Incident Atrial Fibrillation and Intoxicants

I remain very interested in the cardiac and brain complications of medications and substances that are commonly used to get high or create altered states.  I am also very interested in the popular trend to characterize cannabis as some previously undiscovered medication that can cure everything ranging from anxiety to obstructive sleep apnea.  I was naturally interested when I saw this paper (1) looking at the issue of incident atrial fibrillation and common intoxicants.

The authors examine a very large database in California that included anyone who had been seen in an emergency department, ambulatory surgery center, or hospital over a period of 10 years (2005-2015).  After they eliminate minors, subjects with persistent atrial fibrillation, and subjects with missing data they had a total of 23,561,884 people. 998,747 of those people had incident atrial fibrillation (defined as the first encounter for atrial fibrillation).  Since their study design is a retrospective observational study they also recorded substance use was considered present if Substance use was considered present if there was coding for any indication of use of methamphetamine, cocaine, opiates, or cannabis.  Knowing the atrial fibrillation and substance use diagnoses – the authors calculate the hazard ratio for each of the substances of interest.

Hazard ratios are basically the ratio of the people exposed to intoxicants who developed atrial fibrillation over the unexposed who developed atrial fibrillation.  So any number greater than 1 means that the population exposed to intoxicants had greater risk.  The corrected hazard ratios were noted to be 1.86 (methamphetamine), 1.74 (opioids), 1.61 (cocaine), and 1.35 cannabis. The authors adjusted for common atrial fibrillation risk factors and ran an additional negative control analysis and looked at the scatter of data pints for these 4 substances and hazard ratios of developing appendicitis, connective and soft tissue sarcoma, and renal cell carcinoma and showed no consistent pattern for these illnesses.

There are a couple of interesting considerations relevant to this study.  The first is the mechanism of action in each case. With stimulants there is a direct hyperadrenergic effects and depending on the individual and dose of the drug varying degrees of tachycardia, palpitations, and hypertension.  Long term users frequently end up with cardiomyopathy from these effects and in some cases ventricular arrhythmias and congestive heart failure. There can also be acute vascular effects like ischemia either due to the increased cardiac demand or pre-existing arteriosclerosis. Atrial fibrillation has not typically been placed in that group of morbidities from stimulant use. Patient with atrial fibrillation often notice emotional precipitants for discrete episodes or atrial fibrillation although a recent study showed that the only reliable precipitant was alcohol use (2). There were significant limitations with that study with attrition and length of the study although I generally agree that alcohol is a clear participant.  Precipitants need to be carefully approached and I suspect that attentive physicians have noted variable phenomenology on an individual basis. 

The high hazard ratio for opioids is a little puzzling. Hyperadrenergic states can occur with the euphorigenic effects and withdrawal effects as well. Direct comparison with stimulants may be difficult due to rapid dose escalation and some degree of tachyphylaxis.  Cannabis is not surprising to me at all. Many initial cannabis smokers notice that their heart is pounding and don’t know why.  They find it unexpected given the conventional wisdom that cannabis is supposed to be a benign substance. Many initial users also get increased anxiety and, in some cases, have a panic attack that may be due to the cardiac sensations. The primary heart pounding sensation is because cannabis causes hypotension and they are experiencing reflex tachycardia. The effects may be less predictable because cannabis use can affect both sympathetic and parasympathetic pathways that can potentiate arrhythmias. A case report of cannabis induced atrial flutter (3) was described as occurring in a woman with a history of hypertension that eventually had to be terminated by an intravenous antiarrhythmic.   

Atrial fibrillation and other cardiac arrhythmias are another good reason for avoiding intoxicants including alcohol (in the supplementary analysis alcohol had a Hazard Ratio of 2.37).  It could be argued that it is basically a numbers game – since most people who use these intoxicants do not develop incident atrial fibrillation.  As of this moment, even if you have had your DNA analyzed for what are known about atrial fibrillation genes – you can’t be certain that you are not susceptible to the problem. And as outlined above there are many additional cardiac problems and that are possible from using these compounds.  The safest path is to avoid these intoxicants all together.

