Friday, July 31, 2020

The Memory of Places Long Gone

I had a dream last night about my old inpatient psychiatric unit. I was moving up and down the hallways like I used to do looking for people to interview. It always seemed like I had to track people down in order to talk with them. In my dream, I was in and out of familiar rooms and talking with familiar staff. I have known some of the staff people for over 20 years. The place was congested, noisy, and malodorous. There were the associated tensions and anxiety. Everything was in the exact spatial order that I remember it being in - including all of the disarray in my old office. I eventually woke up from that dream somewhat anxious and decided that I was done sleeping.

As I drank a first cup of coffee, I thought about the various meanings in the dream and developed three or four different threads. I am used to analyzing my own dreams and the dreams of others so I had all my theories finalized by my 2nd cup of coffee. At that point I started to think about the visuospatial memory necessary to create that dream. Dreams are certainly fascinating if you just pay attention to the content and the emotional tone but to be they are more fascinating when you consider how much computational power it takes to create a Technicolor dream of your real life experience. I have asked neuroscientists to speculate about this for years now and nobody has come up with any ideas.  I came up with a few of my own based on very simplistic extrapolations of the bandwidth of single neurons and simplistic bundles of neurons. One of the problems is that bandwidth and information calculations are valid only for typical electronic devices. Bandwidth and biological systems has been talked about for 20 years but there are no straightforward or consistent calculations.

A first approximation might be a two-dimensional photograph. Everyone these days is used to seeing photographs and an estimate of how much information is in that picture. But when you are walking through a building, you are essentially walking through an infinite number of two-dimensional photographs with multiple soundtracks and additional sources of information. Even if a measure of the information it takes to portray that data in real time and space was possible the next question is - what happens when it is represented in the brain?

I pulled up Facebook and noticed that someone had posted a photo of my old high school. As I looked at the front of the school I located all the windows where my classes were held. I was in that building for the last six years of school because in our town it contained grades seven through 12. It took me a few minutes to look at the windows and think about significant events that occurred in those classes. When I think about those years, there is a lot of confusion and anxiety. I did not have a very positive experience in middle school or high school. I was one of the most obedient kids in the history of the world and yet I managed to have contentious relationships with teachers. Back in those days if you were on the wrong side of the teachers – you were basically on the wrong side.  Parents didn’t question teacher authority and I knew better than to bring that information back home. But just like my dream I was focused on the structure this building. I still remember the creaky wooden floors and stairwells. I remember the bad acoustics and echoes. I remember where my locker was on the first floor. I remember what the place smelled like. I remembered how to go to the ground floor and take the tunnel to a connected building where I had some regular classes but also mechanical drawing and technical graphics. In other words, I still had the memory of the three dimensional space - long after that space had ceased to exist. I made a short list of other structures where that was also true including my old inpatient unit. That building was demolished about three years ago.

If you think about it visuospatial memory is a fascinating area of study. It takes more than remembering a list of words or calculation or how to play a musical instrument. The data have to be stored and retrieved in a way that makes spatial sense. When I think about the way we assess this memory clinically, the tests are generally crude and two-dimensional. Real live visuospatial memory is much different. As an example I can visualize being in an English class at the northwest corner of my high school. I know the exit I would have to take and the stairwell to get out of the building. I know the directions to get to my locker and I can run through all of this traveling in my head. At some level that is a declarative memory function because I know the information I want, I can retrieve it, and I can do an operation on it and in this case imagine myself traveling according to that information. Why my brain elects to access visuospatial information while I am dreaming is not clear and I don’t think anyone knows the answer to that question.

