MDMA, "Drugs Live," and a life update.

It's been a while.

Last summer, I became inspired to write an article about the potential benefits of the club drug, MDMA, otherwise known as Ecstasy or Molly. The blog post got turned into an article for my alma mater's science magazine, The Synapse, and was published a few months ago. With permission, I am cross-posting it here.

A quick life update for anyone who is interested will be at the bottom of this post.

In Europe and the United States, the drug known as ecstasy is the magic bullet that loosens the inhibitions of many dancers at all-night dance parties known as “raves.” Ecstasy—or “Molly” in its allegedly purer form—is a psychedelic drug with a signature high that produces an intense sensory experience coupled with feelings of euphoria and closeness with others. However, ecstasy's tendency to raise body temperatures and dehydrate users in over-packed, sweltering clubs creates a dangerous situation that troubles parents and politicians alike.

Though ecstasy has been the culprit behind some tragic deaths since its popularization in the mid-eighties, death and injury from ecstasy are relatively rare compared to other drugs scheduled I or II by the DEA. The number of emergency room visits per year resulting from the use of ecstasy are tens of thousands fewer than those due to the use of cocaine, heroin, and marijuana. Every year, the number of deaths from ecstasy are miniscule relative to tobacco- and alcohol-related deaths. Some experts believe that MDMA, the primary chemical constituent behind the ecstasy high, isn't the real danger of ecstasy. Instead, they believe that it is the crowded, hot dance floors combined with the effects of the many other substances ecstasy is famously adulterated with that puts users in danger.

Despite the risks, MDMA's signature high has not only beguiled party-goers. The drug has also intrigued many scientists with its potential therapeutic benefits. In hushed sessions behind closed doors, therapists in the seventies and eighties began to explore the drug's ability to release patients from painful emotions attached to traumatic experiences and to strengthen the therapist-patient alliance. Although the anecdotal evidence was in favor of MDMA as a therapeutic drug, no placebo-controlled clinical trials had been performed by 1985, which was when MDMA was on the table for scheduling by the DEA. Due to the lack of clinical data, and MDMA's perceived dangers in the club scene, the drug was labeled as Schedule 1: a harmful drug with no medical benefits. All research on the therapeutic effects of ecstasy were halted for the next two and a half decades.

Nevertheless, MDMA has only become more ubiquitous among young people since 1985, and the cries to research the actual effects of MDMA on the human body have gradually swelled to a dull roar. However, the US and British governments have little to no precedent for funding studies on MDMA in humans. In 2010, Channel 4 in London endowed Professors David Nutt and Val Curran with funding to begin the first fMRI study of MDMA's effects in the human brain. The results of the study were broadcast live in a TV special called Drugs Live: The Ecstasy Trial late last September.

In the trials, conducted in September 2011, 25 volunteers came in for testing twice. Each time a volunteer came in, they received either an 83 milligram dose of MDMA or a placebo. The study was double-blind, so neither the administrators nor the subjects knew which drug they were getting. 30 minutes after they took the pill, the volunteers entered a fMRI scanner, where they were monitored for 90 minutes while answering questions about their subjective experiences. Throughout this process, volunteers were also asked to recall positive and negative memories from their lives. After the volunteers came out of the scanner, they performed a task in which they rated the trustworthiness of various faces, testing their feelings of closeness with others.

Drugs Live features the experiences of five volunteers: an ordained priest, an ex-soldier, a journalist, an actor, and a former member of Parliament. The show itself consists of clips of the five volunteers' trials on ecstasy, interviews with them and members of the audience, a debate between David Nutt and his loudest dissenter, Andrew Parrott, short videos of recreational MDMA users out dancing or just enjoying a night in with friends, and a video of an illegal therapy session with MDMA. The program is punctuated by fleeting explanations of the results of the study, described by Nutt and host Jon Snow with the aid of a giant, plastic brain with flashing lights indicative of the various structures within.

The first major discovery presented in episode 1 is MDMA's effects on the neural circuit between the posterior cingulate cortex and the prefrontal cortex. This circuit is known to become overactive in people suffering from anxiety disorders and depression, and is believed to lead to the excessive rumination characteristic of mood disorders. Normally, the two nuclei fire in sync with one another, but MDMA releases a deluge of serotonin and causes the two nuclei to start firing out of line, hushing the circuit between them and alleviating anxiety, which leads to the characteristic euphoria of the drug.