 

George Dawson, MD, DFAPA

 

 

References:

1:  Lin AL, Nah G, Tang JJ, Vittinghoff E, Dewland TA, Marcus GM. Cannabis, cocaine, methamphetamine, and opiates increase the risk of incident atrial fibrillation. Eur Heart J. 2022 Oct 18:ehac558. doi: 10.1093/eurheartj/ehac558. Epub ahead of print. PMID: 36257330.

2: Marcus GM, Modrow MF, Schmid CH, Sigona K, Nah G, Yang J, Chu TC, Joyce S, Gettabecha S, Ogomori K, Yang V, Butcher X, Hills MT, McCall D, Sciarappa K, Sim I, Pletcher MJ, Olgin JE. Individualized Studies of Triggers of Paroxysmal Atrial Fibrillation: The I-STOP-AFib Randomized Clinical Trial. JAMA Cardiol. 2022 Feb 1;7(2):167-174. doi: 10.1001/jamacardio.2021.5010. PMID: 34775507; PMCID: PMC8591553.

3: Fisher BA, Ghuran A, Vadamalai V, Antonios TF. Cardiovascular complications induced by cannabis smoking: a case report and review of the literature. Emerg Med J. 2005 Sep;22(9):679-80. doi: 10.1136/emj.2004.014969. PMID: 16113206; PMCID: PMC1726916. [full text] 

A Second Look At Recreational Cannabis - Already?

I don't know how many other people are weary of the onslaught of pro-cannabis propaganda over the past two decades.  The goal was clear to me at the outset - legalize marijuana.  I have previously posted that I think there will be legalized marijuana in every state in the United States.  I have also posted that "medical" marijuana or cannabis is basically a front for the legalize recreational marijuana movement.  I am very weary of all of the arguments about how cannabis is a miracle drug, how it will lead to stunning new discoveries, how it will lead to less opioid use and misuse, and all of the permutations of these pseudoscientific arguments.  Many of the legal arguments are just straight off-the-wall.  Those include put all the cannabis dealing cartels out of business, create jobs, and tax it as a great source of tax revenue.  The considerable downsides of adding another intoxicant to the culture seems to be mentioned only by a few psychiatrists who are familiar with a great many of the downsides from treating patients who have been using it for a lot longer than the legalization arguments have been in vogue.

A few of those problems became more evident last week. Colorado Governor John Hickenlooper came on CNN and discussed several correlates of cannabis legalization in Colorado.  Property crimes and violent crimes are up.  The number of homeless in Denver is up and some believe this is a correlate of increased crime.  The number of lethal motor vehicle accidents involving cannabis are up.  He did not mention health care related phenomena including a doubling of cannabis related hospital billing codes, a five-fold increase in cannabis related mental health codes, and an 80% increase in cannabis related calls to poison control centers (3).  Unintentional pediatric exposure to cannabis was also observed (4) to increase.  None of the costs of this medical care has been calculated as an offset of the tax revenue from the cannabis.  Gov. Hickenlooper made the point that recent tax revenues were about $200 million relative to a state budget of $30 billion and about 1/3 of that revenue goes for associated law enforcement and educational activities.  He advised against any state making the decision to legalize cannabis based on a tax revenue argument (5).  The articles in the popular press seem to emphasize the need for flexibility with the great social experiment of recreational cannabis and the Governor seems all for that up to a point.  That point is if it is apparent that the social costs in terms of crime and motor vehicle accidents is really up. At that point he suggests that the current cannabis laws can be reversed. 

Rather than get caught up the old causation versus correlation argument, I can say unequivocally that it is naive to assume that the legalization of another intoxicant would not lead to more problems.  The suggestion that problems would be less and that society will be improved overall by the use of more intoxicants can only be seen as a blatant political ploy.  There will be more accidents, more acute toxicity, and more psychiatric morbidity due to cannabis.  I don't know if Colorado is adding up those costs and trying to compare them to any advantages of legalized cannabis, but I would not be surprised at all if Colorado taxpayers don't incur more liability from cannabis than revenue.

Before any cannabis promoters attempt to teach me about the costs of alcohol - read this blog.  There is more posted here on the costs of alcohol than you will find in most places.  My point is not that alcohol doesn't cost more.  My point is fairly obvious and that is every time you add an intoxicant to society it costs you something.  It is not free or a net benefit.   Once cannabis is legal in all 50 states it will be easier to estimate the total damage.