Early information from lesion studies of parietal cortex was involved in visuospatial memories especially the right parietal cortex.  That was largely because patients with lesions in this area could not complete the basic construction tasks on bedside cognitive screening. Parietal cortex is important in the subjective experience of memory.  For example patient with bilateral parietal cortex lesions have similar recall as controls but they have less confidence in their recall (2).  One of the most well-known studies of visuospatial recall and brain structural changes was a study of London cab drivers.  They are required to acquire a significant amount of visuospatial information about London geography and be tested on it. In the initial study (3) the authors showed that acquiring this information was associated with greater cross sectional area of the right posterior hippocampus on MRI scan.  They suggested: “These data are in accordance with the idea that the posterior hippocampus stores a spatial representation of the environment and can expand regionally to accommodate elaboration of this representation in people with a high dependence on navigational skills.”  In a recent study of typical (non-expert) taxi drivers navigational skills did not seem to correlate with right posterior hippocampal volume (5).  One of the explanations that the authors had for this issue is that the posterior hippocampus is only one part of the structures necessary for the navigational map.

Since this thread of research on the hippocampus, the area of spatial learning has become a lot more complex.  As an example, there are now three different types of spatial learning (6).  Landmark knowledge is specific for objects encountered in the environment.  Route knowledge involves environmentally dependent decisions that have to occur at specific times to move through the environment.  Survey knowledge is a detailed representation of the relationship between all objects in the environment. In reference 6, the authors look at testing all of these types of spatial learning in a large group of people who are navigating a nuclear facility and looking at the impact that maps of varying complexity have on their learning that environment.

As a psychiatrist, one of my concerns is what the neural substrate of spatial learning is for both my own thought experiments but also the patients I see with known brain lesions or who have clear deficits in spatial navigation.  One of the most useful reviews I could find (7) looked at a summary of the available data and proposed a navigational network that is really a rough sketch.  In a fairly complex paper the authors suggest that the occipital place area (OPA), retrosplenial complex (RSA) and parahippocampal place area (PPA) may function for landmark recognition in the context of a larger network involving the hippocampus, parahippocampus, retrosplenial cortex, and entorhinal cortex.  From a clinical standpoint many of these structures are compromised in dementias like Alzheimer Disease with severe associated problems in spatial maps and orientation.   

The story of spatial mapping and memory is an incomplete one at this time, but the details are building. At some point in the near future we will have a better idea of what the brain substrate is for this memory and the various kinds of real or imagined navigation. How it is activated and placed in dreams will probably take additional research effort.  And at some point, I really would like to see a practical approach to estimating the information content and flow necessary to accomplish these tasks. 

The most important aspect of spatial representations may be the emergent properties of the system.  Consciousness scientist Christof Koch (11) has stated that there are an "uncountable" number of spatial relationships associated with any human experience.  Integrated into those spatial relationships are also sensory and affective dimensions. That results in a powerful system for recall of real physical systems or building new ones in your dreams. 


George Dawson, MD, DFAPA




1:  Rosen ML, Stern CE, Devaney KJ, Somers DC. Cortical and Subcortical Contributions to Long-Term Memory-Guided Visuospatial Attention. Cerebral Cortex (New York, N.Y. : 1991). 2018 Aug;28(8):2935-2947. DOI: 10.1093/cercor/bhx172.

2:  Simons JS, Peers PV, Mazuz YS, Berryhill ME, Olson IR. Dissociation between memory accuracy and memory confidence following bilateral parietal lesions. Cereb Cortex. 2010;20(2):479-485. doi:10.1093/cercor/bhp116

3:  Maguire EA, Gadian DG, Johnsrude IS, et al. Navigation-related structural change in the hippocampi of taxi drivers. Proc Natl Acad Sci U S A. 2000;97(8):4398-4403. doi:10.1073/pnas.070039597

4:  Maguire EA, Woollett K, Spiers HJ. London taxi drivers and bus drivers: a structural MRI and neuropsychological analysis. Hippocampus. 2006;16(12):1091-1101. doi:10.1002/hipo.20233

5:  Weisberg SM, Newcombe NS, Chatterjee A. Everyday taxi drivers: Do better navigators have larger hippocampi?. Cortex. 2019;115:280-293. doi:10.1016/j.cortex.2018.12.024

 6: Stites MC, Matzen LE, Gastelum ZN. Where are we going and where have we been? Examining the effects of maps on spatial learning in an indoor guided navigation task. Cogn Res Princ Implic. 2020 Mar 20;5(1):13. doi: 10.1186/s41235-020-00213-w. PMID: 32198712; PMCID: PMC7083990.

