Expanding our consciousness: Illuminating how the brain responds to hallucinogens like LSD

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Bicycle day occurs every April 19. It commemorates the first time a person purposefully took LSD. That person was Albert Hoffman, a Swiss chemist working for a pharmaceutical company that eventually became Novartis (also of Toms River fame). Hoffman was part of a lab that was isolating the active ingredients from a variety of medicinal plants and fungi. One of those was the ergot fungus, which can infect various grains. Historically, ergot extracts had been used by midwives to prevent bleeding death in childbirth (Chemistry World). Notably, this is the same fungus that scientists speculated led to the Salem Witch Trials, however, subsequent research has called this idea into question.

When he started working with the ergot alkaloids and their active ingredient, lysergic acid, he wanted to develop a new stimulant of the circulatory system. He based his design of LSD-25 on the successful drug Coramine (nicotinic acid diethylamide). Hoffman's first synthesis of lysergic acid diethylamide (LSD)-25 in 1938 yielded nothing of interest in his pharmacological assessment. His curiosity about the chemical structure of the drug led him to make the product again one day in 1943, when he accidentally dosed himself with the synthesized product. Curious to learn more about the "not unpleasant" experience, he repeated the dosing on April 19, 1943 and road his bike home from the lab. Here is a shortened version of his now famous description of his experience:

"The faces of those present appeared like grotesque coloured masks;...a feeling of suffocation; confusion alternating with a clear appreciation of the situation. I lost all control of time: space and time became more and more disorganised and I was overcome with fears that I was going crazy....Occasionally I felt as being outside my body. I thought I had died. My ’ego’ was suspended somewhere in space and I saw my body lying dead on the sofa. I observed and registered clearly that my ’alter ego’ was moving around the room, moaning."

Dragnet's LSD story

In 1947, Hoffman patented the drug under the name Delysid. The timing of Hoffman's discovery coincided with the discovery of serotonin and the birth of neuroscience and the eventual rise of psychopharmacology,leading to a surge in usage of LSD in both psychiatric practice and scientific research in the 1950s and 60s. The rise of hippie culture  and concerns about the corruption of youth led to LSD being made illegal in 1967 (the same year as Dragnet's famous Blue Boy episode) and listed as a schedule 1 drug in 1970. As argued here and here, these restrictions have made it difficult for researchers to get the approval to do human studies on LSD and other psychoactive drugs. Thus, they have relied on studies in animals, which have limitations for several reasons, namely that we can't really ask them about their acid trip. 

There are several unanswered questions about the neurochemistry of LSD: why are its effects so potent and long lasting?; why does LSD induce hallucinations while other serotonin receptor agonists (activators) don't?  To answer this question, researchers solved the structure of LSD bound to its serotonin receptor (5-HT) and measured the rates at which LSD binds and dissociates from the receptor. The results, published in Cell and covered here and here, show that the LSD molecule binds to a pocket in the receptor (5-HT_2B), after which the "lid" of the pocket closes itself, which makes it difficult for LSD to disengage. The conclusions from the structure are consistent with their kinetic measurements, which showed very low off rates for LSD from serotonin receptors. When they generated a 5-HT mutant that increased the mobility of the "lid", they found that LSD could bind and dissociate much more quickly. These results help to explain the long-lasting effects of LSD, which can last up to 20 hours even at moderate doses. They also investigated the effects of the binding of LSD on the downstream signaling protein arrestin. They found that when LSD is bound to 5-HT receptors, arrestin can bind more tightly than when LSD is not bound. This is not true for other 5-HT receptor agonists, which may explain the unique effects of LSD.

