Rapping About Replication

science-scienceLast year, a paper came out in the journal Science that made waves in the scientific community and the public at large (it was even voted the #5 most publicly cited paper of 2015 by Altmetric).


So why am I writing about a paper over a year old and one that has already received plenty of public attention? Well, because this paper is a huge deal. Why you may ask? One of the most important words in the entire scientific enterprise: Replication.

In brief, this study was done by the Open Science Collaboration (OSC), a massive consortium of hundreds of researchers. The OSC team attempted to replicate 100 research papers in the experimental psychology field. The scientists decided which studies were to be included in the analysis, shared methods and tools, and agreed on criteria for how they would critically evaluate the studies (in some cases, the original authors provided the original test materials).

Unfortunately, the results were not good. The authors found that 2/3 of the original findings could not be replicated with any degree of statistical confidence. When taken as group, the effect sizes of the 100 replication studies compared to the originals were only about half as a great. In other words, more than half of the 100 papers could not be replicated.

But what does this mean and why is it a big deal?

Science is all about uncovering “how stuff works” but at a far more fundamental level, what science really is, is a method or system to figure out “how stuff works” and “what causes what” and uncovering the underlying principles of nature, etc.

And how does a scientist know that why they discovered about how this or that works is actually real? Well, one way is for other scientists to run the same experiment. If they get the same result, then it’s a pretty good chance then the discovery is “real”.

One of the biggest challenges the scientific research field has been grappling with is this issue of replication and ability to replicate other people’s work. If what people are reporting in papers is real, then why are so many findings so difficult to replicate?

There’s about a million ways to answer that question but the simplest answer is that doing science is really, really hard. Even if you think you designed the perfect experiment, collected the best data you could, and analyzed it the best way you know how, you might have gotten something wrong. You might have forgotten to control for a variable that you never thought of or even more mundanely, you forgot to report some crucial detail that other scientists need to know but you have taken for granted.

The failure to replicate is NOT about making up results (though a few bad apples have done that) is about not having time and money to thoroughly consider the results of the field. Science has a way of weeding out ideas that just don’t hold water but it requires other scientists to delve into the work of their colleagues and try to expand on their initial colleagues.

And just to be clear, there’s plenty of outstanding work being done that has been replicated and is scientifically solid.

Regardless, scientists need to resolve how to solve this problem with replication.

As bad as it is can be in biology, it’s a whole lot worse for a “soft science” like psychology. Many psychological studies have either been discredited or shown to be outright frauds (one of the more sensational stories involved years of forged data by the psychologist Diederik Stapel).

Thankfully, the field as a whole is trying to acknowledge their past failings and improving the integrity of their discipline. It would be a huge step forward for other fields, such as in the biomedical research field, to also take on such an endeavor.

And in the end, this is why this paper is so ground breaking and worth talking about (again). The field acknowledged they had a problem, did a systematic analysis of all available studies, and tried to replicate which ones are good and which are bad.

But there’s one more layer to this too. There’s also no incentive to replicate findings either. The pressure to publish only “sexy” results and get the big research grant almost prohibits scientists from trying to replicate each others work.

As someone who has spent that last 10+ years in academic research labs, I’ve heard the concerns from friends and colleagues about how quickly they need to publish their results out of fear of being “scooped” by a competing lab working on the same topic. And I and anyone in the academic research knows the the near constant anxiety about how to come up with new exciting ideas for the big grant that your entire livelihood is dependent upon (maybe a little over-dramatic but seriously, only a little).

If a scientist is under pressure to publish a new finding as quickly as possible, sometimes mistakes are made or a critical control was overlooked on accident. One facet of the replication crisis may be this competitive drive between labs. In business, competing tech companies are pressured to release a product that may be cheaper or more appealing to the public. However, competition has the exact opposite effect in scientific research. Increased competition may actually hurt scientists. And of course, the root cause of competition to publish is competition for a limited pool of grant money, without which there would be no basic research at all.

The replication study is an important milestone and idealizes the self-correcting tradition of the scientific enterprise in general. Scientists are supposed to be the most critical of their own work and the community should be able to recognize if an initially exciting finding cannot be replicated.

With increased funding and reduced pressure to publish only “sexy” results in top-tier journals, perhaps the scientific community will turn away from competition and prestige and return to the spirit of openness, sharing, and collaboration. Maybe then the failure to replicate will become unable to be replicated.

Update: Changes to site, Cocaine review article

Good-bye NYC! (Photo © Derek Simon 2015)

Good-bye NYC!
(Photo © Derek Simon 2015)

Change is coming!

After a several month hiatus, I’m happy to be posting again!

I wanted to announce that I recently switched fields from basic neuroscience research to a fellowship position in the LGBTI Office at the US Agency for International Development (USAID)!

This means good-bye NYC and hello Washington DC! It also means that the scope, style, and range of topics I’ll write about will greatly expand beyond just drug addiction. I’m still figuring out those details….

But in the mean time:

Cocaine Addiction Review Article

About two years ago I wrote a review article for a new academic book about addiction. Finally, the book and the article have been published!

The book is Neuropathology of Drug Addictions and Substance Misuse. My article appears in Volume 2.

Feel free to download a pdf of my article for free!

PDF of Cocaine Review Article.

I first present an overview of the pathology and neurobiology of cocaine addiction and then discuss some of the research findings about changes that occur in the brain because of cocaine addiction.

A summary of key points discussed in the article:

  • Cocaine is a widely abused drug that has significant economic, medical, and social costs and no effective pharmacotherapeu­tic treatments.
  • Cocaine addiction progresses from initial use to repetitive cycles of heavy, short-term use (“binge” use), abstinence, and relapse.
  • Unlike other drugs of abuse (which only primarily affect DA release), cocaine’s mechanism of action consists of blocking the reuptake of all monoamine neurotransmitters (DA, 5HT, and NE) by antagonizing the monoamine transporters (DAT, SERT, and NET) thus leading to an accumulation of these neu­rotransmitters in the synapse of the mesolimbic reward path­way and other regions of the brain.
  • Genetic and environmental factors contribute to the suscepti­bility of an individual to becoming addicted to cocaine, and based on twin studies, it has been estimated that genetics may account for 30–60%, and as high as 78% of this susceptibility.
  • Acute cocaine use activates the HPA axis while chronic cocaine use sensitizes the HPA axis and blunts the stress response, which contributes to relapse behavior.
  • Accurate behavioral models used to study cocaine addiction, such as self-administration and the “binge” model, are useful because they attempt to recapitulate the human disease.
  • Cocaine use results in upregulation of dynorphin mRNA and protein and subsequent elevation of KOPR/dynorphin tone in the VTA/CPu/NAc circuit in virtually every behavioral model tested.
  • Modulation of the KOPR/dynorphin system may represent a viable pharmacotherapeutic target for treatment of cocaine addiction.

The Consequences of Childhood Abuse Last Until Adulthood: What are the Implications for Society?

(© Derek Simon 2015)

(© Derek Simon 2015)

One of the great questions in the addiction field is why do some people become full-blown addicts while other people can use drugs occasionally without progressing to anything more serious? One part the answer definitely has to do with the drug itself. For example, heroin causes a more intensely pleasurable high than cocaine and people that try heroin are more likely to become addicted to it than cocaine. But that’s not the whole story.

I’ve written previously about how a negative, stressful environment can have long-lasting negative impacts on the development of a child’s brain (also known as early-life stress of ELS). ELS such as childhood abuse (physical or sexual) and neglect can increase the risk for a whole host of problems as an adult such as depression, bipolar disorder, PTSD, and of course drug and alcohol abuse. There’s even a risk for more physical ailments like obesity, migraines, cardiovascular disease, diabetes, and more.

Childhood abuse/neglect = psychological and physical problems as an adult.

Attitudes towards childhood development have certainly changed! Child coal miners ca. 1911 (wikipedia.org).

Attitudes towards childhood development have certainly changed! Child coal miners ca. 1911 (wikipedia.org).

This idea doesn’t sound too controversial but believe it or not, the idea that a bad or stressful situation as a child would do anything to you as an adult was laughed away as not possible. It’s only within the last decade or so that a wealth of research has supported this idea that ELS can physically change the brain and that these changes can last through the abused child’s entire life.

This recent review paper (published in the journal Neuron) is an excellent, albeit technical, summary of dozens research papers done on this subject and the underlying biology behind their findings.

Paradise lost childhood abuse review 2016 title

I especially love the quotes the author included at the beginning of the article:

Paradise lost childhood abuse review 2016 quotes

And even more recently, yet another research paper has come out that highlights how important childhood is for the development of the brain and how a stressful childhood environment can impact the function of a person as an adult.

Childhood abuse paper 2016

This most recent report, published in the journal Neuropscyhopharmacology concludes that early childhood abuse affects male and females differently. That is to say that the physical changes that occur in the brain are distinct for men and women who were abused as children.

Studies like this one are done by examining the brains of adults who were abused as kids and then comparing the activity or structure of different parts of the brain to the brains of adults who were not abused. The general technique of examining the structure or activity of the brain in a living human being is called neuroimaging and includes a range of techniques such as MRI, PET, fMRI, and others. (I’ve written about some of these techniques before. In fact, the development of better methods to image the brain is a huge are of research in the neuroscience field).

However, this study did not examine behavioral differences in the subjects, but as I said above, a great number of many other studies have looked at the psychological consequences of ELS. But this paper is really primarily interested in the gender differences in the brains of adults that have been abused as kids.