 7: Epstein RA, Patai EZ, Julian JB, Spiers HJ. The cognitive map in humans: spatial navigation and beyond. Nat Neurosci. 2017 Oct 26;20(11):1504-1513. doi: 10.1038/nn.4656. PMID: 29073650; PMCID: PMC6028313.

 8:  Bellmund JLS, Gärdenfors P, Moser EI, Doeller CF. Navigating cognition: Spatial codes for human thinking. Science. 2018;362(6415):eaat6766. doi:10.1126/science.aat6766

 9:  He Q, Brown TI. Environmental Barriers Disrupt Grid-like Representations in Humans during Navigation. Curr Biol. 2019;29(16):2718-2722.e3. doi:10.1016/j.cub.2019.06.072

10:  Eichenbaum H. The role of the hippocampus in navigation is memory. J Neurophysiol. 2017;117(4):1785-1796. doi:10.1152/jn.00005.2017

11:  Christof Koch. The Feeling of Life Itself.  MIT Press. Cambridge, MA, 2019. p. 7-8.



Friday, July 17, 2020

Toward A Better Sedative Hypnotic Medication

(Click to enlarge the above graphic)

I made the mistake of suggesting that we need a better version of quetiapine for insomnia on Twitter.  That triggered the usual comments that basically suggested that I did not know anything about quetiapine or what I was doing in general.  This post is for cooler heads. Let me start out by saying quetiapine came out early in my career.  The early concern was ocular side effects and of course cardiac conduction problems (prolonged QTc). Since that time the ocular side effects are not a primary concern (both retinal hyperpigmentation and cataracts were a concern with phenothiazines).  Since I was in acute care psychiatry, the main concern was that this medication did not work fast enough for acute mania or psychosis.  There was a time lag of days to weeks relative to more potent atypical antipsychotics (AAP). And not too long after they were released the metabolic problems were noted including dyslipidemia, insulin resistance and overt diabetes mellitus, metabolic syndrome, and weight gain.  Since most Americans are overweight and have a moderate risk of diabetes mellitus Type 2 in middle age – this is the primary reason to avoid using most medications in this class. Theoretical considerations suggest that the newer AAPs – aripiprazole, lurasidone, and brexpiprazole have less risk, but I have certainly seen people who gained substantial amounts of weight on these agents.  I have also seen several people develop diabetes without gaining a pound. That risk is clearly there and it is significant.

Indications for both olanzapine and quetiapine include schizophrenia and mood disorders typically bipolar variants or psychotic depression. Ideally the medication will also work for any associated sleep disturbance but that is not always the case. Sleep is important in primary psychiatric disorders because the person with the disorder generally does better if they are sleeping well. In the real world that ideal solution is not always there. As an example, the patient may be responding well to a non-sedating AAP like aripiprazole but continuing to not sleep. They do not want to take the chance of significant weight gain, but at the same time practically all the other medications in the above table have been tried and are ineffective. In that case low doses of quetiapine are often added to the primary AAP, not for additional treatment of psychotic or mood symptoms, but in the hope of normalizing sleep. That can make a significant difference even though the risk of metabolic problems remains.

The above table was constructed to look at non-benzodiazepine drugs for sleep. I plan to revisit the benzodiazepine issue again this year and am working on a table. For the purpose of this post, I am referring to all high potency and low potency benzodiazepines as well as the z-drugs (zolpidem, eszopiclone, and zaleplon). As I wrote about a few years ago, this class of medications poses a significant risk of the term the side effects and also dose escalation and uncontrolled use. Since they were invented to replace barbiturates and were clearly safer than that class of medications, there was a lag time before physicians found that they also posed unique risks.  Benzodiazepines are also extremely risky for patients with diagnosed substance use problems and should generally be avoided in that population. The population also has very significant sleep problems as well as problems with anxiety and depression.