The other article that came out last week had to do with the 420 holiday and a very interesting plot by Staples and Redelmeirer (see Figure 1).  In this essay the authors look at the 420 holiday which is a celebration of cannabis.  The celebrants gather for mass consumption of cannabis. They studied 25 years of fatal crash data between the hours of 4:20PM and 11:59PM on April 20 and compared the crashes at that time to crashed on control days (April 13 and April 27 during the same time interval).  The Forest Plot below shows the findings across a number of comparisons.

The risk of fatal crashes was higher on 420 and significantly higher for younger drivers. On geographic analysis absolute risk of a fatal crash was highest in New York, Texas, and Georgia.  Relative risk (see original article) was decreased only in Minnesota.  The authors comment that even though the majority of the population does not celebrate 420 (or even know that it exists) the traffic accident risk is similar to what is seen on Super Bowl Sunday and policy makers might want to take this into consideration.  So might anyone interested in the drunken driving issue.  Is it possible that cannabis intoxicated drivers as a population are more impaired than alcohol intoxicated drivers?

Those are the considerations from last week.  I am sure that more will occur as the United States legalizes cannabis in very state and as it becomes a legitimate industry.  An issue flagged by the CDC several years ago was the use of synthetic cannabinoids in order to avoid occupation related drug screens, but their initial data was from a time before cannabis was legalized in Colorado.  And once again this post is not an argument for or against legalization.  I hope that I have been quite explicit in saying that I anticipate widespread legalization of cannabis.

This post and most of the posts on this blog are to document the expected fall out from increasing the amount of intoxicants consumed by the population. It is neither benign or beneficial as suggested by the advocates.   


George Dawson, MD, DFAPA



References:

1: Staples JA, Redelmeier DA. The April 20 Cannabis Celebration and Fatal Traffic Crashes in the United States. JAMA Intern Med. 2018 Apr 1;178(4):569-572. doi: 10.1001/jamainternmed.2017.8298. PubMed PMID: 29435568; PubMed Central PMCID: PMC5876802.

2: Colorado Attorney General Announces Indictment of Massive Illegal Marijuana Trafficking Conspiracy. June 28, 2017.

3: Wang GS, Hall K, Vigil D, Banerji S, Monte A, VanDyke M. Marijuana and acutehealth care contacts in Colorado. Prev Med. 2017 Nov;104:24-30. doi: 10.1016/j.ypmed.2017.03.022. Epub 2017 Mar 30. PubMed PMID: 28365373; PubMed Central PMCID: PMC5623152.

4: Wang GS, Le Lait MC, Deakyne SJ, Bronstein AC, Bajaj L, Roosevelt G.Unintentional Pediatric Exposures to Marijuana in Colorado, 2009-2015. JAMA Pediatr. 2016 Sep 6;170(9):e160971. doi: 10.1001/jamapediatrics.2016.0971. Epub 2016 Sep 6. PubMed PMID: 27454910.

5: All Things Considered.  Colorado Gov. On How Federal Marijuana Decision Could Affect State.  January 4, 2018.



Graphics Credit:

1.  Photo at the top is a commercial cannabis grower from Shutterstock per their standard licensing agreement.

2.  Figure 1 above is reproduced with permission from [JAMA Intern Med. 2017. 178(4):569-572. doi: 10.1001/jamainternmed.2017.8298. Copyright©(2017) American Medical Association. All rights reserved." from reference number 1. License number 4335700705440.

American Academy of Sleep Medicine versus Minnesota Medical Cannabis Program

The American Academy of Sleep Medicine (AASM) came out with a position statement about the use of medical cannabis for obstructive sleep apnea (OSA).  In brief they think it is not a good idea.  The entire statement can be read at the link.  I think that it is important to keep in mind that they concerns about safety and efficacy are generally dependent on the fact that like most of the conditions on the Minnesota list,  there is minimal to no scientific data to back up the suggested uses.