After a clip showing a therapy session, in which a woman talks through her feelings towards her recently deceased, abusive father, Nutt walks toward the giant brain to explain how MDMA is helping this woman work through her traumatic memories. When a person recalls a traumatic memory, there is an activation of the amygdala and the prefrontal cortical region. According to Nutt, the prefrontal cortical region modulates the emotions associated with a particular memory, and MDMA works to dampen the firing of that region. Without the chatter of the emotional overlay, patients are better equipped to engage with and process those memories, making MDMA a particularly exciting potential therapy for post traumatic stress disorder.

Though the program opened with a claim of being politics-free, “unvarnished science,” many viewers felt that Drugs Live was more of a “pro-drugs” circus than a lucid exposition of the science behind MDMA. Indeed, there was little discussion of the negative aspects of MDMA, including the “Tuesday blues” experienced by one volunteer in the study and the overall negative experience the ex-soldier had during the trials. There was also little air time for the debate between Nutt, Curran, and Parrott, which some viewers with a scientific background were particularly interested in.

Perhaps the positive bias in Drugs Live is unsurprising to those who know David Nutt for famously suggesting that drugs like cannabis, ecstasy, and LSD were less dangerous than alcohol and tobacco while on the Advisory Council on the Misuse of Drugs. His comments were largely responsible for his subsequent firing from the Council.

Regardless of Nutt's personal opinions on illicit substances, the study performed in Drugs Live is still an exciting contribution to a sparse body of research on the effects of MDMA in humans. Many other studies on MDMA are funded by government agencies such as the National Institute on Drug Abuse (NIDA). These studies tend to be performed on animals with the intention of finding the harmful neurological effects of MDMA. Such studies have shown significant depletion of neurons that produce serotonin that lasts for years after a single round of MDMA administration. However, these single doses are given intravenously over the course of three or four days. Critics say such dosages are not representative of how the drug would be administered in therapy (a low dose taken orally once or twice in a patient's lifetime), nor do they reflect how most recreational users take ecstasy (taken orally once or twice a month.)

Studies on humans are often relegated to surveying cognitive faculties in recreational users of ecstasy, using hair and urine drug tests to determine what sorts of drugs subjects have been taking. There are many criticisms of these studies as well, many citing poor control for subjects who have taken ecstasy in combination with other drugs or alcohol. However, these studies still show many deficits in memory, as well as higher levels of anxiety in current and former ecstasy users. Theseresults foster skepticism for the therapeutic benefits of MDMA.

A viewer watching Drugs Live likely wouldn't catch the troublesome findings of such research on MDMA just from watching the few short minutes where Andrew Parrott attempted to explain it. This was one of many issues that commenters brought up about Drugs Live after it aired. Some criticized Channel 4 for not giving enough credit to its viewers for being able to hold their attention on scientific facts for more than a few seconds. It seemed as though the content of Drugs Live wasn't much different from that of ecstasy found on the street: very little though potent science adulterated with an abundance of questionable filler.

Life update: For anyone who is wondering what I've been up to this past year, I'm still writing! I have also been working a lot waiting tables to save up for graduate school. I will be beginning the science communication graduate program at University of California Santa Cruz in the fall. In addition, I have been writing for The Synapse, and I will be posting my newest article once it comes out in print!

The Unsung Scientist, Louis-Antoine Ranvier

To many who read this blog, Notes of Ranvier is a title that probably evokes no thoughts of science or history. There is a backstory to the name, however, and a reason why I chose it as the title.

Notes of Ranvier is meant to be a play on words referring to the nodes of Ranvier, anatomical structures in certain types of neurons that have a myelin sheath. Every neuron has a long projection called an axon that transmits electrical signals to other neurons. Around the axons of some neurons is the myelin sheath, a fatty tissue that insulates the axon like plastic around a copper wire. Electricity can't travel though myelin, so there are even gaps between the sheath where the neuron is exposed and electrical currents can be propagated down the axon. These gaps were discovered by French scientist, Louis-Antoine Ranvier (pronounced rahn-vee-yeh), and thus bear his name as Ranvier's nodes or the nodes of Ranvier.