Despite the roadblocks and difficulties in getting approval for research with restricted drugs, there are a few labs looking at the effects of psychedelics on humans. Three papers from the Nutt lab have looked at the effects of LSD on the brain using state-of-the-art neuroimaging techniques. In a study published in PNAS, the researchers used three complementary approaches to compare the effects of LSD and placebo in 20 healthy volunteers using a within subjects design, in which they would perform imaging in each patient with one treatment (placebo or LSD) and then repeat the experiment a few weeks later with the other treatment. This allowed them to create difference maps to see what parts of the brain were active after taking LSD in each patient. When combined with answers from their "altered consciousness questionnaire (ACQ)", they were able to characterize the neurological attributes of the LSD state. They observed an increased activity in the visual cortex, which correlated with increased hallucinations. They also found a set of characteristic changes observed in subjects that reported "ego dissolution" or "altered meaning".

Two subsequent papers from the Nutt lab explored the brain regions that are involved in these two specific responses to LSD. To understand the basis of LSD-induced ego dissolution, which is defined as the "a compromised sense of possessing an integrated and distinct personality or identity" (exactly what Hoffman described on his bike trip). Their paper, published in Current Biology, used fMRI imaging to look at the connections in the brain in people experiencing this effect. Consistent with the known neuropharmacology of LSD, the images revealed increases in connectivity in areas of the brain high in serotonin receptors. The observed increases in connectivity of the brain correlated with reports of ego dissolution. Interestingly, they also found that LSD increased the connections between sensory systems, creating unusual links between visual cortex, auditory cortex, and senso-motor cortex. These results could explain the occurrence of hallucinations and general feelings of increased senses as well as well as synesthesia (think that sound seems orange or that tastes blue).

Neuroimaging of the same brain on placebo vs. LSD shows increased connections.

Another paper, published in Current Biology (covered here), was entitled "The Fabric of Meaning and Subjective Effects of LSD-Induced States." This idea of "meaningfulness" feels a bit unscientific, but it is part of everyday life for most people and we don't understand how the brain makes the connections that denote something as meaningful or meaningless. Because LSD changes the perception of meaning for the brain, it can be used to figure out what parts of the brain are involved in this response. To that end, they used neuro-imaging in combination with the ACQ to compare brain maps in different LSD states in subjects that were given LSD with a placebo or LSD with a serotonin antagonist (ketanserin) that blocks the effects of LSD. To test the development of personal relevance, they used musical stimuli that the subjects had previously judged as either meaningful, neutral, or non-meaningful. They performed imaging of the brain while the subjects listened to music in these three categories. When they compared the brains of people listening to meaningful music, they observed an increase in signal in the frontal brain region, which was not observed when subjects listened to meaningless music. Strikingly, LSD increased the meaningfulness of all music and these effects were abolished with ketanserin, suggesting an important role for serotonin receptors in the attribution of meaningfulness.

While interesting in their own rights, these papers can also have implications for understanding the function of the brain in both healthy and pathological states. For example, several psychiatric disorders increase the attribution of personal relevance (e.g., paranoia). Knowing that increased serotonin receptor activity is associated with misattribution of meaning can help doctors determine the right pathways to target for psycho-pharmacological treatment.

Hoffman originally intended LSD for a very different purpose and when he tried the drug, he knew its potential for psychiatry and neuroscience. Today, the clinical possibilities of LSD and other hallucinogens remain under explored. A recent retrospective study re-examined work from the 50s and 60s that treated alcoholics with LSD. Using current statistical meta-analyses, they found that alcohol misuse was less frequent after the dose of LSD (59% reported less misuse vs. 38% in placebo-treated controls). One clinical trial showed that psilocybin "magic mushrooms" could help control anxiety; MDMA is currently in clinical trials to help people conquer fear induced by PTSD.

One of my early post on this blog reviewed the book Elephants on Acid and Other Bizarre Experiments. The book includes the titular experiment combining pachyderms and hallucinogens as well as other experiments on LSD. The reason I liked that book was that it highlights how unusual science, which frankly can seem frivolous, can have unexpected applications.