*Note: the following discussion is entirely my own and is not mentioned or alluded to by the author’s of this study at all.

This work—and the many studies that preceded it—has important implications because as a society, we have to realize that part of our personality/intelligence/character/etc. is determined by our genetics while the other part totally depends on the environment we are born into. I don’t want to extrapolate too much but the idea that childhood abuse can increase the risk of psychological problems as an adult also supports the broader notion that a great deal of a person’s success is determined by entirely random circumstances.


The Adverse Consequences Pyramid perfectly illustrates how ELS/abuse/neglect (the bottom of the pyramid) leads to much greater problems in later life. (wikimedia.org).

The science shows that a child born into a household rife with abuse will have more chance of suffering from a psychological problem (such as addiction) as an adult than someone who was born into a more stable life. The psychological problem could hurt that person’s ability to study in school or to hold down a job. And the tragic irony, of course, is that no child gets to choose the conditions under which they are born. A child, born completely without a choice of any kind over whether or not he or she will be abused, can still suffer the consequences of it (and blame for it) as an adult.

As a society, we often always blame a person’s failures as brought on by his or her own personal failings, but what if a person’s childhood plays an important role in why that person might have failed? How, as a society, do we incorporate this information into the idea of ourselves as having complete control over our minds and our destinies, when we very clearly do not? As an adult, how much of a person’s personality is really “their own problem” when research like this clearly show that ELS impacts a person well after the abuse has ended?

If the environment a child is born into has a tangible, physical effect on how the brain functions as an adult, than this problem is more than a social or an economic one: this is a matter of public health. Studies that support findings such as these provide empirical significance for public policy and public services for child care such as universal pre-K, increased availability of daycare, health insurance/medical access for children, increased and equitable funding for all public schools regardless of the economic situation of the district that school happens to be located in, etc.

One of our goals as a society (if indeed we believe ourselves to be a functioning society…the success of Donald Trump’s candidacy raises some serious doubts…but I digress) is the improvement of the lives of ALL of our citizens and securing the prosperity of the society for future generations. Reducing childhood poverty and abuse quite literally could help secure the future generations themselves and improve the ability of any child to grow up to become a successful and productive adult.

Public programs are essential because the unfortunate reality for many people born into poverty is that they must work all the time at low paying jobs in order to simply survive and may not be able to give their children all the advantages of a wealthier family. And this is where government and public policy step in, to correct the imbalances and unfairness inherent to the randomness of life and level the playing field for all peoples. Of course, the specific programs and policies to reduce childhood poverty and abuse would need to be evaluated empirically themselves to guarantee an important improvement in development of the brain and health of the child when he/she grows up.

And this is the real power of neuroscience and basic scientific research papers like this one. Research into how our brains operate in real-life situations reveal a side of our minds and our personalities that we never may have considered before and the huge implications this can have for society. The brain is a complex machine and just like other machines it can be broken.

Of course, we shouldn’t extrapolate too much and say that, for example, a drug addict who was abused as a child is not responsible for anything they’ve ever done in between. But is important to recognize all the mitigating factors at play in a person’s success and simply dismiss someone’s problems as “their own personal responsibility.” As a neuroscientist, I might argue that that phrase and the issues behind it are way more nuanced than the how certain politicians like to use it.

Special endnote Due to some recent shifts in my career, Dr. Simon Says Science will be expanding the content that I write about. Addiction and neuroscience will still be prominently featured but I plan to delve into a variety of other topics that I find interesting and sharing opinions that I think are important. I hope you will enjoy the changes! Thanks very much!


Tragedy in Orlando: A Call to End Gun Violence, Terror, and Homophobia.

Orlando imagePulse

Once again an American citizen (not an immigrant or refugee of any kind) has mass murdered other American citizens using a legally purchased weapon, a weapon that exists for no other reason than to be used to kill as many people as possible. The attack in Orlando is a confluence of so many problems in the US and world today: gun violence, homophobia, racism, religious extremism and Islamist terrorism. Sadly, there will be a portion of this country that won’t really care about these attacks because 1) they specifically targeted gay people and 2) minority men were primarily killed in the attacks. Narcissistic demagogues like Donald Trump will use the attacks to expand his racist rhetoric and hate speech in order to galvanize the furor of his supporters—he’ll profiteer from the loss of human life to boost his poll numbers (by the way, Trump was endorsed by the NRA so don’t expect any comments on gun control).

I could spend my time talking about how attacks like these are only possible because of the ease in which guns can be purchased in the United States but why? Supporters of stricter gun control already know these arguments while the people that need to hear them never will. But there’s another issue here.

The massacre in Orlando brought to national attention something that is common but unknown by many. Gay people are the victims of violence, hate and terror all over the world. Terrorist groups such as ISIS specifically target gay people and murder them in horrific ways. But it’s not just the Islamist philosophy that promotes homophobia. The silent victimization of gay people is promoted by religious extremism in all its forms. I’ll even go one step further and make the claim that homophobia’s ONLY proponent is archaic religious beliefs. All adult humans beings have a capacity for love and all adult human beings should be allowed to express their love however way they want without fear of reprisal or intimidation from bigots.

In this Pride month is important to remember the progress that has been made but the shadows of the past follow us no matter how far forward we march. The Nazi’s used the pink triangle to mark gay men in the same way the Star of David was used to mark Jews. That symbol has been reclaimed as reminder of how the horror of the past can motivate strength in the present.

Stay united in support for the victims of the Orlando attacks. Mourn their loss and celebrate their lives. But be angry too. Use that anger to fight for an end to gun violence, an end to Islamist and religious extremism, an end to homophobia and persecution of LGBT people around the world.


NIH Scientists Identify a Potential New Treatment for Depression: A Metabolite of Ketamine

In a remarkable example of scientific collaboration, a new study produced by scientists at various research centers at the National Institutes of Health (NIH) have identified how ketamine works as powerful and fast-acting anti-depressant. This discovery may lead to an effective and potent new treatment for depression.

Ketamine is normally used as an anesthetic but at low doses, it has been shown to have rapid acting and long-lasting anti-depressant effects in humans. Fast relief of depression is incredibly important because most anti-depressant medications are not very effective or can take weeks (or even months in some cases) for maximal effect, which hurts the recovery of patients suffering from this crippling psychiatric disorder. However, despite its rapid action, ketamine has many side effects such as euphoria (a “high” feeling), dissociative effects (a type of hallucination involving a sense of detachment or separation from the environment and the self), and it is addictive.

If ketamine could be made safe to use without any of its other more dangerous properties, it would be a powerful anti-depressant medication.

With this goal in mind, scientists at the National Institute of Mental Health (NIMH), National Institute on Aging (NIA), National Center for Advancing Translational Sciences (NCATS), University of Maryland, and University of North Carolina-Chapel Hill sought to unravel the mystery of how ketamine works.

When ketamine enters the body it is broken down (metabolized) into many other chemical byproducts (metabolites). The team of scientists identified that it’s not ketamine itself but one of it’s metabolites, called HNK, that is responsible for ketamine’s anti-depressant action Most importantly HNK does not have any of the addictive or hallucinogenic properties of ketamine. What does this mean? This special metabolite can now be produced and can be given to patients while ketamine (and all its unwanted negative side effects) can be bypassed.

depressionOf course, many tests still need to be done in humans to confirm the effectiveness of HNK, but the study is an amazing example of how an observation can be made in the clinic, brought in the lab for detailed analysis, and then brought back to the clinic as a potential effective treatment.

But how did the scientist’s do it and how do they know that this HNK is what’s responsible for ketamine’s depression-fighting power? Keep reading below to find out.

Also, check out the NIH’s press release on the study.

The original study can be found here.

What is ketamine?


Chemical structure of ketamine (wikimedia.org).

Ketamine has traditionally been used an as anesthetic due to it’s pain relieving and consciousness-altering properties [1]. However, at doses too low to induce anesthesia, it has been shown that ketamine has the ability to relieve depression [2]. Even more remarkably, the anti-depressant effects of ketamine occur within a few hours and can last for a week with only a single dose. Most anti-depressant medications can take weeks before they start relieving the symptoms of depression (this is due to how those medications work in the brain).

However, ketamine also has unwanted psychoactive properties, which limits its usefulness in the treatment of depression. Ketamine causes an intense high or sense of euphoria as well as hallucinogenic effects such as dissociation, a bizarre sense of separation of the mind from the self and environment. Ketamine is also addictive and is an abused party drug [3].

A debate has been going about whether ketamine should be used for the treatment of depression and if its risks outweigh its benefits [4]. However, what if ketamine itself is not responsible for the anti-depressant function but a chemical byproduct of ketamine? This is what the scientist’s in this study reported: it’s HNK and not ketamine that are responsible for the powerful anti-depressant functions. This discovery was made in mice but how do scientists even study depression in a mouse?


How do scientists study depression in rodents?


Depression is a complex psychological state that is difficult to study but scientists have developed a number of tests to measure depressive-like behavior in rodents. While any one particular test is probably not good enough to measure depression, the combination of multiple tests—especially if similar results are found for each test—provide an accurate measurement of depression in rodents.