The AASM is not the first professional society to take a position on medical cannabis.  One of the first purported applications of medical cannabis was for glaucoma.  The American Academy of Ophthalmology has a position statement on Cannabinoids for Glaucoma  that reviews the history of this application and concludes that although cannabinoids can lower intraocular pressure, the duration of this effect is too short and the side effect profile too problematic for cannabinoids to be used for this application.  The statement points out that long acting cannabinoids for this application were recommended by the Institute of Medicine in 1999, but as of 2018 statement - there has been not suitable cannabinoid derivative.

That brings me back to the familiar refrain on this blog and that is the fallacy that cannabinoids or any street drug for that matter represents some form of miracle drug. Humans have been aware of cannabis for many applications for about 5,000 years.  A reasonable question is why some miracle application or even one less than a miracle has not been found at this point in time.  Why for example, were opioids developed as effective pain medications from the natural compounds over the same period of time?  I have attended the lectures on physicians who advocate for medical cannabis.  Some of them invoke Chinese medicine and quasi-scientific explanations like the entourage effect  about why the whole plant needs to be smoked. I don't really see a need for physicians to certify people to access these largely unproven treatments, especially when medical colleagues are describing them as potentially unsafe and ineffective.

I have no problem with the state of Minnesota supplying medical cannabis to people with a condition that has no clear cut treatment. I have no concerns about the state supplying cannabis to people who are terminally ill.  I do have a problem when cannabis is listed as a treatment when in fact there is little to no evidence that it is effective and vastly superior treatments exist.  Glaucoma and obstructive sleep apnea are two of these conditions.  From a purely psychiatric standpoint post traumatic stress disorder, and autism have existing treatments and autism has a newly approved treatment.  In the case of Tourette's syndrome and other movement disorders - the data remains very preliminary.     

As a prescribing physician, I have serious doubts about the thinking that goes into prescribing cannabis as an actual medication.  I prescribe medications every day.  These medications are all approved for use by the FDA.  There are specific indications and off label uses. There are potentially serious side effects.  The medications have to be prescribed to take the patient's chronic illnesses into account.  For example, I would not prescribe a sedative to a patient who I thought might have obstructive sleep apnea.  Prescribing cannabis, even in a special program that eliminates smokable cannabis continues to not make any sense to me. 

The list at the top of this page is directly from the Minnesota Medical Cannabis program as of today.  It lists all of the current conditions that qualify a person to take it.  I see the list as a political compromise to delay and potentially thwart the recreational marijuana movement.  It should not be a surprise that medical cannabis has always been a mainstay of the strategy to legalize recreational marijuana.  While that drama plays out - I hope that people in Minnesota don't forgo effective medical treatment for medical cannabis.  Today that means CPAP for obstructive sleep apnea and glaucoma drugs and surgery for glaucoma.

There is no evidence that medical cannabis can come close to the medical effectiveness of those options. At the political level - this is also a great example of how politics negatively impacts quality medical care.


George Dawson, MD, DFAPA


References:

1:  Ramar K, Rosen IM, Kirsch DB, Chervin RD, Carden KA, Aurora RN, Kristo DA, Malhotra RK, Martin JL, Olson EJ, Rosen CL, Rowley JA; American Academy of Sleep Medicine Board of Directors. Medical cannabis and the treatment of obstructive sleep apnea: an American Academy of Sleep Medicine position statement. J Clin Sleep Med. 2018;14(4):679–681.

2:  Petitions to Add Qualifying Medical Conditions to the Medical Cannabis Program.  This document documents the review process for adding qualifying conditions to the list.  Link 



Graphic: 

The table at the top of this post is directly from the Minnesota Medical Cannabis web site and is used here as a public document.