Publishing your scientific paper: tips and tricks from a scientific editor

I have written several posts about my work as a scientific editor, but I haven't talked about performing institutional visits, which I sometimes combine with an author workshop discussing the publication process. At Elsevier, these author workshops are given by many different people across the company and they start with the title "How to Publish in Scholarly Journals". Over time, my talk has evolved to focus on the scientific editor's perspective on the publication process; I try to give the audience my pro-tips for navigating peer review from start to finish. The major theme of my talk is making it easy for people to read and interpret your paper: first, the journal's editors (who you want to send it out for review), then the reviewers (who you want to review it fairly and favorably), and finally the readers (who you want to read the paper so they can cite it). I have given this talk enough times that it is starting to feel like my own. I even have a couple of good zingers, including one about the authors who requested that no one from Japan review their paper (obviously we could not satisfy that exclusion request).*

Every time I give this talk, I refer to several online resources that I have found useful in putting together my slides.** Because my blog audience is much broader than my typical seminar audience, I decided to put together a collection of the best of these resources in combination with some of my own tips. 

General Tips: 

• Advice from a scientific editor (my post from a few years ago)
• Milka Kostic, Editor for the journal Structure, wrote a nice set of posts on Getting Your Paper Published that covers many of the steps in the process: craft your title and abstract, put your cover letter to work, tell a story, keep it simple, and be mindful of your audience. 
• Elsevier's Publishing Campus has lots of great resources for writing your research article.
• How to get published in academic journals: top tips from editors (Guardian)

Preparing your Manuscript:

• 11 steps to structuring a science paper that editors will take seriously (Elsevier)
• 8 ways to help reviewers assess your manuscript (Cell Press)
• How to get the most out of your reviewer suggestions (Cell Press)
• How to avoid publishing conflicts (Elsevier)

Preparing your Figures/Image Manipulation Policies: 

• Common Pitfalls in Figure Preparation (Cell Press)
• What's in a picture? The temptation for image manipulation (Journal of Cell Biology)
• Image Manipulation: cleaning up the scholarly record (Scholarly Kitchen)
• Checking out our figures (Cell Press)  
• JCB did a ten part series that covered "Everything you need to know about image screening at the Rockefeller University Press" (Journal of Cell Biology)

Revisions and Rejections: 

• Decoding the Decision Letter (Cell Press)
• If at first you don't succeed, cool off, revise, and submit again (Science)

Getting Your Paper Noticed: 

• After your paper is published, remember to share your work with others and follow how your paper is doing. 
• First, you might want to read this post on Scholastica about why this is important.
• Elsevier's Publishing Campus has additional tips and tricks
• Altmetric and Mendeley Stats can help you gauge the impact of your article before citations start. 

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* The Tufts Post doc association has a blog post about my visit.

** I recently noticed that I refer frequently to the Cell Press CrossTalk blog in my author talk. While I work for the same company as the Cell Press folks, I do not actually receive any click-through dividends. It just happens to be a great site with many useful posts.

Resources for finding a career away from the bench

If you are a graduate student or postdoc in the sciences, you are likely aware of the "PhD problem"*, the academic bottleneck caused by an increasing number of PhDs with a concomitant decrease in the number of tenure track positions. Unfortunately, the statistics suggest that the problem is not likely to get better any time soon. In fact, the issue has gotten so bad that even the mainstream media has picked up the story. The default pathway is no longer PhD to postdoc to tenure track; this great infographic from ASCB  (see below) suggests that the tenure track is the real alternative career. While the statistics may seem grim, I think there is some good news: the academy is starting to wake up to the harsh reality**. In the past, postdocs and grad students complained that PIs were only capable of training them to become a PI. Increasingly, PIs and universities are aware of the prospects for their trainees and they are starting to find ways to help guide them for a number of careers.

ASCB.org infographic

As a Scientific Editor, I often get questions from graduate students, post docs, and PIs about my transition away from the bench. After a recent chat with a grad student at a meeting, I decided it was time to put together a post of useful resources for finding a career away from the bench. Because I am in publishing, my links tend to focus on that path, but all of the websites I list below have articles about other career paths as well. 

The first two places you should be looking for a job in science are Nature Jobs and Science Careers. Both websites have listings for a variety of careers paths as well as an array of great content for helping you navigate your job search. Whether you are just starting to think about your future directions or preparing for an interview and negotiating your salary, there are relevant articles for you.