Some of the tests include:

Forced Swim Test

As the name reveals, in this test rodents are place in a cylinder of water in which they cannot escape are a forced to swim. Mice and rats are very good swimmers and when placed in the water will swim around for a while, searching for a way to escape. However, after a certain amount of time, the mouse will “give up” and simply stop swimming and will just float there. This “giving up” is used as a proxy for depression, similar to how people that are depressed often lack perseverance or motivation to keep trying. If you a give drug and the mice swim for much longer than without the drug, then you can make the argument that the drug had an anti-depressant effect. See this video of a Forced Swim Test.

Learned Helplessness Test

One theory of depression is that it can result from being placed in a bad situation in which we have no control over. This test models this type of scenario.

First, mice are place in chamber where they experience random foot shocks (the learning about the bad, hopeless situation). Next, they are place in a chamber that has two compartments. When a foot shock occurs, a door opens to a “safe” chamber, which gives the mouse an opportunity to escape the bad situation. One measure of depression is that some mice won’t try to escape or will fail to escape. In essence, they’ve given up at trying to escape the bad situation (learned helplessness). You can then take these “depressed” mice, and run the experiment again but this time with the anti-depressant drug you want to test and see how they do at escaping the foot shocks. Read more here.

Chronic Social Defeat Stress

Imagine you had a bully that would beat you up every day but the bully lived next door to you and would stare at you through his bedroom window? It would probably make you feel pretty crummy, wouldn’t it? Well, in essence, that’s what chronic social defeat stress test is all about [5].

A male mouse is placed in a cage with a much larger, older, and meaner male mouse that then attacks it. After the attack session, the “victim” mouse is housed in a cage where it can see and smell the bigger mouse. This induces a sense of hopelessness or depression in the “victim” mouse and it will not try to interact with a “stranger”” mouse if given a choice between the stranger and an empty cage (mice are pretty curious animals and will usually sniff around a cage with a unfamiliar mouse in it). This social avoidance is a measure of depression. In contrast, some mice will be resilient or resistant to this type of stress and will interact normally with the “stranger” mouse. Similar to above, you can test an anti-depressant drug in the “resilient” mice and the “depressed” mice.

There are a few others but these are three of the main ones used in this paper.

How did the NIH scientists figure out how Ketamine works to fight depression?

It was believed that ketamine’s anti-depressant function was due to its ability to inhibit the activity of the neurotransmitter glutamate. Specifically, ketamine inhibits a special target of glutamate called the NMDA receptor [6].

The first thing done is this paper was to study ketamine’s effects in rodent models of depression and sure enough, it was effective at relieving depression-like behavior in the mice.

Ketamine comes in two different chemical varieties or enantiomers, R-ketamine and S-ketamine. Interestingly, the R-version was more effective than the S-version (this will be more important later).

Recall that ketamine is though to work because it inhibits the NMDA receptor, but the scientists found that another drug, MK-801, that also directly inhibits the NMDA receptor, did have the same anti-depressant effects. So what is it about ketamine that makes it a useful anti-depressant then if not it’s ability to inhibit the NMDA receptor?

Ketamine is broken down into multiple different other chemical byproducts or metabolites once it enters the body. The scientists were able to isolate and measure these different metabolites from the brains of mice. For some reason one of the metabolites, (2S,6S;2R,6R)-hydroxynorketamine (HNK) was found to be three times higher in females compared to males. Ketamine was also more effective at relieving depression in female mice compared to male mice and the scientists wondered: could it be because of the difference in the levels of the ketamine metabolite HNK?

To test this, a chemically modified version of ketamine was produced that can’t be metabolized. Amazingly the ketamine that couldn’t be broken down did not have any anti-depressant effects. This finding strongly suggests that it’s really is one of the metabolites, and not ketamine itself, that’s responsible for the anti-depressant activity. The most likely candidate? The HNK compound that showed the unusual elevation in females vs males.

Similar to ketamine, HNK comes in two varieties, (2S,6S)-HNK and (2R,6R)-HNK. The scientists knew that the R-version of ketamine was more potent than the S-version so they wondered if the same was true for HNK. Sure enough, (2R,6R)-HNK was able to relieve depression in mice while the S-version did not. The scientists appeared to have identified the “magic ingredient” of ketamine’s depression-relieving power.

These experiments required a great deal of sophisticated and complex analytical chemistry. However, this is beyond my area of expertise so unfortunately cannot discuss it further.

So now the team had what they thought was the “magic ingredient” from ketamine for fighting depression. But could they support their behavior work with more detailed molecular analyses?

The next step was to look at the actual properties of neurons themselves and see if (2R,6R)-HNK changed their function in the short and long term. Using a series of sophisticated electrophysiology experiments in which the activity of individual neurons can be measured, the scientists found that glutamate signaling was indeed disrupted. However, it appeared that a different type of glutamate receptor was involved: the AMPA receptor, and not NMDA receptor. The scientists confirmed this with protein analysis; components of the AMPA receptor increased in concentration in the brain over time. These data suggest that it is alterations in glutamate-AMPA signaling that underlies the long-term effectiveness of HNK.

OK, so great! HNK reduces depression but does it still have all the other nasty side effects of ketamine? If it does, then it’s no better than ketamine itself.

For the final set of experiments, the scientists looked at the psychoactive and addictive properties of ketamine. Using a wide range of behavioral tests that I won’t go into the details of, 2R,6R)-HNK had a much lower profile of side effects than ketamine.

Finally, ketamine is an addictive substance that can and is abused illegally. A standard test of addiction in mouse models is self-administration (I’ve discussed this technique previously). Mouse readily self-administer ketamine, which indicates they want to take more and more of it, just like a human addict. However, rodent’s do not self-administer HNK! This means that HNK is not addictive like ketamine.

mental health

In conclusion, (2R,6R)-HNK appears to be extremely effective at relieving depression in humans, has less side-effects than ketamine, and is not effective. Sounds pretty good to me!

Next step: does HNK work in humans? To be continued….

Selected References

  1. Peltoniemi MA, et al. Ketamine: A Review of Clinical Pharmacokinetics and Pharmacodynamics in Anesthesia and Pain Therapy. Clinical pharmacokinetics. 2016.
  1. Newport DJ, et al. Ketamine and Other NMDA Antagonists: Early Clinical Trials and Possible Mechanisms in Depression. The American journal of psychiatry. 2015;172(10):950-66.
  1. Morgan CJ, et al. Ketamine use: a review. Addiction. 2012;107(1):27-38.
  1. Sanacora G, Schatzberg AF. Ketamine: promising path or false prophecy in the development of novel therapeutics for mood disorders? Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2015;40(5):1307.
  1. Hollis F, Kabbaj M. Social defeat as an animal model for depression. ILAR journal / National Research Council, Institute of Laboratory Animal Resources. 2014;55(2):221-32.
  1. Abdallah CG, et al. Ketamine’s Mechanism of Action: A Path to Rapid-Acting Antidepressants. Depression and anxiety. 2016.


What is naloxone? Should it be available over the counter?


New blog post for addictionblog on naloxone, an antidote for opioid overdoses.

Read my post at addictionblog here!



CDC Reports Zika Virus Causes Microcephaly

Aedes aegypti mosquitoes (commons.wikimedia.org)

Aedes aegypti mosquitoes (commons.wikimedia.org)

A few weeks ago I wrote a post All About Zika virus epidemic. The million-dollar question is does Zika cause microcephaly (or abnormally small heads and severe brain damage) in the fetus if a pregnant woman is infected with virus? At the time I wrote my first post, the evidence strongly suggested that it did but scientists were reluctant to declare a direct causal relationship.

Earlier this month, scientists at the CDC published in the New England Journal of Medicine that there is now enough evidence to confirm that:

Yes, Zika virus does cause microcephaly.

The team from the CDC examined all the available reports and studies on the Zika virus and microcephaly and did a systematic analysis of all the evidence using a strict set of criteria to determine causality.

Read the full study.

While no one report or piece of evidence is the “smoking gun” all of the pieces put together reveal the truth. Just like only when all the pieces of a puzzle are fit together is the whole picture clear.

This conclusion is extremely important because the risks for pregnant women are very real. The CDC has released important information for pregnant women or women who intend to become pregnant in areas were Aedes mosquitoes (Zika carrying mosquitoes) are prevalent.

Read the CDC’s Information for Pregnant Women.

It’s important to remember that while Zika does cause microcephaly is does not cause it in 100% of pregnancies. Some pregnant women bitten by Zika will have no problems with the developing fetus. One thing we still don’t know is what is the risk that the Zika will cause microcephaly and who are the mothers most in danger of this happening?

As more information is gathered on this epidemic and more scientific studies published, the more we will learn about how to fight it.


The CDC Fights Back Against the Opioid Epidemic


The CDC has released important information on dealing with the prescription opioid pain medication and heroin epidemic. Opioids are a class of drugs that include pain medications such as morphine, oxycodone, hydrocodone, methadone, fentanyl and others and the illegal drug heroin. I’ve spoken a great deal about this problem in various other posts (see here here here and especially here and here). Just to summarize some of most disturbing trends: the US is experiencing a surge in deaths due to overdose on opioids (overdoses/year due to opioids are now greater than fatalities from car crashes), virtually all demographics (age groups, income levels, gender, race) are affected, and many people addicted to opioid pain pills transition to heroin and as such, a huge increase in heroin abuse is also occurring; teenagers and adolescents are especially hard hit. The CDC’s report, released on Friday, March 18 provides a thorough review of the clinical evidence around prescription opioid pain medications and makes 12 recommendations to help control the over-prescription of these powerful drugs in attempt to reduce the amount of overdose deaths and addiction.

Read the full report.

