The British Medical Journal (BMJ) Calls for an End to the “War on Drugs”

war-on-drugs-no

A recent editorial in the British Medial Journal (the BMJ) has called for an end to the “War on Drugs”, which costs about $100 Billion/year and has failed to prevent both drug use and drug proliferation.

The article points out how the “War on Drugs”, the term used to collectively describe the laws penalizing drug use, has had a wide-range of negative effects. For example, the US has the highest incarceration rate in the world and about half of those arrests are due to drug-related arrests.

The health effects have been drastic as well. Stigma against opioid replacement therapies like methadone has resulted in increased deaths due to opioid overdose in countries that limit access. Stigma and discrimination against addicts, as well of fear of punishment for for usage, often leads away from health care services to unsafe drug-use practices that can spread HIV and Hepatitis C, and other unintended poor-health outcomes.

Importantly, the editors call for rational, evidence-based, drug-specific approach to regulation and strong involvement of  the scientific and medical communities. Obviously, the risks of something like marijuana are much lower than for heroin but how will drug policy reflect this? Research is required to support any efforts in order to identify the best practices and strategies.

The editors point out that a recent article in the Lancet “concluded that governments should decriminalise minor drug offences, strengthen health and social sector approaches, move cautiously towards regulated drug markets where possible, and scientifically evaluate the outcomes to build pragmatic and rational policy.”

Above all, a change in drug policy must benefit human health and there will be no “one size fits all” approach. The road ahead is difficult but one thing is certain, the road that led us here is a dead end. The “War on Drugs” has failed; the call now is to develop a national and international drug policy that won’t.

The Fall

black-box

I always thought that I lived in a good country. Sure, America was never perfect but it was far from a horrible place to live. I thought people, for the most part, were generally decent. We may not always agree on the best course for the country, but respect for each other opinions and an open and honest discussion could always led to a compromise for the greater good. I thought people respected values like wisdom, knowledge, tolerance, decency, civility, inclusion, open-mindedness, desire to learn and improve ourselves and our country,  and a willingness to keep moving forward—hope—even in tough times, a common-belief that things only get better with time, that we are all working together towards a greater goal, a more perfect union.

After last night, I now know that none of those things are true.

It never once occurred to me that a racist, misogynistic, homophobic, bigoted, petulant, arrogant, chauvinistic, narcissistic, ill-tempered monster could even be running for the presidency, never mind have the remotest chance of winning it. How can this have happened? How is it that there are this many desperate, narrow-minded morons in this country? How can the people of this country have completely abandoned truth for racism and vague promises? I understand fear, I understand the sense of a loss of control over the present, I understand the sense of being left behind, but to abandon even the most basic commonsense, the most basic of our core values? That is something I do not understand.

I don’t know what’s going to happen next. No one does because this demagogue, this proto-tyrant, never actually spoke about policy. All we can do now is wait. But I am not hopeful. I am fearful.

Yesterday, I saw America abandon reason for conspiracy theories and emotionalism. Desperation has overcome the American tradition of tolerance and social progression. Independent thought and an embrace of the truth are dead.

Fear has Trumped hope.

It’s raining in DC today, as if the city itself is weeping in anticipation of the coming terror. I weep along with. I weep for the Fall of American Greatness.

The NIH Announces a Commitment to Research on LGBT Health

lgbt-med

Every person has a right to live a healthy life. One part of that vision is equal access to health care for all. But unsurprisingly, not everyone have the same ability to receive health care due to things like socioeconomic status, race, gender, or even sexual orientation. Indeed, LGBT people often have less access to health care than their non-LGBT counterparts, most often due to discrimination and stigma [1].

The Director of the National Institute on Minority Health and Health Disparities, part of the National Institutes of Health (NIH), announced “the formal designation of sexual and gender minorities (SGMs) as a health disparity population for NIH research.” Read the full announcement here.

What does this mean? That the NIH is officially recognizing that LGBT people have less access to health care and that improved research on LGBT-specific (defined here broadly as sexual and gender minorities) health issues is essential to improved health care.

The long-overdue announcement was supported by an important report released by the non-partisan National Academies of Science (NAS) in 2011. The report identified gaps in the research on the health of LGBT persons and made recommendations for improving this research that could benefit not just LGBT people, but the health care system overall.

LGBT individuals have unique health challenges that many doctors do not understand or address. For example, certain types of cancer seem to be more prevalent among gay men compared to straight men, which means different cancer screenings would be important for gay men [2].

The new designation by NIMHD will hopefully increase research and knowledge about the health challenges of LGBT people and will hopefully result in improved health care for all people, regardless of sexual orientation, gender identity, or gender expression.

Selected References

  1. Hatzenbuehler ML, Bellatorre A, Lee Y, Finch BK, Muennig P, Fiscella K. Structural stigma and all-cause mortality in sexual minority populations. Social science & medicine. 2014;103:33-41. doi: 10.1016/j.socscimed.2013.06.005.
  2. Quinn GP, Sanchez JA, Sutton SK, Vadaparampil ST, Nguyen GT, Green BL, et al. Cancer and lesbian, gay, bisexual, transgender/transsexual, and queer/questioning (LGBTQ) populations. CA: a cancer journal for clinicians. 2015;65(5):384-400. doi: 10.3322/caac.21288.

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).

replication-study

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_ACE_Pyramid
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?

(±)-Ketamine_Structural_Formula_V1.svg
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?

mice-162163_960_720

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?

Naloxone_(1)

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

Read my new post 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.