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.
Of 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.
Ketamine has traditionally been used an as anesthetic due to it’s pain relieving and consciousness-altering properties . However, at doses too low to induce anesthesia, it has been shown that ketamine has the ability to relieve depression . 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 .
A debate has been going about whether ketamine should be used for the treatment of depression and if its risks outweigh its benefits . 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 .
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 .
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.
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….
The report identified five central questions regarding the concerns over opioids:
Is there evidence of effectiveness of opioid therapy in long-term treatment of chronic pain?
What are the risks of opioids?
What differences in effectiveness between different dosing strategies (immediate release versus long-acting/extended release)?
How effective are the existing systems for predicting the risks of opioids (overdose, addiction, abuse or misuse) and assessing those risks in patients?
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.
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.
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.
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.
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.
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).
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).
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).
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.
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.
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:
Zika is a virus that was discovered in the Zika Forest in Uganda in 1947 . 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.
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).
While it may have been discovered in 1947 , it’s been spreading slowly across Africa since then. A distinct Asian variety of the virus was first discovered in 1966 in Malaysia . 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 . We know that the virus in the Americas is related to the Asian variety.
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 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 .
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  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]*
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 . 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 . 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).
Nevertheless, 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.
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 . 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.
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 . 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 . 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.
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?
As 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 ).
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 . Keep in mind it is only a single case study but provides probably the most thorough analysis of a microcephaly case.
The 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.
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  and a surge in cases has also accompanied the epidemic in Brazil . A recent study  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)  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?
Unfortunately, there are currently no treatments or vaccines for Zika virus. The best method for treating the virus is prevention (see below).
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 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 . 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) . 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.
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:
The Zika virus should be treated seriously but not hysterically.
The risk of a Zika epidemic the scope of Brazil’s occurring in the United States is extremely low.
The link between Zika and microcephaly is strong though not scientifically conclusive.
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.
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.
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Significantly, Marijuana is the also the most widely used illegal substance amongst youths. Adolescence (ages 12-17) is an extremely critical period for brain development [3, 4] yet the effects of marijuana on the brains of kids have not been thoroughly studied. A recent paperout of Dr. Steven R. Laviolette’s laboratory at the University of Ontario sought to answer this question: what happens to brains of adolescent and adult rats that have been exposed to THC?
Why was the research done? What is the hypothesis?
There have been a number of studies published that suggest there might be an association between prolonged marijuana use (especially of high-potency strains) and schizophrenic-like or psychotic-like symptoms [5, 6] although there is disagreement in the scientific community on the evidence [7, 8] (I may write a blog post discussing this issue in the future). It is has even been suggested that youths that smoke marijuana are more at risk for psychotic symptoms as adults [9, 10]. The author’s sought to test this directly by injecting adolescent and adult rats with THC for a number of days, waiting a period of time after the injections, then measuring the long-term effects on the rats. The team hypothesized THC would have induced long-term changes in the brains of adolescent but not adults rats, and subsequent changes in psychotic-like behavior.
How was it done?
Adolescent and adult rats were injected with THC twice daily for 11 days. The dose of THC administered was increased (escalating dose) to account for any tolerance that may occur. As an important control, separate groups of adolescent and adult rats were injected with vehicle (the solution that THC was dissolved in but minus the THC itself). Following a 30-day abstinence period after the last injection, THC-adolescent, control-adolescent, THC-adult, and control-adult rat groups were subjected to number of behavioral and molecular tests to see what effect the drug had on the animals. I need to point out that the 30-day abstinence period is significant in the rat life-span. This is enough time for the adolescent rats to become adults so what the scientists are primarily studying is the long-term effects of THC on adolescents vs adults in adulthood.
In the behavioral neuroscience field, we have devised another of tests to measure various aspects of animal behavior. Obviously we can’t inject humans with THC and see what happens so we have to use rodents and identify behaviors that approximate a similar behavior in humans. Of course, rodent behavior is no where near as complex as humans but rats are remarkably sophisticated animals (ask anyone living in New York) and scientists have developed a number of ways to measure things from motivation to social behavior to anxiety to depression.