In treating this population, insomnia can be related to intoxication and withdrawal states, the chronic sleep effects of intoxicants, circadian rhythm disturbances due to patterns of substance use, secondary to a substance induced psychiatric disorders, as well as an ongoing primary insomnia that has never been addressed. Some withdrawal states most notably opioids, benzodiazepines, and alcohol can produce long-standing severe insomnia that can last for weeks or more. That insomnia can be considered life-threatening if it perpetuates the cycle of ongoing substance use. I often hear: “If you can't give me something that will help me sleep, I know what will do it.” That discussion invariably comes back to using heroin or alprazolam or alcohol or possibly a combination of all three in order to get to sleep. The sleep does not have to be “normal” in any way. It might only involve 3 to 4 hours of interrupted sleep but that is considered better than nothing or one or two hours.  This is typically referred to as "self-medication" and it illustrates that this concept has very little to do with normalization of function.  Self medication with addictive compounds is a semi-rational process that only partially addresses the problem.

With the exception of the above orexin receptor antagonists, amitriptyline, and trimipramine,  I use all of the compounds in the above table for the treatment of insomnia. The most commonly used medication is trazodone. It is generally well tolerated and effective. Like all medications it is not 100% effective and most common reasons people request changes are excessive morning sedation, daytime drowsiness, excessive dreaming, and nasal congestion.  The remaining sedating antidepressants all depend heavily on anti-histaminergic effects enter probably as well tolerated but have unique side effects that need to be monitored. The only antidepressant that has an FDA indication for sleep is doxepin and that is in a proprietary dosage form of 3 and 6 mg.  According to the Ki values, doxepin is the highest affinity for H1 receptors. Insurance company constraints usually result in people getting low-dose generic doxepin rather than the FDA approved proprietary version Silenor.  Silenor comes in 3 mg and 6 mg tabs and the smallest generic dose of doxepin that I can typically prescribe is 10 mg.

Antihistamines are typically over-the-counter sleep medications - usually diphenhydramine or doxylamine.  In the table, hydroxyzine seems to have a comparative advantage due to the lower Ki value, but the metabolism of this compound is extensive and one of the metabolites cetirizine has a high affinity for H1 receptors but also no brain penetration – so it is ineffective for sleep.  There is also a concern about prolonged QTc interval with hydroxyzine that has led European regulators to limit the total daily dose of hydroxyzine to 100 mg.  I typically see hydroxyzine prescribed for anxiety and insomnia in patients with substance use problems.  It is generally not very effective for either anxiety or sleep.

In the clinical population I see practically everyone has access to melatonin. It appears to be much less effective than trazodone but has the appeal that it is a “natural” supplement. That also means it is not monitored by the FDA in terms of bioequivalence. The dose of melatonin that most people take is many times the amount that is produce physiologically. I was told by one of the top sleep experts in the country several years ago that the appropriate way to take it is taking 1 or 2 mg at five or 6 PM to mimic the physiological release of melatonin. I often make that suggestion people who tell me they feel like they are taking too much with a 5 to 10 mg dose at bedtime. Ramelteon is available as melatonin receptor agonist and seems to be effective for sleep onset in about 30% of the people I see.