When you learn about Ranvier's nodes in class, not a lot of attention is paid to how they were discovered or why they have Ranvier's name instead of some other scientist. The treatment of the subject is far more along the lines of, "these exist, this is what they do, moving on." But the question still gnaws, who was Ranvier? How did he find these nodes, and how did he figure out what they do?

Ranvier was a histologist in 19th century France. Histology is the study of organic tissues, employing techniques such as staining and preserving tissues and examining them under a microscope to better understand their anatomy and physiology. When you looked at slides of cells dividing in high school biology, you were performing histology.

While histology and microscopy are so common today that even small children learn how to use microscopes in class, the microscope was renounced by many French scientists and doctors in the 19th century. The dismissal of the microscope was largely related to the dismissal of the cell. Even as late as the 1800's, the theory of the cell being the building block for all living things was still pretty far-fetched to many scholars. This idea known as cell theory, was hotly debated for centuries. But in the latter half of the tumult was Ranvier holed away in his laboratory, with his icepick of a microscope, diligently scratching and scraping on the surface of physiology.

From the time Ranvier was born in 1835 to the peak of his career, histology began to make a sea change in the eyes of French scholars. Histologists were developing newer and more advanced techniques for preserving and staining samples. Ranvier saw the merits of histology for studying anatomy and physiology. In particular, he valued the scrupulousness involved in preparing tissues for histological examination which allowed him to reveal the nodes between myelin sheaths and determine their function.


For a long time it was known that myelin sheaths existed and that they were made up of fatty cells. The cells were and still are called Schwann, after the scientist who identified them. Ranvier wanted to better understand how cells insulated by myelin sheaths were able to exchange nutrients (such as oxygen and ions) with the blood since carmine tissue stains demonstrated that such nutrients could not penetrate through Schwann cells. Closer examination with different chemicals and a more exacting technique revealed the nodes pictured below.

Ranvier's Nodes (e). Image from Barbara, J (2007). Originally from Ranvier, 1878.

Ranvier wasn't finished there. He still wanted to know whether the nodes really were the site for nutrient exchange between the neuron and the capillary. Around the neurons in your body is a small sheet of connective tissue that protects them from mechanical damage. Ranvier destroyed this tissue, and then poured water onto the exposed nerves of living animals. This caused the Schwann cells to swell and expand to cover the nodes. The result? A loss of neuron function and paralysis. Ranvier correctly deduced that the nodes were important for the conduction of signals through neurons.

Ranvier went on to develop some of the first legitimate theories on nerve cell degeneration with his experiments on myelin. Meanwhile, furious debate raged on about the nature of cells and their contributions to the function of the human body. Ranvier, all the while, was only interested in facts and improving his histological techniques. His mentality led to many great discoveries in his life, some of which contributed to our modern understanding of neurophysiology.

He was a man truly deserving of respect and admiration, and his approach to his work should be an inspiration to scientists and science writers alike.

Sources:
Bracegirdle, B. The History of Histology: A Review of Sources. (1977) Hist. Sci., 15:77-101

Barbara, J. Louis Ranvier (1835-1922): The Contribution of Microscopy to Physiology and the Renewal of French General Anatomy. (2007). Journal of the History of Neurosciences, 16:413-431.

Salty Penguins Filter Salt Out Their Nose

The Venture Brothers season 1, episode 5, via [adult swim]

Why yes, penguins do have an organ that converts sea water into fresh water! Except it's not an organ, it's a gland. And it doesn't directly convert sea water to fresh water, it filters salt from the blood.

Hm, maybe I should start from the beginning.

First of all, this organ/gland/whatever that Dean is talking about is called the supraorbital gland, and it's something all marine birds have. Basically any mammal or bird that is going to have to drink sea water to quench thirst is going to need this gland.

Normally, salt that we ingest is absorbed into the blood stream, filtered out by the kidneys, and secreted in urine. However, the penguin's small kidneys can only filter out enough salt to create urine that's about 1/3 the concentration of sea water. If the blood is still too salty, then water must be taken from other tissues to dilute it, and this quickly leads to dehydration.

Penguins have a very high salt load because they drink sea water to quench thirst and eat a lot of salty foods like crustaceans. Located above the nose, in between the eyes, the supraorbital gland lends a helping hand. Both the kidney and supraorbital gland filter salt from the blood in a process called counter-current exchange.