In this experiment, a social test was used, two different types of anxiety tests and a motor activity test. The tests measured effects on motivation, exploratory-behavior (another indicator of how motivated rats are), social interaction, and anxiety.
The scientists also measured the activity of dopamine-releasing neurons in the living animal using a technique called in vivo electrophysiology. Recall from my post I am Neuron! that when activated, brain cells (called neurons) conduct an electrical current that results in the release of neurotransmitters onto another neuron. This electrical current is called an action potential and we can measure this by inserting a special probe into the those neurons in the animals brain (the probe measures electrical currents). Therefore, with in vivo electrophysiology we can measure every time a neuron fires (i.e. an action potential is generated) in a specific part of the brain. Using this technique, the scientists measured dopamine neurons in an important region of the brain called the VTA and how often these neurons fire in THC vs control rats. Check out this video for more details on in vivo electrophysiology.
Finally, brains from animals were dissected and a number of protein molecules were studied using a common technique in molecular biology called a Western blot (or known as an immunoblot). A Western blot takes advantage of antibodies that are able to recognize and stick to one specific type of protein. Therefore, this assay can tell you two main things 1) if your protein of interest is present in your sample and 2) approximately how much of your protein there is compared to other samples. In this paper, tissue from a specific brain region is used and the protein is analyzed by Western blots in order to comparing quantities of proteins between the different experimental groups. Of course, the limitation of a Western blot is if you have a good antibody for your protein of interest. Luckily there are many biotech companies such as Cell Signaling that specialize in making and testing reliable antibodies. The scientists used the Western blots to study many proteins in a region of the brain called the prefrontal cortex (PFC), which is believed to be important in self-control and other high-function brain processes. Check out this video for more details on Western Blots.
What did they find?
THC-adolescent rats exhibited deficits in numerous behavioral experiments compared to controls while THC-adult rats did not appear to have any behavioral changes.
*Recall that these experiments were conducted 30 days after the last THC dose so the author’s show that these are long-term effects of THC on the brain of adolescent rats.
In the social activity test, rats showed little interest in interacting with a stranger rat (normal rats are usually curious about the novel stranger). THC-adolescents also did not walk around or explore a new cage as much. In the two different anxiety tests, THC-rats appeared to have be more anxious (demonstrated more anxiety-like behavior).
In the electrophysiology experiment, VTA DA neurons fired more frequently for some reason in THC-adolescents compared to the other groups.
Finally, numerous protein changes in the PFC were observed in a number of important signaling pathways such as Wnt and mTOR pathways. Interestingly, THC-adolescents vs THC-adults seemed to have opposite effects on this proteins.
Limitations to the study?
The behavioral changes observed were statistically significant (meaning, most likely a real effect and not some kind of fluke of random chance) but were modest changes in some of the tests performed. Would the changes last beyond the 30 days post injection in this study?
There are impressive arrays of behavioral tests that rats can perform to measure numerous aspects of cognition (for example, memory and learning) but none of these experiments were performed. A far greater range of behavioral experiments would have made this study more compelling.
While the electrophysiology and Western blot data are intriguing, the author’s performed no experiments to determine if these changes are responsible for the difference in behavior (association vs causation). These changes could merely be an incidental change and have nothing to do with the behaviors studies.
The doses that the mice were injected with, while based on a previous study, are somewhat arbitrary. Would the changes be more pronounced or less pronounced with higher/lower doses or a shorter/longer dosing regimen?
Only male rats were studied. Would the same behavioral and molecular changes occur in female rats?
What does it mean?
Based on the behavioral and molecular data presented, this data paper suggests that adolescent rats (but not adults) exposed to THC have long-lasting changes in the brain. The author’s argue that these effects recapitulate schizophrenia-like symptoms but I am not entirely convinced. Also, THC given to rats is not the same thing as marijuana smoked by human teenagers. So it’s important to keep in mind that this is one study. In science, we never draw grand conclusions about anything based on one study. Nevertheless, several other reports have corroborated these findings (see this review paper for a summary of many of them ). Indeed, it does seem that marijuana use can cause long-term deficiencies in human and rodent brains. The results of this paper are certainly intriguing and, if true, a whole host of stricter regulations on marijuana use in states that have legalized it may need to put in place to help curb increasing marijuana abuse amongst youths.