Gabapentin and pregabalin are unique compounds in that their primary action is through N-Type Voltage Gated Calcium Channels (VGCC).  A small segment of the population will experience these medications as very sedating.  Most people do not.  In addiction psychiatry, there was a trial of gabapentin in alcohol use disorder that showed that the treatment group (600 mg TID) had less insomnia, less anxiety, fewer cravings, and were less likely to relapse to alcohol use.  In the sleep literature, both are used for restless leg syndrome (RLS) and I have seen patients who experienced significant relief from these compounds when nothing else seemed to work.  These medications are currently controversial because of some concern of overuse in the context of limited efficacy.  In addiction, they are prescribed mostly for off label indications and sleep is one of those indications.  Even though I work in one of the strictest prescribing environments with regard to controlled substances, I do prescribe gabapentin for sleep, anxiety, chronic pain, and protracted benzodiazepine withdrawal (all off-label) but generally to patients with alcohol use disorders (per the clinical trial).  I generally avoid prescribing gabapentinoids for people with opioid use disorders because there is some evidence that they may escalate the dose and try to enhance the euphorigenic effects of opioids.  I also advise people ahead of time about these potential effects and encourage them to self-monitor for either euphorigenic effects or a tendency to escalate the dose.  Gabapentinoids should be discontinued in those circumstances.

I have not started using the orexin receptor antagonists yet.  Based on my previous review they look like very interesting compounds, but their clinical effects do not seem to match the theoretical effects at this point.  I think a clinical trial is needed to see if they can be safely used in populations with substance use disorders.  I hope to be of assistance designing and working on that trial.

 That brings me to the issue of quetiapine for sleep.  It is quite an emotional topic for some.  Some people will fly into a rage over the very mention of quetiapine being used off label for sleep.  As I mentioned AAPs present unique risks that other medications do not and if those risks are present they are basically cardiovascular risk factors. A significant proportion of the population being treated by psychiatrists already has cardiovascular risk factors like tobacco smoking that effectively reduces their life span by about 25 years. The addition of quetiapine of any AAP is a serious matter. 

In my capacity as a tertiary consultant, I am in the position of seeing large numbers of people for evaluations who are already taking quetiapine for sleep.  There is a selection bias in place because 100% of the people I see have a substance use disorder.  A substantial number overuse benzodiazepines and in some cases have been using very high doses for years before I see them.  If I am discussing treatment with a person at the end of my initial assessment and they are taking quetiapine, my first order of business is to inform them that according to Minnesota State Statutes – they need to sign a written consent form to take it and I review the sections on general side effects, metabolic effects (increased appetite, weight gain, diabetes, dyslipidemia) and the neurological effects – some of which may be irreversible (tardive syndromes).  That point is typically a defining point in the interview and I hear one of two things:

“Nobody ever told me about that before.”

“I have tried everything else for sleep and it doesn’t work.  And you know I can’t take benzodiazepines.”

In the case of the first response, additional details will depend on whether or not the patient has gained weight.  In some of those cases they will be irate.  Some will respond on the basis of a family history of diabetes and tell me there is no way they want to get it.  The majority of these patients will want to stop the quetiapine and in many cases they have never tried medications from the above table and one of them will work.  Those responses indicate to me that quetiapine was probably prescribed prematurely - before some of the other alternatives were tried.

In the case of the second response, I get very interesting histories of severe treatment refractory insomnia associated with substance use.  Most people take 25-150 mg of quetiapine for sleep but some take doses that are typically used for the stabilization of bipolar disorder (300-800 mg at night).  And they have been taking it for years. My basic job is to make sure they do not have tardive dyskinesia, diabetes mellitus, or cardiac conduction problems but things can get even more complicated than that.  For example, what about the person who already has diabetes mellitus Type II, hypertension, dyslipidemia, heart disease and a severe alcohol use problem?  What if they tell you: “Look doc – if I can’t use quetiapine for sleep my go to is alcohol and I know that alcohol is killing me.  You have to let me use that quetiapine or I will end up drinking myself to death”.

An equally compelling situation occurs in the person with opioid use disorder who refuses agonist treatment with buprenorphine of methadone.  After years of opioid use, severe insomnia generally does not resolve very easily and it can last for weeks or months.  Can a physician not prescribe a medication that can typically work for this insomnia based on the idea that some people consider the medication to be “bad”?  I think the answer is that the physician cannot.  If an assessment has been made that none of the other medications in the table are suitable, and the patient has a potentially life-threatening illness associated with insomnia and they have given adequate informed consent, then the medication must be prescribed.  Not sleeping and risking relapse to alcohol and drug use is a life threatening problem for most of the people I see.  In short, quetiapine should not be used casually for insomnia but there are situations where it may be required.

