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New analysis claims the FDA rushed ketamine's approval for depression treatment
Clinical trials by Janssen Pharmaceuticals showed troubling results.
- A new analysis in The British Journal of Psychiatry claims the FDA approval process for ketamine was rushed.
- Only one of three clinical trials showed efficacy, while the discontinuation trial produced troubling outcomes.
- Ketamine's side effects include anxiety, poor appetite, delusions, hallucinations, paranoia, rage, and craving.
There was a lot of excitement when the FDA fast-tracked trials for ketamine as a depression treatment in 2016. The announcement marked a major turning point in our understanding of psychedelics, which were deemed a Schedule 1 substance as part of Richard Nixon's racist 1970 "War on Drugs." Ketamine was approved for use as an anesthetic that same year; due to increasing recreational usage in the 1990s, however, it was deemed Schedule III in America in 1999.
Though ketamine is not a traditional psychedelic—they have an agonist (or partial agonist) effect at brain serotonin 5-HT2A receptors—it falls into this class due to its hallucinogenic and dissociative effects. Recently it has been referred to as a "party psychedelic." Psychedelic therapy advocates were pleased when the FDA approved a nasal spray medication for treatment-resistant depression known as esketamine in 2019. Janssen Pharmaceuticals launched Spravato shortly after.
This move is exciting. Trials of two types of ketamine—racemic ketamine and esketamine—showed early positive results, even though researchers are not exactly sure how it functions in depression treatment. We do know antidepressants and antipsychotics are showing less efficacy and more chronic side effects than previously believed, however.
There is precedent in the psychedelic realm. Psilocybin, ayahuasca, ibogaine, MDMA, and LSD are showing early positive results in treating anxiety, depression, addiction, and PTSD. This does not mean we should rush blindly ahead, however.
That's the consensus reached by Mark Horowitz (writer) and Joanna Moncrieff (editor), whose recent analysis, published in The British Journal of Psychiatry, concludes that we're moving too fast in clinically adopting ketamine. As their data shows, caution is necessary.
Since its discovery in 1962, ketamine has been used broadly as a sedative and anesthetic; to aid in emergency surgeries in war zones; as a bronchodilator for severe asthmatics; to treat certain type of seizures; in postoperative pain management; and now, as a nasal spray to treat depression. Unlike SSRIs and SNRIs, esketamine works immediately—in as little as two hours—making it more attractive to patients and clinicians.
The Experimental Ketamine Cure for Depression
While treatment-resistant depression sounds extreme, Horowitz notes the definition: patients unsuccessful with two different antidepressants, a low bar for the term "resistant." The problem with trying esketamine, he writes, falls back on the FDA fast-tracking of the drug.
"Out of the three short-term trials conducted by Janssen only one showed a statistically significant difference between esketamine and placebo. These were even shorter than the 6–8 week trials the FDA usually requires for drug licensing."
Each trial lasted only four weeks. The FDA normally requires that two such trials show better results than the placebo; in this case, only one achieved this goal. The successful trial showed a four-point margin on a scale that goes to 60.
Failing to provide two effective trials, the FDA allowed Janssen to submit a discontinuation trial as evidence. This 16-week trial let patients either continue or stop treatment. The problem: side effects were treated as evidence of relapse, not withdrawal symptoms.
Ketamine users have a long history of withdrawal issues, including anxiety, poor appetite, delusions, hallucinations, paranoia, addiction, rage, and craving. The discontinuation trial considers such effects as proof of ketamine's efficacy, not as symptoms of withdrawal.
Science writer Peter Simons explains why this is worrisome:
"Perhaps even more concerning is the fact that, within the discontinuation trial, a single site in Poland drove the apparent finding of efficacy. Data from this site suggested that 100% of the placebo group supposedly relapsed (compared with about 33% of the placebo group in all the other sites)—an unlikely result. When data from this suspicious outlier was removed, the study analysis showed no evidence that esketamine was better than the placebo."
Add to this that six people in the esketamine group died during the trials, including three by suicide—two of whom had previously shown no signs of suicidal ideations—and a troubling picture emerges. The FDA accepted Janssen's explanation: the problem wasn't esketamine, but their underlying condition. This is possible, but the company did not provide conclusive evidence.
Jennifer Taubert, executive vice president and worldwide chairman of Janssen Pharmaceuticals, Johnson & Johnson, testifies before the Senate Finance Committee on "Drug Pricing in America: A Prescription for Change, Part II" February 26, 2019 in Washington, DC. The committee heard testimony from a panel of pharmaceutical company CEOs on the reasons for rising costs of prescription drugs.
Photo by Win McNamee/Getty Images
According to Horowitz, this is a chronic problem with clinical trials and governing agencies.