The blood flowing along the gland and the fluid within the gland flow counter, or in opposite directions to one another. One of the principles of osmosis is that molecules will move from fluids with high concentrations of solutes (in this case, salt) to fluids with lower concentrations. I.e. they move down their concentration gradient. So salt leaves blood and goes to the relatively less salty fluid in the duct. Since the blood and the duct fluid are moving in opposite directions, the blood will always remain saltier than the duct fluid, therefore a concentration gradient will be maintained, and the salt will always flow out the blood to the fluid in the duct.

Still confused? There's a pretty great diagram here. For the more verbally inclined, here's a metaphor: Imagine the blood stream and the fluid stream are two trains moving parallel to each other in opposite directions (I promise this won't involve any math). Every car in the "blood" train is full of (rather salty) people, and every car in the fluid train is empty. As the trains meet, the first two cars of each train will be facing each other, and the people from the blood train (with great nimbleness) will jump from the blood train to the fluid train, until the first car in the fluid train is full. Then as the the trains continue to pass, people will continue to jump from the blood train and fill all the cars in the fluid train. People will not jump back onto the blood train from the fluid train because remember, they're going in opposite directions. So as the people that jumped on the first car of the fluid train keep going, they're passing the full cars of the blood train going in the other direction.

What would happen if the blood and the fluid were running in the same direction? That would be called concurrent exchange. The salt would still move from the blood, but quickly the concentrations of salt within the blood and the fluid would become the same and there wouldn't be any net gain or loss of salt in either the blood or the fluid. Pretend those trains are now running in the same direction, and people jump onto the fluid train, but then they see open space in the blood train and jump back. Since there will always be space in both the fluid and the blood trains, and they keep running along next to each other, passengers will keep jumping back and forth.

This diagram illustrates the difference between concurrent (top) and counter-current (bottom) exchange. Blue, in this case, would indicate low salinity, and red would indicate high salinity. As for the percentages, there is never "near 100%" absorption of salt from the bloodstream, as that would be as deadly as having too much salt. So take the percentages with a grain of salt.

From Wikimedia commons

The result is a fluid that is actually saltier than sea water. It flows from the gland and is excreted through the nasal passages. Penguins will often look like they have runny noses, but it's really this salty substance coming out their noses. You could, supposedly, say that they pee out their nose, but that would take away some of the mystique from the magestic emperor penguin, wouldn't it?

Immature jokes aside, this gland allows penguins to consume massive amounts of salt, and still be healthy. Considering how high sodium intake contributes to heart disease, maybe penguins could unlock the biotechnology of the future to allow us to have our salt cake and eat it, too!

Reference:

John Sparks & Tony Soper. (1987). Penguins. Facts on File, Inc. 460 Park Avenue South, New York, NY.

Lizards!

Lizards.

I grew up in the North--first New Jersey and then I went to college in Oberlin, Ohio.  So when I recently moved down to Florida to start a new job, one of the most exciting things I found about my new location was the new fauna.  Particularly all the little lizards running around!  The most common lizards to Florida belong to the Polychrotidae family, and are generally known as Anoles.  However, "lizards" are a broad and diverse group, with many different species with very different morphologies and life styles.  Here are a few fun facts about lizards:

• Lizards hear through the conduction of sound through small bones in their lower jaw vibrating a tympanic membrane (sometimes visible on the outer skin surface)
• Some lizards have prehensile (grasping) tails that aid them in climbing.
• Other lizards have more elongated tails that they can use for defense as whips.
• Some only have two limbs, while others are limbless (not to be confused with snakes).
• Some have webbed limbs and even specialized skin flaps that act as parachutes or gliders (I highly recommend that you go and watch that link, it's a really cool video from Animal Planet that I couldn't embed here.)
• Some have specialized fringes on their toes that allow them to run on water!  (See video)

However, being a nerd I find one of the most intriguing things about all lizards is that--unlike us--they are ectothermic, or basically cannot internally regulate their own body temperature.  This is what is generally referred to by the term "cold-blooded," although that term is considered a bit archaic by the scientific community due to the fact that cold-blooded animals do not have cold blood.  In fact, most of the time lizards probably have blood that is warmer than the blood of "warm-blooded," or endothermic animals (i.e. mammals and birds).