These are a couple of things I am working on with regard to sleep right now.  The Kis in the above table are only part of the story.  Coming up with better theories about quetiapine will hopefully lead to better ideas about sleep medications.

George Dawson, MD, DFAPA


Table added to clarify the muscarinic acetylcholine receptor (mAChR) functions and the subtype most implicated in delirium. (click to enlarge).


1.  Fukasawa H, Muratake H, Ito A, et al. Silicon-containing GABA derivatives, silagaba compounds, as orally effective agents for treating neuropathic pain without central-nervous-system-related side effects. ACS Chem Neurosci. 2014;5(7):525-532. doi:10.1021/cn500053d

2.  Kroeze WK, Hufeisen SJ, Popadak BA, et al. H1-histamine receptor affinity predicts short-term weight gain for typical and atypical antipsychotic drugs. Neuropsychopharmacology. 2003;28(3):519-526. doi:10.1038/sj.npp.1300027

3. Nishiyama K, Shintani Y, Hirai K, Yoshikubo S. Molecular cloning and pharmacological characterization of monkey MT1 and MT2 melatonin receptors showing high affinity for the agonist ramelteon. J Pharmacol Exp Ther. 2009;330(3):855-863. doi:10.1124/jpet.109.155283  (monkey receptors)

4. Ancizu S, Castrillo N, Pérez-Silanes S, et al. New quinoxaline derivatives as potential MT and MT receptor ligands. Molecules. 2012;17(7):7737-7757. Published 2012 Jun 25. doi:10.3390/molecules17077737

5.  Taylor CP, Angelotti T, Fauman E. Pharmacology and mechanism of action of pregabalin: the calcium channel alpha2-delta (alpha2-delta) subunit as a target for antiepileptic drug discovery. Epilepsy Res. 2007;73(2):137-150. doi:10.1016/j.eplepsyres.2006.09.008 (human recombinant n 2— Type 1 subunit proteins)

6.  Salvi V, Mencacci C, Barone-
Adesi F. H1-histamine receptor affinity predicts weight gain with antidepressants. Eur Neuropsychopharmacol. 2016;26(10):1673-1677. doi:10.1016/j.euroneuro.2016.08.012

7.  Gillard M, Van Der Perren C, Moguilevsky N, Massingham R, Chatelain P. Binding characteristics of cetirizine and levocetirizine to human H(1) histamine receptors: contribution of Lys(191) and Thr(194). Mol Pharmacol2002;61(2):391-399. doi:10.1124/mol.61.2.391

8.   Roth, BL; Driscol, J. "PDSP Ki Database"Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved July 5, 2020.

9.   Hshieh TT, Fong TG, Marcantonio ER, Inouye SK. Cholinergic deficiency hypothesis in delirium: a synthesis of current evidence. J Gerontol A Biol Sci Med Sci. 2008;63(7):764-772. doi:10.1093/gerona/63.7.764

Monday, July 13, 2020

Airborne Transmission Denial Dies Hard ........

I started this post as I left a staff meeting today on containing the coronoavirus. We had a similar meeting 2 months ago and at that point I added that there was airborne transmission of the virus.  The only comment I got was a condescending remark about how we don't know much about airborne transmission and we need to wait and see and blah, bah, blah. It was "as if" I did not know what I was talking about or any of the surrounding controversy.  To my surprise the same people today were sold on airborne transmission. They were even interested in HVAC issues and negative pressure rooms – all of the stuff I have been studying for 20 years.  Nobody mentioned UVC or air filtration.  I decided just to keep my mouth shut. Just like I usually do when politics seems to be the priority rather than science.  But the good news was undeniable.  Airborne transmission has much greater acceptance than it did prior to the current pandemic and there are clear reasons for it.