"It would seem that themes from history are repeating: a known drug of misuse, associated with significant harm, is increasingly promoted despite scant evidence of efficacy and without adequate longterm safety studies."
He also notes that half of the patients experienced disassociation and one-third experienced dizziness. On this point, allow me to break the fourth wall. I've been experimenting with psychedelics since 1994 and am writing a book on psychedelics in ritual and therapy. I ingested a range of substances during my college years. By far, the most troublesome was ketamine. While I'm now aware of Parecelsus's dictum—what is beneficial in small doses is toxic in large doses—I wasn't measuring it out in the 1990s.
Administered doses in Janssen's trials were considered similar to recreational usage. I recall that a bump provided an energetic lift, yet when I'd occasionally snort a line, all bets were off. After a hearty dose one evening, I laid down, sat up, and stood in succession. I couldn't tell the difference between those three physical positions. Ketamine is the most dissociative substance I've ever taken, and I stopped shortly after that last instance.
Psychedelics are the next wave of mental health treatments—call it a continuation, given their role in traditional rituals. We came to rely on pharmacology too much in the twentieth century; hopefully we're learning from those mistakes. As Horowitz points out, however, it appears we're not.
The important word in psychedelic therapy is ritual. There are environmental and social factors entwined with our health. In the right context, psychedelics have tremendous healing power. And to be fair, some ketamine clinics are taking proper right safety precautions as well as designing treatment rooms to be more conducive to healing than sterile white rooms. Patients are anecdotally reporting success in depression treatment with ketamine. This isn't an either-or situation.
But we cannot make the same mistake we've made with CBD and believe these substances are cure-alls. We also can't afford to designate ketamine under the umbrella term "psychedelics." As Alan Watts wrote, hallucinogen is not a proper definition of the psychedelic experience, though it's fitting when describing ketamine. Conflating substances will only further confusion during a time when we need clarity. If the addictive properties and dangerous side effects of ketamine play out widely, it endangers the entire psychedelic therapy model.
We can hope for a clinically-effective dosage and delivery mechanism of ketamine. We can't, as Horowitz's analysis shows, make the same mistakes over. Pharmacological intervention has a place in psychiatry, but it's come to dominate the industry, often no better than placebo and psychotherapy. We need healing, not more side effects.
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How would the ability to genetically customize children change society? Sci-fi author Eugene Clark explores the future on our horizon in Volume I of the "Genetic Pressure" series.
- A new sci-fi book series called "Genetic Pressure" explores the scientific and moral implications of a world with a burgeoning designer baby industry.
- It's currently illegal to implant genetically edited human embryos in most nations, but designer babies may someday become widespread.
- While gene-editing technology could help humans eliminate genetic diseases, some in the scientific community fear it may also usher in a new era of eugenics.
Tribalism and discrimination<p>One question the "Genetic Pressure" series explores: What would tribalism and discrimination look like in a world with designer babies? As designer babies grow up, they could be noticeably different from other people, potentially being smarter, more attractive and healthier. This could breed resentment between the groups—as it does in the series.</p><p>"[Designer babies] slowly find that 'everyone else,' and even their own parents, becomes less and less tolerable," author Eugene Clark told Big Think. "Meanwhile, everyone else slowly feels threatened by the designer babies."</p><p>For example, one character in the series who was born a designer baby faces discrimination and harassment from "normal people"—they call her "soulless" and say she was "made in a factory," a "consumer product." </p><p>Would such divisions emerge in the real world? The answer may depend on who's able to afford designer baby services. If it's only the ultra-wealthy, then it's easy to imagine how being a designer baby could be seen by society as a kind of hyper-privilege, which designer babies would have to reckon with. </p><p>Even if people from all socioeconomic backgrounds can someday afford designer babies, people born designer babies may struggle with tough existential questions: Can they ever take full credit for things they achieve, or were they born with an unfair advantage? To what extent should they spend their lives helping the less fortunate? </p>
Sexuality dilemmas<p>Sexuality presents another set of thorny questions. If a designer baby industry someday allows people to optimize humans for attractiveness, designer babies could grow up to find themselves surrounded by ultra-attractive people. That may not sound like a big problem.</p><p>But consider that, if designer babies someday become the standard way to have children, there'd necessarily be a years-long gap in which only some people are having designer babies. Meanwhile, the rest of society would be having children the old-fashioned way. So, in terms of attractiveness, society could see increasingly apparent disparities in physical appearances between the two groups. "Normal people" could begin to seem increasingly ugly.