I finally got around to reading the whole thing and am happy to summarize its main analyses and findings. While the report is intended for primary health care providers and clinicians, the report’s findings are important for anyone suffering from short or long-term pain and the risks vs benefits posed by opioids.

But before I dive into the meat of the report, I wanted to clarify an important issue about addiction to prescription opioids. A false narrative exists that those suffering from addiction are “drug seekers” and it is this group of people that is duping doctors in prescribing them too many opioids while good patients that take opioids as directed are not over dosing or becoming addicted. It’s important to remember that opioids are so powerful anyone that takes them runs the risk of overdosing or becoming addicted after repeated use. Most people suffering from addiction and overdoses during the current prescription opioid epidemic are people that used opioids medically and not for recreation. This is true for youths prescribed opioids for a high-school sports injury, and older patients prescribed opioids for chronic back pain, and many other “regular” people. The CDC released this report to help fight back against the over-prescription of opioids and the severe risks that accompany their use. Doctors and patients alike need to be aware of the risks vs benefits of opioids if they decide to use them for pain therapy.

Hydrocodone (wikimedia.org)

Hydrocodone (wikimedia.org)

The CDC’s report had three primary goals:

  1. Identify relevant clinical questions related to prescribing of opioid pain medications.
  2. Evaluate the clinical and contextual evidence that addresses these questions
  3. Prepare recommendations based on the evidence.

Two types of evidence were used in preparation of the report: direct clinical evidence and indirect evidence that supports various aspects of the clinical evidence (contextual evidence). Studies included in the analysis ranged from high quality randomized control studies (the gold standard for evaluating clinical effectiveness) to more observational studies (not strong, direct evidence but useful information nonetheless).

The report identified five central questions regarding the concerns over opioids:

  1. Is there evidence of effectiveness of opioid therapy in long-term treatment of chronic pain?
  2. What are the risks of opioids?
  3. What differences in effectiveness between different dosing strategies (immediate release versus long-acting/extended release)?
  4. How effective are the existing systems for predicting the risks of opioids (overdose, addiction, abuse or misuse) and assessing those risks in patients?
  5. What is the effect of prescribing opioids for acute pain on long-term use?

Based on a close examination of the clinical evidence from a number of published studies, the CDC found the following answer to these questions.

  1. There is no evidence supporting the benefits of opioids at managing chronic pain. Opioids are only useful for acute (less than 3 days) pain and for cancer pain or end-or-life pain treatment.
  2. Opioids have numerous risks such as abuse and addiction, overdose, fractures due to falling in some older patients, car crashes due to impairments, and other problems. The longer opioids are used the greater these risks.
  3. There is no difference in effectiveness between immediate release opioids and long-acting or extended release formulation. The evidence suggests the risk for overdose is greater with long-acting and extended-release opioids.
  4. No currently available monitoring methods or systems are capable of completely predicting or identifying risk for overdose, dependence, abuse, or addiction but severak methods may be effective at helping to evaluate these risk factors.
  5. The use of opioids for treating acute pain increases the likelihood that they will be sued long-term (most likely because of tolerance and dependence).
Oxycodone (wikimedia.org)

Oxycodone (wikimedia.org)

The CDC also examined what they called contextual evidence or studies that didn’t directly answer the primary clinical questions but still provided valuable, if indirect, information about treatment of pain with/without opioids.

  • Non-medication based therapies like physical therapy, exercise therapy, psychological therapies, etc. can be effective at treating chronic pain for a number of conditions.
  • Non-opioid pain medications such as acetaminophen, NSAIDs, Cox-2 inhibitors, anti-convulsants, and anti-depressants (in some instances) were also effective in treating chronic pain for various conditions and have fewer dangers than opioids.
  • Long-acting opioids increase the risk for overdose and addiction. Higher doses of opioids also increase the risk for overdose.
  • Co-prescription of opioids with benzodiazepines greatly increases the risk of overdoses.
  • Many doctors are unsure of how to talk to their patients about opioids and their benefits vs risks and most patients don’t know what opioids even are.
  • The opioid epidemic costs billions of dollars in medical and associated costs. Its estimated  costs due to treatment of overdose alone is $20.4 billion.

Many other findings and important pieces are information were reported but too many to list here.

Based on all results of the analysis the CDC came up with 12 recommendations in three broad categories. I’ll briefly discuss each recommendation.

Category 1: Determining when to initiate or continue opioids for chronic pain.

  • Recommendation 1: Non-pharmacologic (medication-based) therapy and non-opioid pharmacologic therapy are preferred for chronic pain.
    • The risks of overdose and addiction from long-term use of opioids is very high and benefits for actually treating pain are very low for most people. Therefore, other safer and more-effective treatments should be use first. The discussion of the risks vs benefits needs to be made clear by the patient’s doctor.
  • Recommendation 2: Before starting opioid therapy for chronic pain, clinicians should establish treatment goals with all patients, including realistic goals for pain and function
    • Opioids should be used for the shortest amount of time possible but if used for a long-term treatment, at the lowest effective dose.
    • If a patient suffers from an overdose or seems as if dependence or addiction is developing, a patient may need to be tapered off of opioids.
  • Recommendation 3: Before starting and periodically during opioid therapy, clinicians should discuss with patients known risks and realistic benefits of opioid therapy.
    • The risks are high for the use of opioids and it is necessary for doctors to keep their patients informed about these risks.
    • Doctors should be “be explicit and realistic about expected benefits from opioids, explaining that while opioids can reduce pain during short-term use, there is no good evidence that opioids improve pain or function with long-term use, and that complete relief of pain is unlikely.”

Category 2: Opioid selection, dosage, duration, follow-up, and discontinuation.

  • Recommendation 4: When starting opioid therapy, clinicians should prescribe immediate-release opioids instead of extended-release or long-acting opioids.
    • There appears to be no difference in effectiveness at treating pain between the different types of opioids but the long-acting opioids come with a greater risk for overdose and dependence.
    • Long-acting opioids should be reserved for cancer pain or end-of-life pain.
    • It’s important to note that “abuse-deterrent” does not mean that there is no risk for abuse, dependence, or addiction. These types of formulations are generally to prevent intravenous use (shooting up with a needle) but most problems with opioids occur as a result of normal, oral use.
  • Recommendation 5: When opioids are started, clinicians should prescribe the lowest effective dosage.
    • The higher the dose the greater the risk. A low dose may be sufficient to control the pain without risk for overdose or the development of dependence.
    • Opioids are often most effective in the short-term and may not need to be continued after 3 days.
    • If dosage needs to be increased, changes in pain and function in the patient should be re-evaluated afterwards to determine if a benefit has occurred.
    • Patients currently on high-dose long-term opioids for chronic pain may want to consider tapering down their dosage.
      • Tapering opioids can be challenging can take a long-time due to the physical and psychological dependence. Tapering should be done slowly to and the best course of dosage should be determined specifically for the patient.
    • Recommendation 6: Long-term opioid use often begins with treatment of acute pain. When opioids are used for acute pain, clinicians should prescribe the lowest effective dose of immediate-release opioids and should prescribe no greater quantity than needed.
      • Evidence suggests that using an opioid for acute pain can start a patient down a path of long-term use. This should attempted to be avoided by using a low dose if opioid is selected to treat acute pain.
      • Acute pain can often be effectively managed without opioids with non-medication-based therapies (like exercise, water aerobics, physical therapy, etc.) or non-opioid medications (like acetaminophen or NSAIDs).
    • Recommendation 7: Clinicians should evaluate benefits and harms with patients within 1-4 weeks of starting opioid therapy for chronic pain or of dose escalation.
      • Opioids are most effective for the first three days and possible up to a week. If long-term therapy is decided upon, treatment should regularly be reassessed and reevaluated (at least every 3 months for long-term therapy).

Category 3: Assessing risks and addressing harms of opioid use.