Cannabis and Causation

Cannabis use is highly politicized in the US at this time largely due to legalization rhetoric that has spilled over into scientific research on the topic.  Despite the broad movement to legalize cannabis across the US, only a minority of the population are regular cannabis users.  More widespread use will undoubtedly lead to increased problems associated with wider exposure, especially wider exposure in populations with vulnerabilities to the toxic effects of cannabis.  The toxic effects of interest include addiction and psychosis.  It is common in clinical practice to encounter daily cannabis smokers who stopped using the substance after several years because they started to get panic attacks, paranoia, or both.  The people I see have all moved on to something else, but there are also a substantial number of chronic smokers who are addicted.  That number is about 9% of users, and that is comparable to the amount of people who have problems from drinking alcohol.  Inpatient psychiatrists commonly see people with florid psychotic episodes from smoking significant quantities of cannabis.  They also see repeat admissions from people who are either detoxified or treated for these psychotic episodes, are discharged and smoke more cannabis to the point of a repeat psychotic episode.  The longstanding controversy among people who are not doing the work and just speculating is whether any good observational studies can be done to show that cannabis does cause psychosis or if this is an artifact of observational methodology.  In other words,  could a reverse causality bias exist that makes people who are prone to schizophrenia or psychotic episodes more likely to smoke cannabis.  In my opinion, there have been excellent observational studies showing the association between cannabis use and psychosis, but as long as that is the technology these studies will always contain the old association is not causation qualifier.

A recent paper (1) in Molecular Psychiatry may have just illustrated the causation that psychiatrists have been experiencing firsthand for decades.  The authors use a novel genetic appraoch to look at the issue of causation.  The main assumption of this study is that using specific genotypes as the independent variable rather than observed individuals gets rid of the confounding demographic and environmental variables that could be casual.  They point out that any actual clinical trial looking at the issue of whether cannabis causes psychosis would be unethical, but that a model that looks at whether causation can be established by looking at single nucleotide polymorphisms (SNPs) from a Genome Wide Association Study (GWAS) looking at the any cannabis use phenotype.  They looked at the top 10 SNPs from that data that were used to calculate gene-exposure (SNP-cannabis) estimates.  SNP-risk of schizophrenia exposure estimates were calculated from available data from the Psychiatric Genomics Consortium.  Instrumental variable estimates were made by dividing the risk of schizophrenia/risk of any cannabis use.  The instrument variable analyses were pooled across SNPs and analyzed with fixed effect meta-analysis.  The authors provide a detailed discussion and rationale for their statistical calculation in the full text of the article and supplementary material.  At this point I am going to post their main graphics.  Click on any graphic to enlarge it.

The first graphic looks at prospective observational studies.  The authors were interested in determining whether their genetically based analysis was in the same direction of this meta-analysis. Ever use cannabis use was associated with a 43% increase in schizophrenia or psychosis.

Figure 1. Meta-analysis of prospective observational studies reporting an association between use of cannabis and risk of schizophrenia or related disorders. Meta-analysis uses a random-effects model. Studies are sorted by type of outcome (schizophrenia only vs schizophrenia and related outcomes). Odds ratios (ORs) and 95% confidence intervals (CIs) express the risk of schizophrenia or psychotic symptoms for ever use of cannabis (compared with never use). For additional information on each study, see Supplementary Table S1. Dunedin, Dunedin Multidisciplinary Health & Development Study; ECA, Epidemiologic Catchment Area; EDSP, Early Developmental Stages of Psychopathology Study; NEMESIS, Netherlands Mental Health Survey and Incidence Study; SC, Swedish Cohort.

Figure 2 looks at the Mendelian Randomization analysis of 34,241 cases of schizophrenia and 45,604 cases of ever use cannabis.  This shows a 37% risk of cannabis users versus non-users for schizophrenia/psychosis risk.  The authors did a sensitivity analysis of this same data by removing each SNP from the analysis to calculate a summary causal effect of 1.33 across all 10 SNPs or 1.88 when restricted to 2 functional SNPs.

Figure 4 is included here to illustrate the authors' sensitivity analysis showing a summary casual effect of about 1.37 (red line).

All things considered this may be a compelling story for causation.  I qualify that of course in a couple of domains.  First. there are a lot of statistical models and calculations operating here.  In my experience mapping complex statistical estimates onto the most complex object in the universe has not worked out very well.  My first hand experience was statistical modeling of quantitative EEG and claims that is was predictive of psychiatric diagnosis.  Those compelling calculations published in Science (4) did not pan out at all in the long run.  It will be interesting to see if the authors applications are more widely applied to other SNPs to determine disease causation from other risk factors.  The second potential problem is a slight variation on that theme and that is the overall imprecision of meta-analysis.  The known  approximate prediction/concordance rates of meta-analyses for clinical trials (2.3) suggests that it may not be good predictor of a reproducible result.  The authors themselves suggest that the potential limitations of their study start with the fact that none of the chosen SNPs met conventional genome wide significance thresholds.  The specific dose effect of cannabis could not be investigated in the study.  The age at exposure is may be a developmental variable of interest and that was unknown.  The Mendelian Randomization techniques may have not been powerful enough to detect pleiotropic (one gene affecting more than one trait) effects, but they discuss how an alternate analysis applies in this situation.