That staff meeting is a small part of a larger landscape of what airborne transmission advocates like me have been talking about for decades or longer.  Back in the days when I was working in an outdated building that had an HVAC system that was designed to contain heat rather than provide fresh air to dilute and remove airborne pathogens – I routinely observed the effects of this approach on myself and my coworkers.  Upper respiratory infections were endemic.  If one person came into that building with a severe form of a respiratory virus – most people got it. I can recall coming down with an acute flu-like illness one morning at work and getting ill so quickly and severely that I was barely able to make it home due to the cognitive effects.  I was close to delirium.

When you are in medical facilities, the party line is always “wash your hands”. I got the respiratory infections if I washed my hands 20 times a day or a hundred times a day.  The pandemic equivalent of that advice has been “don’t touch your face”.  But it is apparently safe to eat food that has been contaminated with SARS-CoV-2 because the virus is not infectious via gastrointestinal pathways.  The expert opinion is really based on the lack of evidence that eating food or touching food packaging is associated with SARS-CoV-2 infections.  We hear about the virus being infectious through the eyes and nose. It could be rubbed into the eyes from the face or into the nose by nose picking – but how common is that?  Certainly, washing your hands and not touching your face along with physical distancing at 6 feet seem like common sense rules.  But is that going to protect you?

I have never felt like any of those measures was enough and this week a letter came out pointing out the evidence for airborne transmission of respiratory viruses in general and for SARS-CoV-2 in particular.  I was pleased to see Dr. Milton as a co-author of this statement.  I have been reading his work for 20 years on airborne viruses in buildings of different design including the viruses that have been detected both in the air and the occupants of the building. This paper is a brief commentary specific to SARS-CoV-2 with a couple of generalities about airborne viruses and it is signed by 239 scientists who support it. 
The commentary starts out as an appeal to the medical community to recognize the potential for airborne spread of COVID-19.  Airborne transmission is defined as the release of droplets containing viral particles during breathing, coughing, sneezing, and any type of vocalization.  There is no doubt this happens. A distribution of droplet particle sizes occurs.  The larger droplets at a typical velocity settle out of the air in shorter distances typically in about 2 meters or 6 feet. The smaller droplets can travel much longer distances.  The authors cite an example of a 5 µm droplet at an original height of 1.5 meters and expelled at a typical indoor velocity travelling for “tens of meters” before it falls to the floor. This is typical airborne transmission and it will obviously not be contained by hand washing or physical distancing.

The authors on to describe some of the well-known scenarios where COVID-19 was transmitted despite no observed direct or indirect contact among the parties where the transmission occurred by video recordings.  They go on to cite other experiments demonstrating that several viruses (influenza, Middle East Respiratory Syndrome coronavirus (MERS-CoV), and respiratory syncytial virus (RSV) can all be spread by airborne routes. Although they don’t go into a lot of technical detail in the commentary, respiratory viruses are exhaled in normal tidal breathing.  The distribution and velocity of exhaled droplets will vary based on the way they are generated.  Infective viral RNA in small (5 µm) droplets from COVID-19 has been detected.

The critical sentence from this document follows:

“Hand washing and social distancing are appropriate, but in our view, insufficient to provide protection from virus carrying respiratory microdroplets released into the air by infected people.”

The is really a landmark statement from this group of experts. In my opinion it revolutionizes the approach not only to this virus but all respiratory viruses.  They all have access to the same type of spread and many have already been shown to have permeated heating and ventilation systems.  One of the main differences is virulence of the virus.  For example, smallpox or variola virus can cause an infection from the inhalation of a single viral particle (6).  Adenovirus, a much more common respiratory virus can cause an infection by the inhalation of as little as 6 viral particles (3).  Although adenovirus is potentially a flu-like respiratory virus, the main initiative at preventing the associated morbidity and mortality occurs in the military where a vaccination is used. The SARS-CoV-2 infections dose has been estimated to be about 280 particles – but the authors of one study suggest it is in the same ballpark of influenza virus and in that paper suggest that the amount of virus leading to infection in volunteers may be twice the amount of the aerosolized virus (5).