</p><p>But ultra-attractive people who were born designer babies could face problems, too. One could be the loss of body image. </p><p>When designer babies grow up in the "Genetic Pressure" series, men look like all the other men, and women look like all the other women. This homogeneity of physical appearance occurs because parents of designer babies start following trends, all choosing similar traits for their children: tall, athletic build, olive skin, etc. </p><p>Sure, facial traits remain relatively unique, but everyone's more or less equally attractive. And this causes strange changes to sexual preferences.</p><p>"In a society of sexual equals, they start looking for other differentiators," he said, noting that violet-colored eyes become a rare trait that genetically engineered humans find especially attractive in the series.</p><p>But what about sexual relationships between genetically engineered humans and "normal" people? In the "Genetic Pressure" series, many "normal" people want to have kids with (or at least have sex with) genetically engineered humans. But a minority of engineered humans oppose breeding with "normal" people, and this leads to an ideology that considers engineered humans to be racially supreme. </p>
Regulating designer babies<p>On a policy level, there are many open questions about how governments might legislate a world with designer babies. But it's not totally new territory, considering the West's dark history of eugenics experiments.</p><p>In the 20th century, the U.S. conducted multiple eugenics programs, including immigration restrictions based on genetic inferiority and forced sterilizations. In 1927, for example, the Supreme Court ruled that forcibly sterilizing the mentally handicapped didn't violate the Constitution. Supreme Court Justice Oliver Wendall Holmes wrote, "… three generations of imbeciles are enough." </p><p>After the Holocaust, eugenics programs became increasingly taboo and regulated in the U.S. (though some states continued forced sterilizations <a href="https://www.uvm.edu/~lkaelber/eugenics/" target="_blank">into the 1970s</a>). In recent years, some policymakers and scientists have expressed concerns about how gene-editing technologies could reanimate the eugenics nightmares of the 20th century. </p><p>Currently, the U.S. doesn't explicitly ban human germline genetic editing on the federal level, but a combination of laws effectively render it <a href="https://academic.oup.com/jlb/advance-article/doi/10.1093/jlb/lsaa006/5841599#204481018" target="_blank" rel="noopener noreferrer">illegal to implant a genetically modified embryo</a>. Part of the reason is that scientists still aren't sure of the unintended consequences of new gene-editing technologies. </p><p>But there are also concerns that these technologies could usher in a new era of eugenics. After all, the function of a designer baby industry, like the one in the "Genetic Pressure" series, wouldn't necessarily be limited to eliminating genetic diseases; it could also work to increase the occurrence of "desirable" traits. </p><p>If the industry did that, it'd effectively signal that the <em>opposites of those traits are undesirable. </em>As the International Bioethics Committee <a href="https://academic.oup.com/jlb/advance-article/doi/10.1093/jlb/lsaa006/5841599#204481018" target="_blank" rel="noopener noreferrer">wrote</a>, this would "jeopardize the inherent and therefore equal dignity of all human beings and renew eugenics, disguised as the fulfillment of the wish for a better, improved life."</p><p><em>"Genetic Pressure Volume I: Baby Steps"</em><em> by Eugene Clark is <a href="http://bigth.ink/38VhJn3" target="_blank">available now.</a></em></p>
The father of all giant sea bugs was recently discovered off the coast of Java.
- A new species of isopod with a resemblance to a certain Sith lord was just discovered.
- It is the first known giant isopod from the Indian Ocean.
- The finding extends the list of giant isopods even further.
The ocean depths are home to many creatures that some consider to be unnatural.<img type="lazy-image" data-runner-src="https://assets.rebelmouse.io/eyJhbGciOiJIUzI1NiIsInR5cCI6IkpXVCJ9.eyJpbWFnZSI6Imh0dHBzOi8vYXNzZXRzLnJibC5tcy8yMzU2NzY4My9vcmlnaW4ucG5nIiwiZXhwaXJlc19hdCI6MTYxNTUwMzg0NX0.BTK3zVeXxoduyvXfsvp4QH40_9POsrgca_W5CQpjVtw/img.png?width=980" id="b6fb0" class="rm-shortcode" data-rm-shortcode-id="2739ec50d9f9a3bd0058f937b6d447ac" data-rm-shortcode-name="rebelmouse-image" data-width="1512" data-height="2224" />
What benefit does this find have for science? And is it as evil as it looks?<div class="rm-shortcode" data-media_id="7XqcvwWp" data-player_id="FvQKszTI" data-rm-shortcode-id="8506fcd195866131efb93525ae42dec4"> <div id="botr_7XqcvwWp_FvQKszTI_div" class="jwplayer-media" data-jwplayer-video-src="https://content.jwplatform.com/players/7XqcvwWp-FvQKszTI.js"> <img src="https://cdn.jwplayer.com/thumbs/7XqcvwWp-1920.jpg" class="jwplayer-media-preview" /> </div> <script src="https://content.jwplatform.com/players/7XqcvwWp-FvQKszTI.js"></script> </div> <p>The discovery of a new species is always a cause for celebration in zoology. That this is the discovery of an animal that inhabits the deeps of the sea, one of the least explored areas humans can get to, is the icing on the cake.</p><p>Helen Wong of the National University of Singapore, who co-authored the species' description, explained the importance of the discovery:</p><p>"The identification of this new species is an indication of just how little we know about the oceans. There is certainly more for us to explore in terms of biodiversity in the deep sea of our region." </p><p>The animal's visual similarity to Darth Vader is a result of its compound eyes and the curious shape of its <a href="https://lkcnhm.nus.edu.sg/research/sjades2018/" target="_blank" rel="noopener noreferrer dofollow" style="">head</a>. However, given the location of its discovery, the bottom of the remote seas, it may be associated with all manner of horrifically evil Elder Things and <a href="https://en.wikipedia.org/wiki/Cthulhu" target="_blank" rel="dofollow">Great Old Ones</a>. <em></em></p>
We look back at a year ravaged by a global pandemic, economic downturn, political turmoil and the ever-worsening climate crisis.