  • Recommendation 8: Before starting and periodically during continuation of opioid therapy, clinicians should evaluate risk factors for opioid-related harms. Clinicians should incorporate into the management plan strategies to mitigate risk, including considering offering naloxone.
    • Specific risk factors for the specific condition that patient is using opioids for should be considered when developing the treatment plan.
    • Naloxone blocks the effects of opioids and can immediately revive someone that has experienced an overdose. Naloxone should be offered to patients if a patient is using opioids at high-dose for long-term therapy or previously suffered an overdose.
  • Recommendation 9: Clinicians should review the patient’s history of controlled substance prescription using state prescription drug monitoring program (PDMP) data to determine whether a patient is receive opioid dosages or dangerous combinations that put him or her at risk for overdose.
    • PDMPs are state-run databases that collect information on controlled prescription drugs dispensed by pharmacies and in some states, physicians too.
    • While the clinical evidence was unclear if PDMPs were accurate at predicting overdose or addiction, the contextual evidence supported that “most fatal overdoses were associated with patients receiving opioids from multiple prescribers and/or with patients receiving high total daily opioid dosage.”
    • PDMP should be consulted before beginning opioid therapy and during the course of treatment if used for long-term therapy and this data should be discussed with the patient.
    • However, PDMP data must be used cautiously as some patients are turned away from treatment that would otherwise have benefited.
  • Recommendation 10: (not a general recommendation but to be considered on a patient-by-patient basis) When prescribing opioids for chronic pain, clinicians should use urine drug testing before starting opioid therapy and consider urine drug testing at least annually to assess for prescribed medications as well as other controlled prescription drugs and illicit drugs.
    • Urine drug tests can reveal information about potential risks due to combinations with other drugs not reported by the patient (e.g. benzodiazepines, heroin).
    • Urine testing should become standard practice and should be done prior to starting opioids for chronic therapy.
    • Clinicians should make it clear that testing is intended for patient safety and is not intended to deprive the patient of therapy unnecessarily.
  • Recommendation 11: Clinicians should avoid prescribing opioid pain medication and benzodiazepines concurrently whenever possible.
    • Strong evidence suggests that many overdoses occurred in patients prescribed both benzodiazepines and opioids. The two should never be prescribed together if at all possible.
  • Recommendation 12: Clinicians should offer or arrange evidence-based treatment (usually medication-assisted treatment with buprenorphine or methadone in combination with behavioral therapies) for patients with opioid abuse disorder (addiction).
    • Many patients using opioids for chronic pain now may have become physically and psychologically addicted to them and should be offered treatment (estimated at 3-26% of patients using opioids for chronic pain therapy).
    • Methadone and buprenorphine are proven, safe, and effective-treatments that retain patients in treatment and that satisfy an opioid addict’s cravings, prevent relapse to abusing opioids/heroin, and allow the patient to live a normal life (read my blog post on methadone).
    • Behavioral therapy/individual counseling in combination with medication-based treatment may improve positive benefits of treatment even further.
    • However, access to these medications can be extremely limited in some communities due to availability (methadone is restricted to clinics and clinicians need certification in order to prescribe buprenorphine) or cost (treatment often is not covered by insurance).
    • Urine testing or PDMP data may help to reveal if a patient has become addicted and if so, treatment should be arranged.

In Summary, the main takeaways from the report are:

  • Opioids are associated with many risks such as overdose, abuse, dependence, addiction, and others (e.g. fractures from falling or car-crashes due to impairment).
  • No evidence exists that opioids are effective for treatment of chronic pain (with the exception of cancer and end-of-life pain).
  • Opioids are most effective for short term (3-7 days) and in immediate-release formulations.
  • Non-medication based therapies and non-opioid medications are preferred for treatment of chronic pain.
  • Doctors need to clearly explain the risks vs benefits of opioid therapy with their patients.
  • If decided as the best course of action for a particular patient, opioid therapy needs to be repeated re-evaluated to make sure it is still working to alleviate pain.
  • The prescription drug monitoring programs are useful tools that should be consulted prior to beginning therapy in order to help determine a patient’s history with opioids and risk for abuse or overdose.
  • Naloxone should be made available to patients using opioids for long-term therapy in order to prevent possible overdoses.
  • Access to medication-based treatments (methadone or buprenorphine) for dependent individuals should be provided.

Concluding Thoughts

In 1995 Purdue pharmaceuticals released OxyContin (oxycodone, one of the most common prescription opioid pain medications) and launched an enormous push for doctors to use opioids as the primary treatment for chronic pain. The enormous surge in in prescriptions of oxycodone (500% increase from 1999-2011) followed this marketing campaign. One of the most disturbing aspects revealed by the CDC’s report is that despite this surge in prescriptions, there is a complete lack of data on the effectiveness of opioids for long-term chronic pain therapy.

To be fair though, “Big Pharma” is not the sole culprit in this crisis. One argument is that pharma was responding to the need of clinicians for an increased demand by patients for management of chronic pain. It is very disturbing though that the push for the use of opioids for long-term management was initiated without any supporting evidence. This is another example of how medicine must be guided by evidence-based principles and not on personal beliefs and values or medical tradition and culture.

It’s important to remember that some patients do tolerate opioids well and these patients may find them beneficial at treating their chronic pain condition. The guidelines do stress frequent reevaluation of the benefits vs risks of opioids and for some patients benefits will outweigh the risks.

Finally, the CDC’s guidelines are not legally binding. These are recommendations and not laws or regulations. This means no doctors are not legally required to comply with any of the CDC’s recommendations. Hopefully some or all of these recommendations will be formalized into formal laws and regulations because many of them are extremely important in regulating these powerful and potentially dangerous drugs.

(Also check out the Diane Rehm Show’s hour-long discussion of the report. As usual, the show offers a high quality analysis and discussion from a panel of experts.)

All About Zika

Zika virus


 You’d have to be living in a cave on Mars to not have heard anything about the Zika virus epidemic sweeping through South America or it’s link to a dreaded birth defect: microcephaly. But as with every news worthy epidemic, there’s a lot of fear and plenty of misinformation. Fear is natural to something as terrifying as thousands of cases of birth defects linked to a virus that few people have ever heard about until a few months ago, but fear must not cloud our judgment and lead us to claim this or that about the virus without support of the facts. Stop and take a deep breath. Zika is indeed terrifying but like every other disease, science can help us understand what it is, what it does, and most importantly, how to stop it.

Unfortunately, the Internet can be a breeding ground for terrible ideas and conspiracy theories. Just as a quick spoiler on the following conspiracy theories : 1) Zika is not caused by or spread by genetically modified mosquitoes, 2) the epidemic did not occur because of tests with a Zika vaccine, and 3) while it cannot be ruled out entirely, larvicides/pesticides are not responsible for microcephaly (more discussion on these conspiracy theories later).

There’s a lot we still don’t know about the virus still but there’s a lot we have learned already and new information is emerging every day. We must be cautious: as members of a supposedly intelligent democracy, we must be careful to not over exaggerate or underestimate this problem—we must look at the facts and draw our conclusions from there.

Recently I’ve prepared a report on the Zika virus for an outside project, which required a great deal of reading scientific papers, news articles, reports from public health organization, listening to podcasts on the virus, and seminars discussing the most recent findings on it.

I present here, to the best of my ability, the most up-to-date, scientifically verified information about the Zika virus, what we know and don’t know about the risks it poses, and debunking some of the misinformation around it. At the end I make a few suggestions about what should be done about it. I include a glossary of important terms  as well as references to important papers on the zika virus.

This post is really long (probably my longest blog post ever) so feel free to skip to whichever topic about the virus you are most interested in. Here’s links to the different topics:

What is it?


Viral entry into a cell. (wikipedia.org)

Zika is a virus that was discovered in the Zika Forest in Uganda in 1947 [1]. Scientists were looking for other types of viruses and discovered it by chance when one of the test monkeys became ill with something previously unknown.

Zika is a flavivirus, a family of viruses that includes dengue, chikungunya, yellow fever, and West Nile.

Like other viruses, Zika invades specific cells, hijacks those cells in order to force the cell to copy its DNA and make more viral particles.

Viral replication (wikipedia.org)

Viral replication (wikipedia.org)

The reason why Zika is such a problem compared to other flaviviruses like dengue (which is far more common) is that is has been linked to a devastating birth defect, microcephaly (more on this later).

On February 1, 2016 the World Health Organization (WHO) has declared Zika virus a Public Health Emergency of International Concern. The Centers for Disease Control (CDC) in the United States has also issued a travel advisory to pregnant women considering visiting countries with ongoing Zika outbreaks has released guidelines for health care providers in the US who are treating pregnant women whom may have traveled to an area with Zika virus [2, 3].

Where did it come from?

While it may have been discovered in 1947 [1], it’s been spreading slowly across Africa since then. A distinct Asian variety of the virus was first discovered in 1966 in Malaysia [4]. The first epidemic of Zika occurred in the Micronesian island of Yap in 2007. Since then it has spread across the Pacific including an epidemic in French Polynesia in October 2013 to April 14. The virus spread to Easter Island off the coast of Chile sometime after that and the first cases in Brazil were reported in February 2015.

We know how the virus spread  because over the years, scientists have collected viruses from various parts of the word, analyzed the viral DNA and RNA, and compared the results [5]. We know that the virus in the Americas is related to the Asian variety.

Zika outbreaks have been reported in 52 countries, included 31 in the Americas. More recently out breaks in Indonesia and Malaysia have also been reported.

No cases of mosquito-spread Zika have occurred in the US. (When a disease is spread by the an organism that carries it in a place in which that organism lives, we call that autochthonous transmission. Autochthonous transmission of Zika virus in the US would mean that a case occurred because of a mosquito bite. A non-autochthonous case of Zika would be someone traveling to a country with Zika, getting bitten by a Zika-carrying mosquito, then returning home and being diagnosed). So far, the only cases of Zika in the U.S. have been 1) people that traveled to regions in virus outbreaks or 2) a few cases of sexual transmission.

How is it spread?

Zika is spread through bites of the common mosquito Aedes aegypti, a species that bites during the daytime, but it can potentially be spread by any mosquito of the Aedes genus, including the Asian Tiger mosquito (Aedes albopictus), and many other species. Aedes mosquitoes also carry the other flaviviruses (dengue, chikungunya, yellow fever, and West Nile).

Aedes aegypti mosquitoes (commons.wikimedia.org)

Aedes aegypti mosquito (commons.wikimedia.org)

Aedes aegypti mosquitoes are common to most of Central and South America as a well as 12 states in the South Eastern United States. However, Aedes albopictus can be found in 30 states, including along the entire Eastern seaboard [6].

Keep in mind that differences in the USA and Brazil means that the spread of mosquito-borne disease like Zika will also be different. For example, many people in South America don’t have access to running water, which means that water is stored in containers outside, which make perfect breeding ground for Aedes mosquitoes. Also, many people don’t have air conditioning so they do not stay indoors and unexposed to mosquito bites.