The main implication of airborne spread is that sustained inhalation of COVID-19 in poorly ventilated spaces of just being indoors increases risk of transmission. People who are coughing, sneezing, singing or engaged in any activity that results in forceful exhalation will expel small droplets at higher rates of speed and they will remain airborne for a longer period of time and travel much greater distances than the current suggested social distancing of 6 feet. 

To reduce the airborne transmission risk they have straightforward recommendations to avoid overcrowding (every additional person in the room is generating airborne droplets), have adequate ventilation, and supplement these measure with additions like HEPA filtration, germicidal UVC light, and exhausting room air rather than recirculating it. I can recall getting into an argument at one of my Avian Influenza Task Force meetings about a fast way to change the hospital ventilation system in the event of an influx of avian influenza patients.  Recall that the hospital was designed to retain heat by recirculating room air rather than exhausting it – like modern hospital rooms.  At the time, the counterargument was that it was just too expensive to build negative airflow rooms to prevent the flu virus from leaving the room with medical staff caring for the patients.  Most hospital rooms, even the ones I worked in that were built in the 1960s, had windows to the outside.  How difficult would it be to fit these windows with exhaust fans to the exterior of the hospital? 

This consideration is important now that there are political initiatives to reopen schools and other public places.  The ventilation systems of all of these places should be looked at and that assessment incorporated into the overall decision about how safe they are to open.  Further, there should be a systematic approach to how safe buildings are in general from the perspective of transmission of respiratory viruses.  A prospective approach that looks at how buildings in temperate climates need to be designed to minimize the spread of respiratory viruses needs to be a long term goal.  

It took a virus with heightened mortality and morbidity to raise awareness that physical measures rather than any available medication may be the best way to contain respiratory viruses.  Airborne transmission of respiratory virus denial dies hard - but hopefully it is being put to rest once and for all.  That should be a continued priority for everyone and momentum we cannot afford to lose.

George Dawson, MD, DFAPA


1:  Lidia Morawska, Donald K Milton, It is Time to Address Airborne Transmission of COVID-19, Clinical Infectious Diseases, , ciaa939,

2:  Erin Bromage.  The Risks - Know Them - Avoid Them.  Erin Bromage COVID-19 Musings.  May 16, 2020.  Link

3:  Yezli S, Otter JA. Minimum Infective Dose of the Major Human Respiratory and Enteric Viruses Transmitted Through Food and the Environment. Food Environ Virol. 2011;3(1):1–30. doi: 10.1007/s12560-011-9056-7. Epub 2011 Mar 16. PMCID: PMC7090536.

4:    Nicas, M., Hubbard, A. E., Jones, R. M., & Reingold, A. L. (2004). The Infectious Dose of Variola (Smallpox) Virus. Applied Biosafety, 9(3), 118–127.

5:  Schröder I. COVID-19: A Risk Assessment Perspective. J Chem Health Saf. 2020;acs.chas.0c00035. Published 2020 May 11. doi:10.1021/acs.chas.0c00035

Previous Airborne Transmission Posts from this Blog:

SARS-CoV-2 Is An Airborne Virus?

Viruses Are In The Air - Protection From Airborne Viruses

Hand Washing

New Twist On An Old Method To Kill The Flu Virus

Is It Time To Quarantine Air Travelers?


This statement from a recent Nature article:

"But this conclusion is not popular with some experts because it goes against decades of thinking about respiratory infections. Since the 1930s, public-health researchers and officials have generally discounted the importance of aerosols — droplets less than 5 micrometres in diameter — in respiratory diseases such as influenza."

from:  Dyani Lewis.  Mounting evidence suggests coronavirus is airborne — but health advice has not caught up.  Link.

Graphics Credit:

Graphic at the top is from Reference 1 based on the following CC License.  This is an Open Access article distributed under the terms of the Creative Commons Attribution- NonCommercial-NoDerivs licence (,