The other question I had was about epigenetic effects on this model.  The authors were certainly aware of smoking as a confounding variable.  The known epigenetic effects of nicotine on brain chromatin would seem to cloud SNPs as pure genetic risk factors.  But this is nonetheless one of the more interesting models and concepts I have seen in a while.

They conclude that their study is "the closest approximation to a randomized trial on the effect of ever use of cannabis and risk of schizophrenia" when such a clinical trial is unethical.   That is an interesting take on their method and causation.  Hopefully it will open up the way for other studies of causation using these techniques.  If that is the case, it is a good idea to study this paper and the supplementary material (26 pages) and have a good idea about its difference from observational/association studies.  The supplementary material is also very useful for the calculations used in the study, a Venn diagram of the overlap between the schizophrenia-GWAS group (N=79,845) and the ever-use cannabis GWAS group (N=37,957), and their review methods of the best observational studies of cannabis use and  schizophrenia/psychosis.  



George Dawson, MD, DFAPA



References:

1: Vaucher J, Keating BJ, Lasserre AM, Gan W, Lyall DM, Ward J, Smith DJ, Pell JP, Sattar N, Paré G, Holmes MV. Cannabis use and risk of schizophrenia: a Mendelian randomization study. Mol Psychiatry. 2017 Jan 24. doi: 10.1038/mp.2016.252. [Epub ahead of print] PubMed PMID: 28115737.

2: LeLorier J, Grégoire G, Benhaddad A, Lapierre J, Derderian F. Discrepancies between meta-analyses and subsequent large randomized, controlled trials. N Engl J Med. 1997 Aug 21;337(8):536-42. PubMed PMID: 9262498.

3: Ioannidis JPA, Cappelleri JC, Lau J. Issues in Comparisons Between Meta-analyses and Large Trials. JAMA. 1998;279(14):1089-1093. doi:10.1001/jama.279.14.1089

4:  John ER, Prichep LS, Fridman J, Easton P. Neurometrics: computer-assisted differential diagnosis of brain dysfunctions. Science. 1988 Jan 8;239(4836):162-9. PubMed PMID: 3336779.

"The standard for psychiatric diagnosis and categorization in the United States and Canada is now DSM-III and soon will be DSMIIIR. The categories defined therein have often been criticized as nothing more than a compilation of symptoms. The results obtained with neurometrics have shown that at least the categories studied are much more than arbitrary groupings of symptoms. ............. Validity-the great deficiency of psychiatric nosology - is beginning to emerge and, thus far, to reveal an impressive concordance with biology." p. 169

5: Smith GD, Ebrahim S. Mendelian Randomization: Genetic Variants as Instruments for Strengthening Causal Inference in Observational Studies. In: National Research Council (US) Committee on Advances in Collecting and Utilizing Biological Indicators and Genetic Information in Social Science Surveys; Weinstein M, Vaupel JW, Wachter KW, editors. Biosocial Surveys. Washington (DC): National Academies Press (US); 2008. 16. Available from: https://www.ncbi.nlm.nih.gov/books/NBK62433/

Selected References on Mendelian Randomization

Attributions:  All graphics except my home-made one at the top are from reference 1 per a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.




Supplementary 1:

With today's publicly available genetic technology it is possible for a person to search their own DNA for the SNPs found in this study.  When I do that using a database where my DNA analysis resides I found the following SNPs from this study from chromosomes 15, 4, and 12 respectively.  I have linked them  to the dbSNP database at NLM:

rs4984460

rs7675351

rs2099149

It is interesting to speculate on what it means to have 3/10 genetic markers for schizophrenia/psychosis susceptibility if any cannabis exposure.


Supplementary 2:  Click on my homemade graphic to see how beautiful it is.  Blogger does not do it justice.