Nature Jobs has a very well-organized site. I recommend spending some time there to explore their content, especially their blog and their career toolkit. This article from their blog gives a great general overview of the types of jobs available to people with a PhD in the sciences. Be sure to check out The Postdoc Series for articles aimed at post docs at different stages of their careers. Nature Jobs also hosts a career expo, which I have read good things about.

On the Science Careers website, check out the tips and tools and explore the articles in the Career Magazine; they have more than 10 years of content available. By far the most valuable resources I found when I was searching for my current job were this collection of articles about science writing and editing and this 2002 article "Careers in Science Editing". These give a very general idea of what different types of scientific editing jobs entail. This informative article from Cell Press' Debbie Sweet describes the specifics of working for a reviews journal or a primary journal. Once you find something of interest, the related article feature (which seems to be available for newer articles only) will help you find more to read.

Societies relevant to your field will likely also have career resources available. For cell biology, ASCB's Career Development section has a number of articles available. My favorite among these is the Career Publications, which are free to download as PDFs. The ASBMB also has some useful articles, like these Career Case Studies.

The Chronicle of Higher Education is generally best for searching for a faculty job, but they also have some excellent articles on non-academic jobs, such as "The PhD's Guide to a Non-faculty Job Search".

If you are feeling isolated in your decision to leave the bench, you can find some comfort by reading some "quit lit". It seems many scientists find it cathartic to share their story;  indeed, I have written my own quit lit posts on this blog (here and here). Over the years, I have read many posts in this genre; I particularly enjoy finding updates, which tend to have a happier mood than the original post. Eva Amsen's (Outreach Director for Faculty of 1000) "Five Years Later" was very positive and shared some useful links and tips. Likewise, SciCurious (a science writer in neuroscience) tells her story in "The system failed me. It should have failed me sooner." 

To learn more about a career in science writing, read Ed Yong's collection called "On the Origin of Science Writers" where a variety of working science writers share their journey as well as tips on how to make a living writing about science. The National Association of Science Writers also has some great content in their resources section.

In short, these links should give you some ideas of the paths that are available to you. Hopefully you also have some valuable resources at your institution (e.g, postdoc association or a career development office). If you find other useful links, please share them in the comments. 

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* There are numerous suitable links that describe the problem; I have chosen the one that I first discovered. Nature had a 2011 special issue called The Future of the PhD, which included the great story The PhD factory.  

** The Future of Research symposium has been putting together meetings to find solutions to these problems.

Altmetric Explorer as a complement to your news reader for keeping up with exciting new research

Altmetric is one of several tools currently available to track the usage of published articles via social media, mainstream media, and reference managers. The Almetric score is calculated by giving different weights to each mention of a published article, so that a newspaper story counts more than a blog post, which is worth more than a tweet. The benefit of alternative metrics is that it can give researchers instant feedback on the impact of their article. Alternative metrics can also be used by publishers and editors to help determine what could be the next high impact story. Importantly, it is unclear whether Almetric scores correlate with citation rate. At this time, only 15-25% of papers receive any Almetric score, depending on the field.  

 Altmetric Explorer is a new tool from Altmetric for examining the impact of articles using a variety of search parameters. You can search all mentions of papers to see what the most popular stories may be at any given time. By creating workspaces for individual searches, you can have the results updated by email on a regular basis. You can export all the articles or export the Altmetric data to Excel, allowing you to sort for papers based on an individual metric (e.g., Mendeley or blog posts). Workspaces could include searches of a particular set of journals to see all the high-attention content in one space. Alternatively, a search with a keyword can indicate where the most attention-grabbing stories in a particular area are being published. 

Altmetric Explorer is easy to learn to use and the help desk has been very responsive, giving answers in 24 hours. This is a for-fee service, but as an Elsevier employee, I have free access to a publisher account. I started experimenting with Altmetric Explorer as a tool for content development. While it has not been helpful for that purpose, I have found it to be a nice complement to my news reader/RSS feed for finding new, interesting stories published in the journals that I normally follow.