That being said, it is very possible that Zika will spread with the US [7] and we may see local outbreaks but almost certainly nothing compared to what’s happening in Brazil (see below for more).

*It should also be noted that Aedes mosquitoes are widely distributed throughout the globe but studies predict even greater distribution, meaning more areas for mosquito-borne diseases to spread. This is an often forgotten consequence of climate change. As the globe warms and certain regions warm, mosquito spread is predicted to increase, and the disease they carry along with them. [8, 9]*

Global distribution of Aedes aegypti mosquitoes (commons.wikimedia.org)

Global distribution of Aedes aegypti mosquitoes (commons.wikimedia.org)

Can Zika be spread through sex?

Yes, there have been two confirmed reports of sexual transmission occurring in the US and the CDC is currently evaluating a potential 16 more. What this means is that a person traveled to a Zika-containing country, got bit with a Zika mosquito, returned home and had sex with his partner, and the virus was detected in the partner. The virus has also been detected (by RT-PCR) in semen long after the infection has passed and the virus has been cleared from the blood [10]. Men infected with the virus are definitely at risk of passing it to their partners.

What is the risk of a Zika outbreak occurring in the United States?

The risk of outbreaks of Zika occurring in isolated pockets in the US, especially in states such as Texas or Florida (where mosquitoes can breed year round) is likely [7]. However, it is very unlikely that the epidemic proportions we are seeing elsewhere will occur in the US. For example, Dengue outbreaks have been occurring for years in Brazil and other nations in South America but there has never been a Dengue outbreak in the continental US (Dengue is also spread by Aedes mosquitoes). One exception is a Dengue outbreak did occur in Key West in 2009/10 but this is a semi-tropical environment more comparable to Central/South America than the rest of the South Eastern US.

Another example is the West Nile virus outbreak in the late 1990s/early 2000s, another mosquito-borne flavivirus. However, while West Nile may be in the same viral family as Zika, their biology and transmission patterns are quite different. For example, viruses like Zika and dengue require sufficient quantities of virus to build up in their host (e.g. humans) in order for a passing mosquito to pick up the virus and spread it to the next host. For West Nile, while it can infect humans, its host reservoir is primarily birds. This allowed mosquitoes to bite birds, get infected to the virus, and pass it along to humans. Therefore, a continuous cycle can exist for West Nile because birds obviously don’t practice mosquito bite prevention. With humans living in the US, our exposure to mosquitoes is much less so the risk of perpetuating cycle developing that would drive a Zika epidemic is unlikely to occur.

Finally, the differences in lifestyles and economic circumstances of the different populations mean that Americans are less exposed to mosquitoes and thus less likely to be bitten (see above).

In conclusion, will we see autochthonous (mosquito-spread) Zika cases in the United States? Probably. Will it be an epidemic that impacts the whole country? Probably not.

Thankfully the CDC is already issuing guidelines for the detection of the virus in pregnant women that may have traveled regions with virus and taking all the necessary steps to help control the virus in the US. And of course, the best strategy to prevent the spread of Zika to the US is to help Brazil and other Central and South American countries in containing the ongoing epidemic.

What does it do?

Most Zika cases (about 80%) have no symptoms but those that do present with mild symptoms like fever, rash, and swelling lymph nodes. The difficult of diagnosing people infected with the virus (i.e. pregnant women) is one of the major problems health officials in South America are confronting. Work is being done to improve testing for the virus (see below)

The symptoms last for about a week and virus is cleared from the blood in about a month.

The real concern with Zika is that it may be the cause of the severe birth defect microcephaly and the nervous system disease Guillain-Barre syndrome (See below).

How bad is the epidemic occurring in Brazil and other countries in the Americas?

 Unfortunately, this question is difficult to answer because 1) Zika virus is notoriously difficult to detect and distinguish from other flaviruses (see below) 2) direct detection of the virus can is only possible between 7-10 days of the infection 3) symptoms of the virus are similar to other flaviviruses and 4) most cases are asymptomatic (no symptoms at all).

Who-logoNevertheless, as of February 5, 2016 the WHO reported 26 countries have reported Zika outbreaks (this number has been increased to 31 as of March 11). Also, the Brazillian Ministry of Health reported that virus has infected between 500,000 and 1.5 million people. Because the virus is so difficult to diagnosis, the actual number of cases is probably much higher than this.

Zika cases have been reported in 26 countries in the Americas including Mexico and Puerto Rico. Colombia is reporting the second highest number of zika cases at about 20,000.

The full impact of this large number of cases and its implications for microcephaly in Brazil, Colombia, and other countries is unknown but I’ll discuss that shortly.

How is Zika virus detected in a human patient?

When a virus invades a host organism, the host’s immune system launches an attack against the virus. Part of this response involves the generation of specific antibodies to target and clear the virus from the body. Using serological assays, these antibodies can be detected from the serum (the blood minus blood cells and clotting factors). However, because Zika, dengue, and other flaviruses are closesly related, antibodies that detect one seem to detect them all. This makes serological testing somewhat unreliable because you don’t know for sure if a positive result menas Zika, dengue, chikungunya, etc.

Functions of antibodies in the immune system

Functions of antibodies in the immune system

Example of RT-PCR results

Example of RT-PCR results

A more reliable test is for the specific genetic material of the virus itself. A very common experimental technique called RT-PCR (see the glossary) is able to distinguish the genetic material of Zika from other flaviruses [11, 12]. However, this has it’s own problems because the virus can only be detected this way from blood within 7-10 days after infection. After this 10-day window, the virus is cleared from the blood by the immune system.

RT-PCR is also useful for detected the virus in other tissues and so far Zika virus genetic material has been found in semen, breast milk, the placenta, amniotic fluid, and brain tissue of infants diagnosed with microcephaly.

Improved serologic testing is required because antibodies can persist for a very long time while RT-PCR needs to be done immediately.

Does Zika cause microcephaly?

This is the million-dollar question when it comes to Zika and the greatest source of concern about the virus.

Microcephaly is a medical condition defined by an abnormal brain development which results in a small head. According to Wikipedia, “people with the disorder have an intellectual disability, poor motor function, poor speech, abnormal facial features, seizures, and are short.” Microcephaly is a severe birth defect and it is not uncommon for infants with the condition to die at birth or shortly after. It’s causes are poorly understood. No treatments exist for microcephaly.

It is this concern over microcephaly that has prompted the WHO to declare the virus a public health emergency and the prompt the CDC to issues its travel advisory [13]. Dengue virus is far more prevalent than Zika but dengue infections are only rarely fatal (about <1% of infected individuals that receive proper treatment). The striking rise in microcephaly during the time of Zika epidemic has made it clear the Zika virus is an illness that needs to be taken extremely seriously.

Microcephaly compared to normal (wikipedia.org)

Microcephaly compared to normal (wikipedia.org)

However, there is a lack of conclusive scientific evidence that Zika virus infections directly (key word!) cause microcephaly. Importantly, there is a multitude of indirect evidence that strongly suggests that Zika is the culprit. I’ll spend a little time going through what it is we know for sure.

There are some problems with the numbers. First, diagnosis of microcephaly can be difficult [14]. In the most general definition microcephaly is diagnosed head size two standard deviations small than (this means a head size smaller than 95% of births). Microcephaly can also be dtected by ultrasound in the developing fetus in the womb. Between mid-2015 and Jan 30, 2016, the Brazilian Health ministry reported some 4,783 cases of microcephaly. 1,103 cases have completed a rigorous clinical analysis. 404 cases have been confirmed as suffering from microcephaly and 709 cases have been discarded (not microcephaly) but 3,670 cases still need to be evaluated [14]. The yearly average for microcephaly in Brazil is around 150 so clearly there’s already a large increase in microcephaly cases. Cases of microcephaly are also under investigation in Colombia, the country second hardest hit by the virus.

Also, the CDC reported the first case in the US of brain damage in a baby that has been linked to Zika.

Some experts have suggested that the number of microcephaly cases has actually been overestimated. They argue that microcephaly prior to the epidemic is much lower when compared to the US and Europe, which suggests those baseline numbers were under-reported. But now, all of a sudden, health officials are paying close attention, which may be artificially inflating the numbers.

That being said, we’re still looking at at least a 5-20 fold increase in microcephaly cases. The association between microcephaly and the Zika epidemic still seems like a strong association in my book and a real problem (evidently the WHO and CDC do too).

Just to summarize all of this, we can reasonably conclude that there is a significant increase in the number of microcephaly cases that has coincided with the onset of the Zika epidemic. However, additional prospective data is required to confirm these numbers. Besides the number of cases, there’s also a lot of laboratory work that points the finger squarely at Zika. I’ll go through these findings next.

What is the scientific proof that Zika virus causes microcephaly?

MICROCEPHALYAs I alluded to above, the only way to prove definitively that Zika causes microcephaly is to run a large, prospective study in which pregnant mothers who have confirmed Zika infection are examined and followed for their entire pregnancy, other factors like diet, genetics, and environment are excluded, the incidence of microcephaly and other birth defects recorded, and compared to pregnancies without Zika infection. If there’s a significant increased in microcephaly in the proven Zika cases, then we can reasonably conclude that Zika is is the most likely culprit (though even this study would not prove 100% causality).  In order for  to be done successfully, a very large number of people would be required to participate in the study. Fortunately but really unfortunately, the ongoing epidemic provides a large data set to work with. However, patients would need to be identified, diagnosed, and followed for their entire pregnancy which would require a ton of work and money. Concluding a study like this could take a year or longer and would require a huge concerted effort but local doctors, patients, and public health officials. I’m sure a study like this is already being planned and data is probably being collected as I write this. In fact, some small scale prospective studies have already been done (see this paper for a great summary of the various findings from different studies [15]).