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Of course, we all know the prevalence and extent of underage drinking, and the damage alcohol has on the developing brain has been heavily researched, not to mention all the significant secondary problems associated with alcohol abuse (car crashes, sexual assault on college campuses, falling off of balconies… ).
But here’s some numbers anyways: as of 2013, 8.7 million youths aged 12-20 reported past month alcohol use, a shockingly high number for an age group this is not legally allowed to drink alcohol…
Similarly, marijuana, which is still illegal in the vast majority of the US, is nearly as ubiquitous. According to the NSDUH 2013 survey, 19.8 million adults aged 18 or older reported past month marijuana use.
But what if the risk of use of alcohol and marijuana by youths could be reduced? What if a teacher could be given the tools to not only identify certain risky personality traits in their students but also use that knowledge to help those at-risk students from trying and using drugs such as alcohol and marijuana? A series of studies coming out of the laboratory of Dr. Patricia A Conrod of King’s College London report having done exactly that.
I had the pleasure of seeing Dr. Conrod speak at the recent Society for Neuroscience Conference as part of a satellite meeting jointly organized by the National Institute on Drug Abuse (NIDA) and National Institute on Alcohol Abuse and Alcoholism (NIAAA). Dr. Conrod presented a compelling story spanning over a decade of her and her colleague’s work, in which certain personality traits amongst high risk youths, can actually be used to predict drug abuse amongst those kids. Dr. Conrod argues that by identifying different risk factors in different adolescents, a specific behavioral intervention can be designed to help reduce alcohol drinking and marijuana use in these youths. And who is best to administer such an intervention? Teachers and counselors, of course: educators that spend a great deal of time interacting with students and are in the best position to help them.
This ambitious study recruited 2,643 students (between 13 and 14 years old) from 21 secondary schools in London (20 of the 21 schools were state-funded schools). Importantly, this study was a cluster-randomized control trial, which means the schools were randomly assigned to two groups: one group received the intervention while the other did not. The researchers identified four personality traits in high-risk (HR) youths that increase the risk of engaging in substance abuse. The four traits are:
A specific intervention based on cognitive behavioral therapy (CBT) and motivational enhancement therapy (MET) was developed to target each of these personality traits. Teacher, mentors, counselors, and educational specialists in each school that were recruited for the study were trained in the specific interventions. In general, CBT is an approach used in psychotherapy to change negative or harmful thoughts or the patient’s relationship to these thoughts, which in turn can change the patient’s behavior. CBT has been effective in a treating a number of mental disorders such anxiety, personality disorders, and depression. MET is an approach used to augment a patient’s motivation in achieving a goal and has mostly been employed in treating alcohol abuse.
The CBT and MET interventions in this study were designed to target one of the four personality traits (for example, anxiety reduction) and were administered in two 90-minute group sessions. The specific lesson plans for these interventions were not reported in the studies but included workbooks and such activities as goal-setting exercises and CBT therapies to help students to dissect their own personal experiences through identifying and dealing with negative/harmful thoughts and how those thoughts can result in negative behaviors. Interestingly, alcohol and drug use were only a minor focus of the interventions.
The success of the interventions was determined through self-reporting. The student’s completed the Reckless Behavior Questionnaire (RBQ), which is based on a six-point scale (“never” to “daily or almost daily”) to report substance use. Obviously due to the sensitive nature of these questionnaires and need for honesty by the students, measures were taken to ensure accuracy in the self-reporting, such as strong emphasis on the anonymity and confidentiality of the reports and inclusion of several “sham” items designed to gauge accuracy of reporting over time. Surveys were completed every 6-months for 24-months (two years) which is a sufficient time frame to assess the effect of the interventions.
Most importantly, schools were blinded to which group they were placed in and teachers and students not involved in the study were not aware of the trial occurring at the school. The students involved were unaware of the real purpose and scope of the study. These factors are important to consider because it held eliminate secondary effects and helps support the direct efficacy of the interventions themselves.
