  The IDPH advises consumers to watch for bleeding and bruising if they have used these compounds and if it occurs to seek emergency assistance.  The CDC discusses the high cost of Vitamin K therapy and possible shortages, the need to warn post op patients not to use these compounds, and concern that some of the affected patients may be plasma donors.

Addiction docs and acute care psychiatrists need to have a higher index of suspicion, especially in settings where people are admitted rapidly for detoxification and stabilization and if the patient gives a history of synthetic cannabinoid use.  The commonest current coagulopathy in those settings is probably alcohol related and that is relatively rare.

Additional concerns would include the possibilities that the rodenticide could be sprayed on some cannabis plants and be ingested or smoked by people who believe they are using cannabis.  An associated concern is that the contaminated synthetic material was considered plant waste from cannabis products and just used as a carrier for the synthetic cannabinoids.  That is a potential reason why the synthetics were contaminated with brodifacoum in the first place.

As far as I know there have been no reports of the problem in cannabis smokers who were not using synthetic cannabinoids.

The authors of reference 1 point out that since cannabis is not regulated as an agricultural product there are no regulations about what can be applied to it when it is grown.  It seems like another disadvantage of a laissez-faire approach to drug regulation.

Coagulopathy is just another in a long list of reasons to stay away from synthetic cannabinoids and to beware of other toxic effects from street drugs.  There has always been some concern over what chemicals and biologicals end up in smoked or ingested cannabis. Rodenticide should be added to that list until it is effectively ruled out by sampling and testing of the products being sold.




George Dawson, MD, DFAPA


References:

1:  Franklin AB, Carlson PC, Rex A, Rockweit JT, Garza D, Culhane E, Volker SF,Dusek RJ, Shearn-Bochsler VI, Gabriel MW, Horak KE. Grass is not always greener: rodenticide exposure of a threatened species near marijuana growing operations. BMC Res Notes. 2018 Feb 2;11(1):94. doi: 10.1186/s13104-018-3206-z. PubMed PMID: 29391058;

2: Brodifacoum on ToxNet.

Brodifacoum

3: Minnesota Department of Health.  Health Advisory: Significant Bleeding Associated with Contaminated Synthetic Cannabinoids. April 5, 2018.

4:  Minnesota Department of Health.  Health Advisory Network.  See additional links.  





Graphics:


1:   Mechanism of warfarin slide at the top is from Visiscience slides online per their user agreement.

2:  Brodifacoum chemical structure from PubChem.