In order to understand the implications of being ectothermic, we should first consider the importance of body temperature in general, regardless of how it is regulated within an organism.  At it's most reduced, life is the result of many physical and chemical interactions occurring within the cells and tissues of the body.  The chemical interactions in particular (such as the transcription of DNA into RNA, and the translation of RNA into proteins; the breakdown of proteins and fats by enzymes; and the break down of ATP into ADP for energy... the list goes on), will function most efficiently within a certain temperature range.  If that temperature is too low, for example, then all those processes happen much slower.

What is it like to not be able to physiologically regulate your own body temperature?  Well for one, it vastly limits the type of environment you can live in.  While there are a few lizards that live in higher latitudes and altitudes, most lizards live in very warm climates.  This is because in order to keep their body temperature within an ideal range (somewhere around 40° C), they have to bask in sunlight and on warm substrates to keep warm, and then get to shade or be able to bury themselves in colder dirt or sand when the surrounding environment gets too hot.  In this way, you could consider lizards as behaviorally regulating their own body heat, but they still lack the physiological mechanisms by which endothermic animals regulate their own body temperature.

As you may guess, the environment ends up playing a very large role in determining the lizard's activities throughout the course of the day.  But as with any trait, it wouldn't have lasted so many generations if there wasn't a significant benefit.  Endothermic animals, in order to maintain their high internal body temperature, must have a very high metabolism to produce enough heat.  This high metabolism needs to be powered by energy gained from food, so a significant amount of the animal's time and energy must be allocated into foraging just to maintain their metabolic rate.  Lizards and other ectotherms don't have that problem; none of their energy intake needs to be put towards generating heat, so they can spend less time foraging and thus can allocate their energy towards rapid growth, social behavior, and reproduction.

The social behavior is what personally intrigued me by the Anoles of Florida.  If you watch these little guys for more than a few minutes, you will probably see them bob their heads up and down and extend a red projection from their neck, known as a dewlap.  This general behavior is seen in male Anoles, and is thought to serve to both establish territoriality and dominance over other males, as well as to attract females.  Moreover, the specific factors such as number of body push-ups, head bobs, and the degree of extension of the dewlap can convey specific signals within the same species of Anole.  It is also thought that the color of the dewlap varies between species, and that Anoles are able to visually detect the differences in color.  Some lizards are even capable of detecting ultraviolet wavelengths, thus adding another dimension to the visual spectrum that we cannot see ourselves.  Accordingly, the dewlaps of these lizards are able to reflect UV light.

In addition to being able to communicate with each other visually on a wider spectrum of visible wavelengths than we can, lizards (and many other animals) are also able to communicate using chemical signals called pheromones.  While the jury is still out on whether or not humans use pheromones to communicate, it is pretty well known that lizards can emit and detect such chemical signals.  In lizards, there seems to be some differences in the methods by which the two sexes employ the chemical signals.  Males seem to emit pheromones to communicate with other males, whereas females use their pheromones in a more male-directed fashion.  Lizards are able to detect these chemical signals using their olfactory system (sense of smell,) their gustatory system (sense of taste) and another sensory system a little foreign to us, the vomeronasal system, which specifically detects pheromone chemicals.  In lizards, the vomeronasal ducts open to the mouth, and they use their tongues to pick up the chemicals and then flick them over the olfactory and vomeronasal ducts.  This is the underlying reason for the tongue flicking behavior that you probably associate mostly with snakes.

There is quite a bit more interesting information about lizards, particularly in the shapes of their skulls and how sound is conducted through their lower jaws.  But in the interest of not writing a whole book on the matter, I'll cut this post off here.  But now you know a little more about the crazy lives of lizards!

Reference and disclaimer

Most of the information I find for the posts I write on this blog comes from a combination of knowledge that I gained through classes and through internet sources.  I generally link to these internet sources in the text of my posts, but sometimes I also get information from books (those archaic sources.)  Most of the information from today's post came from Lizards: Windows to the evolution of diversity by Eric R. Pianka and Laurie J. Vitt (University of California press, 2003).  The rest came from my own notes or internet sources where linked.

Thanks for reading!