The results were impressive: reduced frequency and quantity of drinking occurred in the high-risk students that received the intervention compared to the control students that did not. While HR students were overall more likely to report drinking than low-risk (LR) students, the HR students saw a significant effect of the personality-targeted interventions on drinking behavior.
A study of this size is incredibly complex and the statistics involved are equally complex. The author’s analyzed the data in a number of ways and published the results in several papers. A recent study modeled the data over time (the 24-months in which the surveys were collected) and used these models to predict the odds that the students would engage in risky drinking behavior. The authors reported a 29% reduction in odds of frequency of drinking by HR students receiving the interventions and a 43% reduction in odds of binge drinking when compared to HR students not receiving the interventions.
Interestingly, the authors report a mild herd-effect in the LR students. Meaning that they believe the intervention slowed the onset of drinking in the LR students possibly due to the interactions between the HR student’s receiving the interventions and LR students. However, additional studies will need to be done in order to confirm this result.
Recall that the Reckless Behavior Questionnaire (RBQ) was utilized in this study to quantify drug-taking behavior. While the study was specifically designed to measure effects on alcohol, the RBQ also included questions about marijuana. So the authors reanalyzed their data and specifically looked at effects of the interventions on marijuana use.
The found that the sensation seeking personality sub-type of HR students that received an intervention had a 75% reduction in marijuana use compared to the sensation seeking HR students that did not receive the intervention. However, unlike the findings found on alcohol use, the study was not able to detect any effect on marijuana use for the HR students in general. Nevertheless, the data suggest that the teacher/counselor administered interventions are effective at reduce marijuana use as well.
While you may be unconvinced by the modest reduction in drinking and marijuana frequency reported in these studies and may be skeptical of the long-term effect on drug use in these kids, keep in mind that the teachers and counselors that administered these interventions received only 2 or 3 days of training and the interventions themselves were very brief, only two 90-minute sessions. What I find remarkable is that such a brief, targeted program can have ANY effects at all. And most importantly, the effects well outlasted the course of the interventions for the full two-years of the follow-up interviews.
These targeted interventions have four main advantages:
Administered in a real-world setting by teachers and counselors
Brief (only two 90-minute group sessions)
Cheap (the cost of training and materials for the group sessions)
The scope of this intervention needs to be tested on a much larger cohort of students in a larger variety of neighborhoods but it is extremely promising nonetheless. Also, it would be interesting to breakdown these data by race, socioeconomic status, and gender, all of which may impact the effectiveness of the treatments and was not considered in this analysis. Finally, how would you implement these interventions on a wide scale? I eagerly look forward to additional work on these topics.
The third and final part of my three part guest blog series on Optogenetics has been published on the Addgene blog. Addgene is a nonprofit organization dedicated to making it easier for scientists to share plasmids and I’m thrilled to be able to contribute to their blog! This post covers the running behavioral experiments utilizing optogenetics.
The second part of my three part guest blog series on Optogenetics has been published on the Addgene blog. Addgene is a nonprofit organization dedicated to making it easier for scientists to share plasmids and I’m thrilled to be able to contribute to their blog! This post covers the material science aspects of running optogenetic experiments.
The first part of my three part guest blog series on Optogenetics has been published on the Addgene blog. Addgene is a nonprofit organization dedicated to making it easier for scientists to share plasmids and I’m thrilled to be able to contribute to their blog!
The biological sciences are in a golden era: the number of advanced technological tools available coupled with innovations in experimental design has led to an unprecedented and accelerating surge in knowledge (at least as far as the number of papers published is concerned). For the first time in history, we are beginning to ask questions in biology that were previously unanswerable.
No field demonstrates this better than genetics, the study of DNA and our genes. With the advent of high-throughput DNA sequencing, genetic information can be acquired literally from thousands of individuals and even more remarkably, can be analyzed in a meaningful way. Genomics, or the study of the complete set of an organism’s DNA or its genome, directly applies these advances to probe answers to questions that are literally thousands of years old.