Billions are at risk of missing out on the digital leap forward, as growing disparities challenge the social fabric.
Image: Global Risks Report 2021<h3>Widespread effects</h3><p>"The immediate human and economic costs of COVID-19 are severe," the report says. "They threaten to scale back years of progress on reducing global poverty and inequality and further damage social cohesion and global cooperation."</p><p>For those reasons, the pandemic demonstrates why infectious diseases hits the top of the impact list. Not only has COVID-19 led to widespread loss of life, it is holding back economic development in some of the poorest parts of the world, while amplifying wealth inequalities across the globe.</p><p>At the same time, there are concerns the fight against the pandemic is taking resources away from other critical health challenges - including a <a href="https://www.weforum.org/agenda/2020/09/charts-covid19-malnutrition-educaion-mental-health-children-world/" target="_blank" rel="noopener noreferrer">disruption to measles vaccination programmes</a>.</p>
A new study explains how a chaotic region just outside a black hole's event horizon might provide a virtually endless supply of energy.
- In 1969, the physicist Roger Penrose first proposed a way in which it might be possible to extract energy from a black hole.
- A new study builds upon similar ideas to describe how chaotic magnetic activity in the ergosphere of a black hole may produce vast amounts of energy, which could potentially be harvested.
- The findings suggest that, in the very distant future, it may be possible for a civilization to survive by harnessing the energy of a black hole rather than a star.
The ergosphere<p>The ergosphere is a region just outside a black hole's event horizon, the boundary of a black hole beyond which nothing, not even light, can escape. But light and matter just outside the event horizon, in the ergosphere, would also be affected by the immense gravity of the black hole. Objects in this zone would spin in the same direction as the black hole at incredibly fast speeds, similar to objects floating around the center of a whirlpool.</p><p>The Penrose process states, in simple terms, that an object could enter the ergosphere and break into two pieces. One piece would head toward the event horizon, swallowed by the black hole. But if the other piece managed to escape the ergosphere, it could emerge with more energy than it entered with.</p><p>The movie "Interstellar" provides an example of the Penrose process. Facing a fuel shortage on a deep-space mission, the crew makes a last-ditch effort to return home by entering the ergosphere of a blackhole, ditching part of their spacecraft, and "slingshotting" away from the black hole with vast amounts of energy.</p><p>In a recent study published in the American Physical Society's <a href="https://journals.aps.org/prd/abstract/10.1103/PhysRevD.103.023014" target="_blank" style="">Physical Review D</a><em>, </em>physicists Luca Comisso and Felipe A. Asenjo used similar ideas to describe another way energy could be extracted from a black hole. The idea centers on the magnetic fields of black holes.</p><p style="margin-left: 20px;">"Black holes are commonly surrounded by a hot 'soup' of plasma particles that carry a magnetic field," Comisso, a research scientist at Columbia University and lead study author, told <a href="https://news.columbia.edu/energy-particles-magnetic-fields-black-holes" target="_blank" rel="noopener noreferrer">Columbia News</a>.</p>
Event Horizon Telescope Collaboration<p>While there might not be immediate applications for the theory, it could help scientists better understand and observe black holes. On an abstract level, the findings may expand the limits of what scientists imagine is possible in deep space.</p><p style="margin-left: 20px;">"Thousands or millions of years from now, humanity might be able to survive around a black hole without harnessing energy from stars," Comisso said. "It is essentially a technological problem. If we look at the physics, there is nothing that prevents it."</p>
A popular and longstanding wave of thought in psychology and psychotherapy is that diagnosis is not relevant for practitioners in those fields.