However, what data exists right now?

As I described above, the drastic increase in microcephaly (even if it may be over reported) coincides with the start of the epidemic and cannot be ignored. This is fairly solid associative evidence, even if it doesn’t prove a direct cause.

Some have argued that there were no incidences of microcephaly in the French Polynesia outbreak of 2014 but in fact, once the Brazil numbers started to be released, health authorities reported they had identified an increase in microcephaly cases but did not publicize the results (perhaps because they thought it was unrelated or didn’t have strong enough data). Also, there was an increased number of abortions during the outbreak (abortion is legal in French Polynesia where it illegal in Brazil) which suggests an increased rate of birth defects in developing fetuses. As of March 11, 2016 the WHO reports that only Brazil and French Polynesia have reported an increase in microcephaly cases but cases in Colombia are currently under investigation.

We also have a strong pool of data about the detection of the virus. The Zika virus genetic material has been detected in semen, breast milk, the placenta, the amniotic fluid, and the brains of babies that were born with microcephaly and died shortly after [10, 16, 17].

What’s amazing (and terrifying) is the detection in the placenta, amniotic fluid, and brain tissues. The placenta has numerous roles in protecting the fetus such as a source of nutrients as well as a quite impermeable protective barrier. Very few viruses (such as the TORCH pathogens) can cross the placenta and that fact that Zika has been detected not only in the placenta but also the amniotic fluid and brain tissues, strongly suggests that virus can indeed cross the placenta and infect the brain of the developing baby.

The most striking and scientifically strong piece of evidence comes from a paper released in the New England Journal of Medicine, the top clinical journal in the world [12]. Keep in mind it is only a single case study but provides probably the most thorough analysis of a microcephaly case.

Microcephaly NEJMThe background behind the patient is a European woman who was 13 weeks pregnant (1st trimester) traveled to Brazil in February 2015 (the start of the epidemic) and displayed symptoms of the Zika virus (though it was not diagnosed as Zika at the time). She returned to Europe but around 26 weeks into her pregnancy (3rd trimester), an ultrasound revealed severe abnormalities in the brain of the fetus, including microcephaly. The woman and her doctor decided an abortion was the best option and the fetus was analyzed post mortem. The scientists found Zika virus in the brain of the fetus and only the brain (no other organs). Importantly, the entire genome (the total amount of genetic material unique to a particular virus) was recovered. This is important because this proves that only Zika, and not any of the other flaviruses, was detected. Furthermore, in addition to microcephaly, the brain has numerous other abnormalities such as calcification. Finally, using a high-powered microscopy technique called electron microscopy, the physical virus itself was detected in the brain tissue.

While it’s not exactly a smoking gun (scientists can be very difficult people to convince…), this study strongly suggests that the Zika virus caused the microcephaly and other brain defects in this particular case. However, other cases are required to confirm this important (and frightening!) finding.

It’s also important to note that compared to the total number of cases of Zika infection, the incidence of microcephaly is relatively low. That being said, any increases in this devastating birth defect caused by Zika are too many and must be taken extremely seriously.

If want to learn more, check out this other blog post provides another great summary of all the data.

Does Zika cause Guillain-Barre Syndrome?

Guillain-Barre syndrome (GBS) is a serious illness that can result in paralysis, permanent disability, or death. GBS is caused by a hyper-reactive response of the immune system that results in the bodies own immune defenses attacking the nerves that control movements. Certain types of infections, including other flaviviruses such as dengue and West Nile, can instigate this type of unexpected attack by the immune system. Therefore, it’s not unexpected that Zika may also been linked to the disorder.

An increased incidence of GBS was first reported during the outbreak in French Polynesia in 2014 [18] and a surge in cases has also accompanied the epidemic in Brazil [15]. A recent study [19] confirms that Zika is most likely cause of the surge of GBS cases that occurred during the French Polynesia outbreak, but the results are not conclusive. The incidence is relatively rare (about 0.24/1000 cases) [18] but at the scale of a country the size of Brazil, the number of GBS cases could be very large indeed.

How is it treated?

Dead mosquitoes

Dead mosquitoes

Unfortunately, there are currently no treatments or vaccines for Zika virus. The best method for treating the virus is prevention (see below).

Several groups are working on a vaccine but it would take years for a final product to be rigorously tested and widely distributed. A vaccine does represent the most long-term strategy to contain Zika and Anthony Fauci, director of the National Institute of Allergens and Infectious Disease (NIAID) predicts a vaccine will very likely be developed.

What can be done right now?

The best way to help keep Zika from spreading to the US is to help Brazil and other countries in the Americas to contain the Aedes mosquito population and prevent mosquito bites.

Mosquito netting (commons.wikimedia.org)

Mosquito netting (commons.wikimedia.org)

Mosquito bite prevention is easy and cheap but as I described above, can be difficult in rural and underdeveloped communities in South America. Aedes mosquitoes primarily bite during the daytime but in the United States, we take for granted things like screen doors and the ability to take refuge from hot days by staying indoors with our air conditioning. But many people in South America don’t have these amenities and are constantly exposed to outside air and thus susceptible to mosquito bites. However, distribution of things like mosquito repellent and mosquito netting treated with repellent are cheap and easy opportunities to help limit bites of mosquitoes. If outdoors, wearing long-sleeves to reduce the amount of exposed skin is another common-sense way of limiting mosquito bites. However, in hot climates, this strategy may not not sound very appealing.

Another problem is the lack of indoor plumbing in many rural areas in South America which means water is stored in open containers. Efforts should be made to help protect these water sources and attempt to clear them of mosquito larvae (i.e. treatment with tested larvicides to kill the mosquitoes in their adolescent stage).

As a long term strategy, the mosquito population must be controlled and this has been attempted in many ways from spraying with harmful pesticides, to treating exposed water with larvicides, to even introducing certain species of fish that thrive on (this review covers many of these attempts to control the mosquito population). Unfortunately, Aedes aegypti mosquitoes need only a tiny amount of water (even that found in soda bottle lid) in order to breed. Thankfully many of these efforts are cheap but require a coordinated effort, especially at the local level. Other more advanced strategies, such as introduction of genetically modified mosquitoes to limit the growth of the mosquito population may represent new alternatives (I’ll discuss this new technological advancement in a future blog post because it’s actually pretty cool).

A recent article by Brazilian public health authorities and published in the Journal of American Medical Association made several recommendations to fight the virus [20]. I summarize the six points here.

  • Increased gathering of epidemiologic data on the virus and research into the consequences of its infection.
  • Development of a fast and reliable serological test for Zika
  • Control of the Aedes aegypti population
  • Define standardized protocols for treatment of Zika infection.
  • Development of a vaccine.
  • Improve the health care system to properly address the epidemic.

These six recommendations are not small tasks but would require a great deal of effort but touch on many of the points I’ve already made about the virus, what we don’t know, and what we need to fight it.

Why is it some new epidemic seems to keep happening, almost out of nowhere?

You probably remember that in 2014 that world was stricken with panic of a far more deadly and horrific virus (though less infectious): Ebola. Similar to Zika, an epidemic spread throughout a region of the world and few isolated cases reached the U.S. Despite significant failures that undoubtedly cost hundreds or even thousands of lives (the WHO was slow to mobilize an international response compared to Zika), that epidemic was eventually contained.

Now we have Zika and a similar pattern is emerging. This time public health agencies are taking it much more seriously and responding quickly, at least when compared to Ebola.

Zika and Ebola have other things in common too. 1) both viruses have been known about for years but were relatively minor global problems 2) they spread incredibly quickly in a particular region.

I want to speak a bit about this second point. How could this have been allowed to happen? If an Ebola or Zika epidemic started in the US, would we have the same type of problem that we are seeing in less developed nations?

One argument is that the failure of local health systems and absence of coordinated public health efforts at the local, regional, national, and international efforts have resulted in the rapid spread of the disease. The failure to coordinate an international effort to help provide aid and support to African nations certainly exacerbated the Ebola epidemic. But with Zika, because it is so difficult to diagnose and it is spread so easily by mosquitoes, this argument doesn’t necessarily hold water. One thing is clear though, an improved international system needs to be put in place to closely monitor emerging diseases. We knew Zika was spreading since the Yap Island outbreak in 2007 but no one could have anticipated the explosion of the virus in Brazil, or the link in microcephaly. The virtual lack of research about Zika undoubtedly contributed to this problem as well. There is no easy answer why outbreaks like Ebola and Zika happen.

Just as a contrast, let’s look at how the HIV virus took the US by surprise. Why did it become an epidemic? One reason may be that governmental leadership (i.e. the Reagan administration) completely ignored it for years despite scientists and public health experts raising the red flags. I won’t say anything more than that, but clearly public health failures can occur in any nation, even “developed” ones. Lack of strong central authority to mobilize a response to a public health crisis inevitably makes the crisis worse. We saw it with HIV, we saw it with Ebola, and things are slowly changing with Zika (as I mentioned, both the WHO and CDC have responded very quickly to this crisis. To what effect remains to be seen…)

But what about the next “Zika”, the one we don’t know about yet?