A recent study, a collaborative effort from scientists in Iceland, the Netherlands, Sweden, the UK, and the US, is an example of power of genomics and to answer these elusive questions.
The scientists posed an intriguing question: if you are at risk for a psychiatric disorder, are you more likely to be creative? Is there a link between madness and creativity?
Aristotle himself once said, “no great genius was without a mixture of insanity” and indeed, the “mad genius” archetype has long pervaded our collective consciousness. But Vincent Van Gogh cutting off his own ear or Beethoven’s erratic fits of rage are compelling stories but can hardly be considered empirical, scientific evidence.
But numerous studies have provided some evidence that suggests a correlation between psychiatric disorders and creativity but never before has an analysis of this magnitude been performed.
Genome-wide association studies (GWAS) take advantage of not only the plethora of human DNA sequencing data but also the computational power to compare it all. Quite literally, the DNA of thousands of individuals is lined up and, using advance computer algorithms, is compared. This comparison helps to reveal if specific changes in DNA, or genetic variants, are more common in individuals with a certain trait. This analysis is especially useful in identifying genetic variants that may be responsible for highly complex diseases that may not be caused by only a single gene or single genetic variant, but are polygenic, or caused by many different genetic variants. Psychiatric diseases are polygenic, thus GWAS is useful in revealing important genetic information about them.
This video features Francis Collins, the former head of the Human Genome Project and current director of the National Institutes of Health (NIH), explaining GWAS studies. The video is 5 years old but the concept is still the same (there’s not many GWAS videos meant for a lay audience).
The authors used data from two huge analyses that previously performed GWAS on individuals with either bipolar disorder or schizophrenia compared to normal controls. Using these prior studies, the author’s generated a polygenic risk score for bipolar disorder and for schizophrenia. This means that based on these enormous data sets, they were able to identify genetic variants that would predict if a normal individual is more likely to develop bipolar disorder or schizophrenia. The author’s then tested their polygenic risk scores on 86,292 individuals from the general population of Iceland and success! The polygenic risk scores did associate with the occurrence of bipolar disorder or schizophrenia.
Next, the scientists tested for an association between the polygenic risk scores and creativity. Of course, creativity is a difficult thing to define scientifically. The authors explain, “a creative person is most often considered one who take novel approaches requiring cognitive processes that are different from prevailing modes of thought.” Translation: they define creativity as someone who often thinks outside the box.
In order to measure creativity, the authors defined creative individuals as “belonging to the national artistic societies of actors, dancers, musicians, and visual artists, and writers.”
The scientists found that the polygenic risk scores for bipolar disorder and schizophrenia each separately associated with creativity while five other types of professions were not associated with the risk scores. An individual at risk for bipolar disorder or schizophrenia is more likely to be in creative profession than someone in a non-creative profession.
The authors then compared a number of other analyses to see if this effect was due to other factors such as number of years in school or having a university degree but this did not alter the associations with being in a creative field.
Finally, the same type of analysis was done with two other data sets: 18,452 individuals from the Netherlands and 8,893 individuals from Sweden. Creativity was assessed slightly differently. Once again creative profession was used but also data from a Creative Achievement Questionnaire (CAQ), which reported achievements in the creative fields described above, was available for a subset of the individuals.
Once again, the polygenic risk scores associated with being in a creative profession to a similar degree as the Icelandic data set; a similar association was found with the CAQ score.
The authors conclude that the risk for a psychiatric disorder is associated with creativity, which provides concrete scientific evidence for Aristotle’s observation all those years ago.
However, future analyses will have to broaden the definition of creativity beyond just narrowly defined “creative” professions. For example, the design of scientific experiments involves a great deal of creativity but is not considered a creative profession and is therefore not included in these analyses, and a similar argument could be made with other professions. Also, no information about which genetic variants are involved or what their function is was discussed.
Nevertheless, this exciting data is an example of the power that huge genomic data sets can have in answering fascinating questions about the genetic basis of human behavior and complex traits.
Why are some drugs of abuse more addictive than others?
This is a central question to the addiction field yet it remains largely a mystery. All drugs of abuse have a similar effect on the brain: they all result in increased amounts of the neurotransmitter dopamine (DA) in an important brain region called the mesolimbic pathway (also known as the reward pathway). One of the core components of this pathway is the ventral tegmental area (VTA), which contains many neurons that make and release DA. VTA neurons communicate with neurons in the nucleus accumbens (NAc). This means that the axons of VTA neurons project to and synapse on NAc neurons. When VTA neurons are stimulated, they release DA onto the NAc, and this is a core component of how the brain perceives that something is pleasurable or “feels good.” Many types of pleasurable stimuli (food, sex, drugs, etc.) cause DA to be released from the VTA onto the NAc (See the yellow box in the diagram below). In fact, all drugs of abuse cause this release of DA from VTA neurons onto NAc neurons.
*Important note: many other brain regions are involved in how the brain perceives the pleasurable feelings of drugs besides the VTA and NAc, but these regions represent the core of the pathway.
Check out these videos for a more detailed discussion of the mesolimbic pathway.
But if all drugs of abuse cause DA release, then why do different drugs make you feel differently? This is a very complicated question but one component of the answer is that different drugs have different mechanisms and dynamics of DA release.
For the opioid drugs like heroin, morphine, and oxycodone, they are able to bind to a special molecule called the Mu Opioid Receptor (MOPR). This action on the MOPR results in an indirect activation of DA neurons in the VTA and a release of DA in the NAc. While all opioid drugs reduce the feeling of pain and induce a pleasurable feeling, they have slightly different properties at the MOPR.
The different properties of the opioids may be a reason why some are more abused than others. For example, a number of studies have suggested that oxycodone may have greater abuse potential than morphine. This means that oxycodone is more likely to be abused morphine.
But do the different properties of morphine and oxycodone on the MOPR affect DA release and is this important to why oxycodone is more likely to be abused than morphine?
This is the question that scientists at the University of Michigan sought to address. Using several different sophisticated techniques, the scientists looked at differences in DA release in the NAc caused by morphine and oxycodone, two common opioid drugs.
Rats were injected with either morphine or oxycodone and then DA release was measured using either fast-scan cyclic voltammetry or microdialysis. I’ve discussed microdialysis in a previous post but in brief, it involves drawing fluid from a particular brain region at different time points in an experiment and then measuring the neurotransmitters present (using advanced chemistry tools that I won’t explain here).
Voltammetry is a more technically complicated technique. In brief, it uses electrodes to measure sensitive voltage changes. Since a molecule has specific electrochemical properties, these voltage changes can be related back to a specific molecule, such as the neurotransmitter DA as in this study. Voltammetry may even allow greater temporal resolution (easier to detect very precise changes at very short time frames, like seconds), which may make it more accurate than microdialysis (which can only measure neurotransmitter release on the scale of minutes).
Because each technology has its own limitations and potential problems, the authors used both of these techniques to show that they are observing the same changes regardless of the technology being used. Showing the same observation multiple times but in different ways is a common practice in scientific papers: it increases your confidence that your experiment is actually working and what you are observing is real and not just some random fluke.
The authors administered a single dose of either morphine or oxycodone to rats and then measured the DA release in the NAc as described above. What they found were very different patterns!
Morphine resulted in a rapid increase in DA (less than 30 seconds) but by 60 seconds had returned to normal. In contrast, oxycodone took longer to rise (about 20-30 sec before a significant increase was detected) but remained high for the entire 2 minutes that it was measured. The difference in DA release caused by morphine and oxycodone is striking!
Many other changes were observed such as differences in DA release in different sub-regions of the NAc, different effects on phasic release of DA (DA is often released in bursts), and differences in the other neurotransmitters such as GABA (morphine caused an increase in GABA release too while oxycodone did not). I won’t discuss these details here but check out the paper for more details.
Of course, do these differences in DA release explain why oxycodone is more often abused than morphine? Unfortunately no, there are many other factors (for example, oxycodone is more widely available than morphine) to consider. Nevertheless, this is some intriguing neuroscientific evidence that adds one more piece to the addiction puzzle.