Improvements in the global public health sector are clearly required in order to identify new emerging viruses, coordinate an international response, and quickly contain the new bug before it can become a much larger problem.

Dispelling myths about Zika virus.

As promised, I want to spend some time debunking some of the absurd myths about Zika that have been floating around the Internet.

Myth #1: Zika virus is caused and spread by genetically modified mosquitoes.

There are numerous things wrong with this. First, we know that the virus originated from the Zika Forest in Uganda in 1947. Second, we have tracked its spread through Africa and the Asian variety that has emerged in a series of outbreaks from Yap island in Micronesia in 2007 to French Polynesia in 2014 to Brazil in 2015. Third, while there is indeed an ongoing trial in Brazil using genetically modified mosquitoes (GMM) produced by the company Oxitec  and with complete support of the Brazillian government , the strategy is intended to control the mosquito population and is actually extremely safe. The mosquitoes used in this trial are sterile males carrying a lethal gene: they breed with wild females, that breeding kills all the eggs they produce, and then the GMM male itself dies. Similar trials already occurred in Cayman Islands and Malaysia between 2009-2012. The trials were extremely successful in controlling the mosquito population (about 80-90% of the native population) [21]. In fact, the GMM strategy may be a powerful new tool to help control disease-spreading mosquito populations. There is zero evidence that GMM have anything to do with the current Zika epidemic or microcephaly. A piece in the New Yorker does a great job of dispelling this absurd myth.

Myth #2: The Zika epidemic and microcephaly is caused by a faulty Zika vaccine.

This falls in to the same type of fear mongering related to vaccines and autism (no such link exists). First, there is not even a Zika vaccine thus any reason why one would have even been tested before the epidemic began in early 2015. Second, for all the reasons I described above, we know where the virus came from and how it spread. Third, vaccines are one of the greatest successes in the history of medicine and have saved millions and millions of lives. There is no evidence anywhere that vaccines would possibly cause microcephaly.

Myth #3: Microcephaly is not caused by Zika but by the use of a dangerous larvicide pyriproxyfen.

Of all the three myths presented here, this one is the most plausible because pesticides and other chemical agents used to control pests can indeed have unexpected ecological and health risks. However, the arguments brought up by the Argentinian group making the claim, do not hold water. First, the location that the larvicide was being used is not consistent with the reports of microcephaly. Second, the usage of the chemical is also not consistent with rise of microcephaly cases. Third, all the evidence I described above showing that Zika is most likely the cause of the microcephaly. For all these reasons, experts largely dismiss the claims about the larvicide.

Check out the Mad Virologists post also debunking Zika myths or the New Yorker article.

Concluding Thoughts

Zika virus is a terrifying virus that is spreading like wildfire but I want to end with five final thoughts specifically for easily frightened Americans:

  1. The Zika virus should be treated seriously but not hysterically.
  2. The risk of a Zika epidemic the scope of Brazil’s occurring in the United States is extremely low.
  3. The link between Zika and microcephaly is strong though not scientifically conclusive.
  4. There is a great deal about the virus and the epidemic that is still unknown so pay attention to what the CDC has to say and don’t overreact to over-hyped stories on the news.
  5. For the people of South America, this is a real threat and just because the risk to America is low doesn’t mean that this a problem that Americans should ignore. Brazil and other nations need our help and the US should be leading the world in the fight against disease.


Aedes: A genus of mosquitoes that carries flaviviruses such as Zika and dengue; includes the species Aede aegypti (the culprit in the current epidemic) and Aedes albopictus.

Antibody: A main defense produced by the immune system. An antibody recognizes a specific disease and marks that infectious agent so that other immune cells can kill it.

Autochthonous: indigenous to a region, in epidemiology, transmission of a disease by a vector in the region of an epidemic (rather than a case reported in a region that is not experiencing the epidemic).Virus: an infectious agent that invades a cell and hijack’s that cell’s molecular machinery to make more viral particles. Usually consists of a small amount of genetic material (DNA or RNA) encapsulated by a protein coat; the genetic material is how the virus hijacks the cell to make more of itself.

Autoimmune disease: A disease in which the body’s immune system attacks its own cells and tissues.

Flavivirus: the family of viruses that includes dengue, chikungunya, yellow fever, West Nile, and Zika.

Genetically Modified Mosquito: A mosquito that has had its DNA scientifically altered so that it can be used to control wild mosquito populations. Two general classes exists 1) mosquitoes that transmit a lethal gene to other mosquitoes or 2) mosquitoes that are resistant to being the host for a particular disease.

Immune System: An organism’s complete system used for the defense against disease.

Larvicide: A chemical compound used to kill an insect when it is in its juvenile, or larval stage.

Microcephaly: A medical condition defined by an abnormal brain development which results in a small head. Numerous neurological problems may result from the disorder, including compromised cognitive function and intellectual disability.

Mosquito-borne disease: a disease such as Zika, dengue, or malaria that is transmitted through mosquito bites.

Pesticide: A chemical compound used to kill insects that are either harmful or a nuisance.

RT-PCR: Reverse-transcriptase polymerase chain reaction. A common technique in molecular biology that is able to analyze a sample for the presence or absence or a specific DNA sequence. Useful in determining the molecular identity of a unknown biological sample. Most labs are capable of running RT-PCR, provided they have the proper reagents.

Serologic testing: Analysis of a serum, a component of blood minus, for specific antibodies that the immune system has generated against an invading virus or other pathogen.

Sexually transmissible: a disease that can be passed from one partner to another through sexual intercourse. However, this does not mean this the primary route of transmission for the disease.

Vector: any organism that can spread a disease, such as a mosquito carrying malaria or Zika, a tick carrying lyme disease, or even a dog with rabies or a human with the flu.

Viral Reservoir: The host animal in which the virus replicates itself to sufficient quantities that it can be spread to other hosts.

Virus: an infectious agent that invades a cell and hijack’s that cell’s molecular machinery to make more viral particles. Usually consists of a small amount of genetic material (DNA or RNA) encapsulated by a protein coat; the genetic material is how the virus hijacks the cell to make more of itself.

Selected References

  1. Dick GW, et al. Zika virus. I. Isolations and serological specificity. Transactions of the Royal Society of Tropical Medicine and Hygiene. 1952;46(5):509-20.
  1. Staples JE, et al. Interim Guidelines for the Evaluation and Testing of Infants with Possible Congenital Zika Virus Infection – United States, 2016. MMWR Morbidity and mortality weekly report. 2016;65(3):63-7.
  1. Oduyebo T, et al. Update: Interim Guidelines for Health Care Providers Caring for Pregnant Women and Women of Reproductive Age with Possible Zika Virus Exposure – United States, 2016. MMWR Morbidity and mortality weekly report. 2016;65(5):122-7.
  1. Enfissi A, et al. Zika virus genome from the Americas. Lancet. 2016;387(10015):227-8.
  1. Faye O, et al. Molecular evolution of Zika virus during its emergence in the 20(th) century. PLoS neglected tropical diseases. 2014;8(1):e2636.
  1. Kraemer MU, et al. The global distribution of the arbovirus vectors Aedes aegypti and Ae. albopictus. eLife. 2015;4:e08347.
  1. Bogoch, II, et al. Anticipating the international spread of Zika virus from Brazil. Lancet. 2016;387(10016):335-6.
  1. Naish S, et al. Climate change and dengue: a critical and systematic review of quantitative modelling approaches. BMC infectious diseases. 2014;14:167.
  1. Medlock JM, Leach SA. Effect of climate change on vector-borne disease risk in the UK. The Lancet Infectious diseases. 2015;15(6):721-30.
  1. Musso D, et al. Potential sexual transmission of Zika virus. Emerging infectious diseases. 2015;21(2):359-61.
  1. Campos GS, et al. Zika Virus Outbreak, Bahia, Brazil. Emerging infectious diseases. 2015;21(10):1885-6.
  1. Mlakar J, et al. Zika Virus Associated with Microcephaly. The New England journal of medicine. 2016;374(10):951-8.
  1. Heymann DL, et al. Zika virus and microcephaly: why is this situation a PHEIC? Lancet. 2016;387(10020):719-21.
  1. Victora CG, et al. Microcephaly in Brazil: how to interpret reported numbers? Lancet. 2016;387(10019):621-4.
  1. Broutet N, et al. Zika Virus as a Cause of Neurologic Disorders. The New England journal of medicine. 2016.
  1. Calvet G, et al. Detection and sequencing of Zika virus from amniotic fluid of fetuses with microcephaly in Brazil: a case study. The Lancet Infectious diseases. 2016.
  1. Martines RB, et al. Notes from the Field: Evidence of Zika Virus Infection in Brain and Placental Tissues from Two Congenitally Infected Newborns and Two Fetal Losses – Brazil, 2015. MMWR Morbidity and mortality weekly report. 2016;65(6):159-60.
  1. Oehler E, et al. Zika virus infection complicated by Guillain-Barre syndrome–case report, French Polynesia, December 2013. Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin. 2014;19(9).
  1. Cao-Lormeau VM, et al. Guillain-Barre Syndrome outbreak associated with Zika virus infection in French Polynesia: a case-control study. Lancet. 2016.
  1. Barreto ML, et al. Zika virus and microcephaly in Brazil: a scientific agenda. Lancet. 2016;387(10022):919-21.
  1. Lacroix R, et al. Open field release of genetically engineered sterile male Aedes aegypti in Malaysia. PloS one. 2012;7(8):e42771.